A Phase III Trial of Accelerated Whole Breast Irradiation With Hypofractionation Plus Concurrent Boost Versus Standard Whole Breast Irradiation Plus Sequential Boost for Early-Stage Breast Cancer
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Radiation Therapy Oncology Group

NRG ONCOLOGY 
Radiation Therapy Oncology Group 
 
RTOG 1005 
 
(ClinicalTrials.gov NCT #: 01349322) 
 
 
A PHASE III TRIAL OF ACCELERATED WHOLE BREAST 
IRRADIATION WITH HYPOFRACTIONATION PLUS CONCURRENT 
BOOST VERSUS STANDARD WHOLE BREAST IRRADIATION PLUS 
SEQUENTIAL BOOST FOR EARLY-STAGE BREAST CANCER   
 
 
Amendment 5:  December 16, 2021 

 
RTOG 1005; version date December 16, 2021 
 
1
NRG ONCOLOGY  
 
RTOG 1005 
 
A PHASE III TRIAL OF ACCELERATED WHOLE BREAST IRRADIATION  
WITH HYPOFRACTIONATION PLUS CONCURRENT BOOST  
VERSUS STANDARD WHOLE BREAST IRRADIATION  
PLUS SEQUENTIAL BOOST FOR EARLY-STAGE BREAST CANCER   
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network 
of NCTN organizations: the Alliance for Clinical Trials in Oncology; ECOG-ACRIN Cancer Research 
Group; and SWOG. 
Study Chairs (16-DEC-2021) 
 
Principal Investigator/Radiation Oncology Chair 
Frank A.Vicini, MD, FACR 
St. Joseph Mercy Oakland 
70 Fulton Street 
Pontiac, Michigan 48341 
248-338-0300/FAX 248-338-0660 
Frank.Vicini@21co.com                
Economics Co-Chair 
James Hayman, MD  
Department of Radiation Oncology 
University of Michigan 
UHB2C490 
1500 E. Medical Center Dr., SPC 5010 
Ann Arbor, MI 48109 
734-647-9956/FAX 734-763-7371 
hayman@umich.edu 
 
 
 
Radiation Oncology Co-Chairs 
Gary M. Freedman, MD 
Department of Radiation Oncology 
University of Pennsylvania 
PCAM/TRC 4 West 
3400 Civic Center Blvd 
Philadelphia, PA 19104 
215-662-3241/ FAX 215-615-5600 
Gary.Freedman@uphs.upenn.edu 
Translational Research Co-Chairs 
Barry Rosenstein, PhD 
Department of Radiation Oncology 
Box 1236 
Mount Sinai School of Medicine  
New York, NY 10029 
212-241-9408/FAX 212-996-8927 
Barry.Rosenstein@mssm.edu 
 
 
 
Julia R. White, MD 
Department of Radiation Oncology 
Ohio State University 
Comprehensive Cancer Center 
300 W. 10th Avenue, Suite 094D 
Columbus, OH 43212 
614-688-7373/FAX 614-688-7356 
Julia.White@osumc.edu 
 
Soren M. Bentzen, PhD, DSc 
University of Maryland School of Medicine 
600 W. Redwood Street 
Howard Hall 109D 
Baltimore, MD 21201 
410-706-8506/FAX 410-706-8548 
sbentzen@som.umaryland.edu 
 
Douglas W. Arthur, MD 
Department of Radiation Oncology 
Virginia Commonwealth University 
MCV Campus, Massey Cancer Center 
401 College St., Box 980058 
Richmond, VA 23298-0058 
804-828-7232/FAX 804-828-6042 
darthur@mcvh-vcu.edu 
 
Medical Physicist Co-Chair 
X. Allen Li, PhD, DABMP, FAAPM 
Department of Radiation Oncology  
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, Wisconsin 53226 
414-805-4362/FAX 414-805-4354 
ali@mcw.edu 
 
 
 
 
 
 
 
 
Study Chairs continued on next page

 
RTOG 1005; version date December 16, 2021 
 
2
 
Quality of Life Co-Chair 
Michele Halyard, MD, FASTRO 
Mayo Clinic  
5777 E Mayo Blvd 
Phoenix, AZ 85250 
480-342-1262/FAX 480-342-3972 
mhalyard@mayo.edu 
Surgery Co-Chair 
Richard J. Bleicher, MD, FACS 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
215-728-2596/FAX 215-728-2773 
Richard.Bleicher@fccc.edu 
 
NRG Oncology/NSABP Co-Chair 
Alphonse Taghian, MD, PhD 
Clark Center for Radiation Oncology  
100 Blossom Street, COX 3  
Boston, MA 02114-2606 
617-726-7559/FAX 617-726-3603 
ataghian@partners.org 
 
Senior Statistician 
Kathryn Winter, MS 
NRG Oncology 
50 South 16th Street, Suite 2800  
Philadelphia, PA 19102 
215-574-3198/ FAX 215-928-0153 
winterk@nrgoncology.org 
 
 
 
                                                                         
        Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 5 
December 16, 2021 
N/A 
Amendment 4 
July 31, 2014 
August 18, 2014 
Closure 
June 20, 2014 
June 20, 2014 
Amendment 3 
April 4, 2014 
May 1, 2014 
Update 
January 9, 2014 
January 9, 2014 
Update 
May 6, 2013 
October 21, 2013 
Amendment 2 
May 6, 2013 
October 21, 2013 
Update  
July 30, 2012 
July 30, 2012 
Update  
June 28, 2012 
June 28, 2012 
Amendment 1 
May 11, 2012 
June 28, 2012 
Update  
June 21, 2011 
June 21, 2011 
Update 
May 24, 2011 
May 24, 2011 
Activation 
May 18, 2011 
May 24, 2011 
 
 
 
Participating Sites (5/6/2013) 
 US Only 
 Canada Only 
 US and Canada 
 Approved International Member Sites  
 
NRG Oncology 1-800-227-5463, ext. 4189 
 
 
This protocol was designed and developed by the NRG  Oncology.  It is intended 
to be used only in conjunction with institution-specific IRB approval for study 
entry.  No other use or reproduction is authorized by NRG Oncology nor does 
NRG Oncology assume any responsibility for unauthorized use of this protocol. 

 
RTOG 1005; version date December 16, 2021 
 
3
 CONTACT INFORMATION (16-DEC-2021) 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
(Sign in at www.ctsu.org, and select  
Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Refer to the patient enrollment section of the 
protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email: 
1-888-823-5923, or ctsucontact@westat.com. 
 
NRG Headquarters 
50 S.16th Street, Suite 2800 
Philadelphia, PA 19102 
 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions.   
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific page located on the CTSU members’ website (https://www.ctsu.org).  Access to the CTSU 
members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires log in with a CTEP-IAM username and password.  
 
 
 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study Data Manager of the Lead 
Protocol Organization 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) Contact 
the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and correspondence will 
be triaged to the appropriate CTSU representative.  
 
 
 
 
 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
4
 
 
 
 
TABLE OF CONTENTS 
 
SCHEMA ....................................................................................................................................................... 6 
 
ELIGIBILITY CHECKLIST ............................................................................................................................. 7 
 
1.0 
INTRODUCTION ............................................................................................................................. 11 
1.1 
Breast-Conserving Surgery and Radiation for Early Staged Breast Cancer .............................. 11 
1.2 
Whole Breast, Hypofractionated Radiation in Early Stage Breast Cancer. ................................ 11 
1.3  
Tumor Bed Boost ........................................................................................................................ 12 
1.4  
Conformal Radiation Methods in Early Stage Breast Cancer. .................................................... 13 
1.5 
Hypofractionation and Concurrent Boost .................................................................................... 14 
1.6  
Radiobiologic Rationale for Proposed Trial of Hypofractionation and Concurrent Boost ........... 14 
1.7  
Other Questions That Remain About Whole-Breast Hypofractionated Radiation ...................... 15 
1.8  
Standardization of IMRT and 3DCRT for WBI ............................................................................ 18 
1.9  
Tissue Banking for Future Translational Research ..................................................................... 18 
1.10  
Breast-Related Symptoms and Side Effects ............................................................................... 21 
1.11  
Conclusions ................................................................................................................................. 22 
 
2.0 
OBJECTIVES .................................................................................................................................. 23 
2.1 
Primary ........................................................................................................................................ 23 
2.2 
Secondary ................................................................................................................................... 23 
 
3.0 
PATIENT SELECTION .................................................................................................................... 23 
3.1 
Conditions for Patient Eligibility ................................................................................................... 23 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 25 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT...................................................................... 26 
4.1 
Required Evaluations/Management ............................................................................................ 26 
4.2 
Recommended Evaluations/Management .................................................................................. 26 
 
5.0 
REGISTRATION PROCEDURES ................................................................................................... 26 
5.1 
Pre-Registration Requirements for IMRT / 3D-CRT Treatment Approach ................................. 26 
5.2 
Digital RT Data Submission to RTOG Using TRIAD................................................................... 27 
5.3 
Regulatory Pre-Registration Requirements ................................................................................ 27 
5.4 
OPEN Registration ...................................................................................................................... 29 
 
6.0 
RADIATION THERAPY ................................................................................................................... 30 
6.1 
Dose Specifications ..................................................................................................................... 30 
6.2 
Technical Factors ........................................................................................................................ 30 
6.3 
Localization, Simulation, and Immobilization .............................................................................. 30 
6.4 
Treatment Planning/Target Volumes .......................................................................................... 31 
6.5 
Critical Structures ........................................................................................................................ 38 
6.6 
Treatment Verification ................................................................................................................. 39 
6.7 
Documentation Requirements ..................................................................................................... 39 
6.8 
Compliance Criteria ..................................................................................................................... 39 
6.9 
R.T. Quality Assurance Reviews................................................................................................. 40 
6.10 
Radiation Therapy Adverse Events ............................................................................................ 41 
6.11 
Radiation Therapy Adverse Event Reporting .............................................................................. 41 

 
RTOG 1005; version date December 16, 2021 
 
5
 
7.0 
DRUG THERAPY ............................................................................................................................ 44 
7.1 
Chemotherapy ............................................................................................................................. 44 
7.2 
Hormonal Therapy ...................................................................................................................... 44 
7.3 
Trastuzumab ............................................................................................................................... 44 
 
8.0 
SURGERY ....................................................................................................................................... 44 
9.0 
OTHER THERAPY .......................................................................................................................... 45 
9.1 
Permitted Therapies .................................................................................................................... 45 
9.2 
Non-permitted Therapies ............................................................................................................ 45 
 
10.0 
TISSUE/SPECIMEN SUBMISSION ................................................................................................ 45 
10.1 
Tissue/Specimen Submission ..................................................................................................... 45 
10.2 
Specimen Collection for Tissue Banking and Translational Research   ..................................... 45 
10.3 
Reimbursement ........................................................................................................................... 48 
10.4 
Confidentiality/Storage ................................................................................................................ 48 
 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 49 
11.1 
Study Parameters ....................................................................................................................... 49 
11.2 
Cosmetic and Quality of Life Outcomes ...................................................................................... 49 
11.3 
Measurement of Response ......................................................................................................... 50 
11.4 
Criteria for Discontinuation of Protocol Treatment ...................................................................... 50 
 
12.0 
DATA COLLECTION ....................................................................................................................... 50 
12.1 
Summary of Data Submission..................................................................................................... 50 
12.2 
Summary of Dosimetry Digital Data Submission ........................................................................ 51 
 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 52 
13.1  
Study Endpoints .......................................................................................................................... 52 
13.2 
Study Design ............................................................................................................................... 52 
13.3 
Accrual ........................................................................................................................................ 55 
13.4  
Analysis Plan ............................................................................................................................... 55 
13.5  
Quality of Life .............................................................................................................................. 57 
13.6 
Treatment Costs .......................................................................................................................... 58 
13.7 
Gender and Minorities ................................................................................................................. 58 
 
REFERENCES ............................................................................................................................................ 60 
 
APPENDIX I ................................................................................................................................................ 66 
APPENDIX II ............................................................................................................................................... 68 
APPENDIX III .............................................................................................................................................. 69 
APPENDIX IV .............................................................................................................................................. 73 
APPENDIX V ............................................................................................................................................... 78 
APPENDIX VI .............................................................................................................................................. 84 
APPENDIX VII ............................................................................................................................................. 88 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
6
 
 
 
 
 
 
 
 
 
 
 
NRG ONCOLOGY  
 
RTOG 1005 
 
 
A Phase III Trial of Accelerated Whole Breast Irradiation with Hypofractionation plus Concurrent 
Boost versus Standard Whole Breast Irradiation Plus Sequential Boost for Early-Stage Breast 
Cancer   
 
 
SCHEMA (6/21/11) 
 
 
 
S 
Age 
 
R 
ARM 1: Standard fractionation  
 
T 
< 50 vs. ≥ 50  
A 
Whole Breast 50.0 Gy/25 fractions/2.0 Gy daily  
 
 
R 
 
 
N 
Optional fractionation of 42.7Gy in 16 fractions permissible  
 
A 
Chemotherapy 
D 
Sequential Boost 12.Gy/6 fractions/2.0 Gy daily or 
 
T 
Yes vs. No 
 
O 
14.0Gy/7fractions/2Gy daily 
 
I 
 
 
M 
ARM 2: Hypofractionation (15 fractions total) 
 
 
F 
ER Status 
  
I 
Whole Breast 40 Gy/15 fractions/2.67 Gy daily 
 
Y 
+   vs.   – 
 
Z 
Concurrent boost 48.0 Gy/3.2 Gy daily 
 
 
 
 
E 
 
                         Histologic Grade 
 
 
1, 2 vs. 3 
 
 
See Section 5.0 for pre-registration requirements 
See Section 6.0 for details of radiation therapy 
 
Patient Population:  (5/6/2013) (See Section 3.0 for Eligibility and additional requirements)  
pStage 0, I, II Breast Cancer resected by lumpectomy 
ypStage 0, I,II Breast Cancer resected by lumpectomy that followed neoadjuvant systemic therapy 
 
 
 
 
Required Sample Size: 2312 
 
 
 
 
 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
7
 
 
 
 
 
 
ELIGIBILITY CHECKLIST (5/6/2013) 
NRG Oncology Institution #   
 
RTOG 1005 
Case #  
 
 
 
      (page 1 of 4) 
_____(Y)  
1. Does the patient have a pathologically proven diagnosis of breast cancer resected by 
lumpectomy?        
 
_____(Y) 
 2 .Is the patient’s stage of breast cancer one of the following? (A, B or C) 
         
 
        A. pStage I, II breast cancer AND at least one of the following: 
▪ 
Age < 50 years 
▪ 
Positive axillary nodes 
▪ 
Lymphovascular space invasion 
▪ 
2 or more close resection margins (> 0 mm to ≤ 2 mm) 
▪ 
1 close resection margin and extensive intraductal component(EIC) 
▪ 
Focally positive resection margins  
▪ 
Non-hormone sensitive breast cancer (ER and PR-negative) 
▪ 
Grade III histology 
▪ 
Oncotype recurrence score > 25  
 
        B. pStage 0 breast cancer with nuclear grade 3 DCIS and patient age < 50 years 
 
        C. ypStage 0, I, II breast cancer resected by lumpectomy after neoadjuvant systemic 
therapy 
 
 
_____ (Y) 
 3. Is the patient female? 
 
_____ (Y)  
4. Will the patient be registered within 50 days from whichever is later: last surgery 
(breast or axilla) or last chemotherapy? 
 
 
 
NOTE: The day of surgery is Day “0” 
 
_____ (Y/N) 
5. Does the patient have multifocal breast cancer?  
 
_____ (Y) 
  If yes, was it resected through a single lumpectomy incision with negative margins? 
 
_____ (Y) 
 6. Has the patient had breast conserving surgery with margins defined as follows?  
▪ 
Negative margins defined as no tumor at the resected specimen edge. 
▪ 
Close resection margins; > 0 mm to ≤ 2 mm defined as:       
o 
One close resection margin and EIC 
o 
2 or more close resection margins 
▪ 
A focally positive resection margin  
 
_____ (Y) 
7.  Was axillary staging performed as outlined in section 3.1.7 of the protocol? 
 
_____ (Y)  
8.   Is the patient ≥ 18 years of age? 
 
_____ (N)  
9. Is there clinical evidence of distant metastases? 
 
_____ (Y)  
10. Was a history/physical examination, including breast exam and documentation of 
weight and Zubrod Performance status of 0-2 done within 28 days prior to study entry? 
 

 
RTOG 1005; version date December 16, 2021 
 
8
_____ (Y)  
11. Was a right and left mammogram done within 90 days of diagnostic biopsy 
establishing diagnosis?  
 
_____ (Y)  
12. Does the patient have adequate bone marrow as specified in section 3.1.12 of the 
protocol 
 
NRG Oncology Institution #   
 
RTOG 1005 
 
 
 
ELIGIBILITY CHECKLIST  (1/9/14) 
Case #  
 
 
 
         (page 2 of 4) 
 
 
_____ (Y/N)  
13. Is the patient of childbearing potential? 
                   (Y/N) if yes, is the patient sexually active? 
     
         (Y) 14a. If yes, is the patient willing/able to use medically acceptable forms 
of      contraception during radiation therapy? 
 
_____ (Y)  
14. For women of childbearing potential, was a urine or serum pregnancy test negative 
within 14 days prior to study entry? 
 
_____ (N)  
15. Is the patient lactating? 
 
_____ (N)  
16. Is the patient’s breast cancer stage AJCC pathologic T4, N2 or N3, M1 pathologic 
stages III or IV, breast cancer? 
 
_____ (N)  
17. Does the patient’s treatment plan include regional node irradiation? 
 
_____ (Y/N)  
18. Has the patient had a prior invasive non-breast malignancy (except non-  
melanomatous skin cancer or carcinoma in situ of the cervix)?  
 
_____ (Y) If yes, has the patient been disease free for a minimum of 5 years prior to study entry? 
 
_____ (N)         19. Has the patient had a prior invasive or in-situ carcinoma of the breast (prior LCIS is      
eligible)?  
 
_____ (N)  
20. Does the patient have two or more breast cancers not resected through a single 
lumpectomy incision? 
 
_____ (N)  
21. Is the patient’s breast cancer only DCIS (without an invasive component) and her age 
≥ 50 years old? 
 
_____ (N)  
22. Does the patient have nuclear grade 1 or 2 DCIS only (without an invasive 
component) and is < 50 years old? 
 
_____ (N)  
23.  Does the patient have invasive breast cancer and low risk for 5 year in breast 
recurrence after lumpectomy with negative margins and does not meet one of the 
eligibility factors in section 3.1.3 A.? 
 
_____ (Y) 
24. Is there a clear delineation of the extent of the target lumpectomy cavity for a boost 
on a CT scan for radiation treatment planning within 28 days prior to study entry?   
 
_____ (N)  
25. Are there suspicious unresected microcalcifications, densities, or palpable 
abnormalities (in the ipsilateral or contralateral breast) that were not biopsied and found 
to be benign?  
 
_____ (N)  
26. Does the patient have non-epithelial breast malignancies such as sarcoma or    
lymphoma? 

 
RTOG 1005; version date December 16, 2021 
 
9
 
_____ (N)  
27. Does the patient have Paget’s disease of the nipple? 
 
_____ (N)  
28. Has the patient had prior radiotherapy to the breast or prior radiation to the region of 
the ipsilateral breast that would result in overlap of radiation therapy fields? 
 
NRG Oncology Institution #   
 
RTOG 1005 
 
 
 
ELIGIBILITY CHECKLIST (5/24/11) 
Case #  
 
 
 
         (page 3 of 4) 
 
 
_____ (N)  
29. Does the patient’s treatment plan include concurrent chemotherapy for the current 
breast cancer? 
 
_____ (N) 
30. Does the patient have active systemic lupus erythematosus, or any history of 
scleroderma, dermatomyositis with active rash? 
 
 _____ (N)  
31. Does the patient have severe, active co-morbidity, as defined in section 3.2.17 
 
 _____ (Y)  
32. Did the patient provide study specific informed consent prior to study entry? 
 
 _____  (N)  
33. Does the patient have a medical or psychiatric condition that would prevent them 
from receiving the protocol therapy or providing informed consent? 
 
 
 The following questions will be asked at Study Registration:  
 “3D-CRT and IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION” 
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (First Middle Last) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 

 
RTOG 1005; version date December 16, 2021 
 
10 
 
         
15. 
Any care at a VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
NRG Oncology Institution #   
 
RTOG 1005 
 
 
 
ELIGIBILITY CHECKLIST (1/9/14) 
Case #  
 
 
 
          (page 4 of 4) 
 
 
 
              (Y/N) 18. 
Have you obtained the patient's consent for her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 19.  
Have you obtained the patient's consent for her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N)    20. 
Have you obtained the patient's consent for her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
               (Y/N)   21. 
Have you obtained the patient's consent for her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's 
disease, or heart disease).  
             
               (Y/N)   22. 
Have you obtained the patient's consent to allow someone from this institution to   
contact her in the future to take part in more research?  
 
               (Y/N)   23. 
Patient has consented to participate in the Cosmesis Study? (NOTE: Non-
chemotherapy Cosmesis subset closed to accrual 3/8/13; chemotherapy 
Cosmesis subset closed to accrual 01/9/14) 
 
 
If no, provide reason: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other: specify_________________ 
 
 
                       24.    
Age (< 50 vs. ≥ 50)  
 
             (Y/N)    25.    
Intention to receive chemotherapy (before receiving protocol RT) (yes vs. no) 
 
             (Y/N)  26.     
ER Status (positive vs. negative)  
 
              (Y/N)    27.   
Specify Radiation Technique (3D-CRT vs. IMRT) (see section 6.4.3. for 
definition) 
 
               
28.      Histologic Grade (G1-2 or G3) 
 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 

 
RTOG 1005; version date December 16, 2021 
 
11 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
1.0 INTRODUCTION 
1.1 
Breast-Conserving Surgery and Radiation for Early Staged Breast Cancer 
Breast-conserving surgery and RT are standard alternatives to mastectomy for eligible 
patients with stage I and II invasive breast cancer (NIH Consensus Conference 1991; 
National Comprehensive Cancer Network 2010).  Post lumpectomy RT is associated with 
long-term local control on the order of 85-95% with equivalent survival outcomes as 
mastectomy (Veronesi 2002; Fisher 2002). The reduction in local recurrence from 
radiation post lumpectomy has also been associated with improved overall survival 
compared to surgery alone (Early Breast Cancer Trialists’ Collaborative Group 2005).  
Therefore it is imperative that new radiation methods post lumpectomy are not inferior in 
terms of local control so that there is not a potential impact on disease free or overall 
survival. 
 
In spite of these benefits of RT, the number of women treated with breast-conserving 
surgery but without RT is approximately 15-20% (Morrow 2001; Polednak 2002). One 
problem with conventional RT to the whole breast may be the 6-7 week length of 
treatment. A conventional schedule given up to 6-7 weeks involves treatment of the 
whole breast at 1.8 - 2 Gy daily fractions for 46 - 50.4 Gy, followed by a sequential boost 
to the tumor bed for 10-18 Gy. Methods for reducing overall treatment time may improve 
the utilization of postoperative RT in eligible women after breast-conserving surgery.   
 
Some methods for shortening overall treatment time (e.g., partial breast RT and 
intraoperative RT) limit radiation to the region of the primary tumor alone with a small 
margin and omit RT to other quadrants of the breast. Not all patients are eligible for these 
methods that require patients with small tumor sizes (≤ 3 cm) and favorable histologic 
characteristics (no extensive intraductal component, no lymphovascular space invasion, 
negative or 1-3 axillary lymph nodes).  In addition, the long-term efficacy of partial breast 
irradiation compared to WBI is being studied in ongoing clinical trials including NSABP B-
39/ RTOG 0413.  
 
1.2 
Whole Breast, Hypofractionated Radiation in Early Stage Breast Cancer. 
Hypofractionation, or delivery of greater than standard 1.8 - 2 Gy fraction sizes per day, is 
a method of shortening overall treatment time in breast cancer.  There are many potential 
benefits in delivering postoperative WBI in a shorter period of time.  The advantages 
include greater convenience for patients, broad applicability to nearly all patients 
following lumpectomy, improved use of postoperative radiation for breast conservation, 
decreased treatment costs, and increased utilization of existing RT resources.   
 
Historically, standard fraction sizes of 1.8-2.0 Gy for radiotherapy were based primarily 
on studies examining squamous cell cancers from cervix and head and neck regions.  
The smaller fraction sizes exploited a biological differential in squamous cell cancer 
fractionation sensitivity versus normal tissue fractionation sensitivity.  This allowed 
relative sparing of surrounding normal tissue from low dose per fraction.  However, 
investigators from the United Kingdom hypothesized that the fractionation sensitivity for 
adenocarcinoma of the breast is close to that of the normal breast tissue and therefore 
with increasing fraction size a sufficiently large reduction of total dose could be 
implemented to keep late toxicity constant without losing tumor control.   
 
Four prospective randomized clinical trials have shown promising results with 
hypofractionated schedules for WBI (Yarnold 2005; Owen 2006; START A, START B 
2008; Whelan 2010). In each of these studies, the goal was to deliver a hypofractionated 
dose schedule that is biologically equivalent to the standard fractionation breast dose of 
50 Gy in 25 fractions of 2 Gy. With 5-10 year follow-up of these studies, there has been 

 
RTOG 1005; version date December 16, 2021 
 
12 
similar in-breast local control between the hypofractionated and standard fractionated 
arms.   
 
Despite these data, widespread adoption of hypofractionated whole breast irradiation has 
been hampered because of two remaining questions:   
1). What is the optimal method to deliver the boost to the tumor bed and the outcome 
with hypofractionation, for those higher risk breast cancer cases requiring boost? ; and  
2). Will newer CT based radiation delivery methods that have emerged using standard 
fractionated WBI demonstrating reduced acute and late toxicity have equivalent results in 
hypofractionated schedules?  
 
This proposed study is designed to address these questions by:  
1). Evaluating a hypofractionated dose schedule that is biologically equivalent for both 
the whole breast dose AND the higher boost dose to the breast tissue at greatest risk of 
recurrence immediately around the lumpectomy cavity; and  
2). Comparing early and late toxicity after standard and hypofractionated radiotherapy 
when adopting CT based WBI treatment delivery methods with 3-dimensional conformal 
radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT).  
 
1.3  
Tumor Bed Boost 
Of the 4 prospective studies for hypofractionated WBI, one did not use a boost, 2 used a 
boost at the discretion of the treating department policy, and only 1 examined the boost in 
a prospective fashion. In all cases the boost was delivered with standard fractionation. 
The boost dose was 10 Gy in 5 fractions in the START trials and 14 Gy in 7 fractions in 
the earlier RMH/GOC trial.  The boost was given sequentially in all 3 trials.  The use of a 
sequential boost of 1-2 weeks in these studies extended the overall treatment time to 
nearly 5 weeks in some cases reducing the potential time-saving benefit to patients.  
None have data on a hypofractionated boost dose schedule that is biologically equivalent 
to the cumulative dose from a conventional tumor bed boost. 
 
Table 1: Boost in randomized trials of whole breast hypofractionation 
 
 
Fractionation 
 
Cosmetic Outcome 
Time 
Study 
# 
Schedule 
% Boost 
% Good/excellent 
Point 
Canadian 
612 
50 Gy / 25 
0 
71.3 
10 years 
 
622 
42.5 Gy / 16 
0 
69.8 
RMH/GOC 
470 
50 Gy / 25 
74.5** 
71 
10 years 
 
466 
42.9 Gy / 13 
 
74 
 
474 
39 Gy / 13 
 
58 
START A 
749 
50 Gy / 25 
60.4 
60* 
5 years 
 
750 
41.6 Gy / 13 
61 
58* 
 
737 
39 Gy / 13 
60.5 
66* 
START B 
1105 
50 Gy / 25 
41.4 
61* 
5 years 
 
1110 
40 Gy / 15 
43.8 
66* 
 
* No moderate/marked change in breast appearance 
** Distribution by trial arm not stated 
 
   
In the RMH/GOC trial, 723 patients were randomized to boost versus no boost.  A further 
687 patients were recommended an elective boost but not randomized.  The 10–year % 
good or excellent cosmetic result was 66% randomized to no boost, 70% randomized to 
a boost, and 70% non-randomized receiving boost (p=not significant). 
 
In two prospective randomized studies in invasive breast cancer, the use of a boost after 
WBI reduced the risk of local recurrence even in patients with negative resection margins 
(Romestaing 1997; Bartelink 2007).   In the first trial, patients were randomized to 10 Gy 
boost after 50 Gy whole breast irradiation.  At 5 years, the risk of local recurrence was 

 
RTOG 1005; version date December 16, 2021 
 
13 
3.6% versus 4.5% (P = .044).  In the EORTC trial, patients were randomized to a 16-Gy 
boost after 50 Gy to the whole breast.  The overall local recurrence rates were 10.2% 
without a boost and 6.2% with a boost, respectively, a proportional reduction of 40%, 
which was statistically significant  This reduction occurred for patients of all ages but was 
greatest in absolute terms for women age 40 years or younger (from 23.9% to 13.5%) 
and ages 51 – 50 years (12.5% to 8.7%).  An international survey of Radiation 
Oncologists in 2001-2002 showed that 85% of American and 75% of European 
respondents would deliver a boost even with negative margins after WBI (Ceilley 2005). 
Current guidelines by the National Comprehensive Cancer Center Network (NCCN) 
suggest that a boost may not be required in all patients (National Comprehensive Cancer 
Network 2009). This reflects the understanding that the magnitude of the benefit of the 
boost may be smaller in some subgroups of patients as seen in the EORTC boost trial. 
The consensus guidelines for 2009 indicate that a boost is recommended for patients 
aged < 50 years, positive axillary nodes, positive lymphovascular space invasion, and/or 
close/positive resection margins.  A boost in other low risk groups is considered optional. 
  
In both prospective randomized studies in invasive breast cancer testing the use of a 
sequential boost, the addition of the boost increased the incidence of late effects such as 
telangiectasias and fibrosis (Romestaing 1997; Bartelink 2007). Therefore, how a boost 
will impact efficacy, cosmesis and risk of complications is essential if hypofractionation is 
to become more widely adopted.   
 
This proposed study will evaluate a hypofractionated dose schedule biologically 
equivalent to the cumulative tumor bed dose given with sequential boost after WBI but to 
be delivered concomitantly during 15 fractions of hypofractionated WBI. 
 
1.4  
Conformal Radiation Methods in Early Stage Breast Cancer. 
Initial experiences with IMRT for breast cancer have shown clinical feasibility, improved 
dose distributions in the treated breast, lower doses given to normal heart or lung tissue 
compared with standard techniques, and a low incidence of acute toxicity (Vicini 2002; 
Chui 2002; Freedman 2006). 
Vicini, et al. (2002) reported on 281 patients with stage 0, I and II breast cancer treated 
with an IMRT technique. The rate of acute grade 2 skin toxicity was 43%, and the rate of 
acute grade 3 skin toxicity was 1%. Cosmesis at 1 year was good or excellent in 99% of 
patients.  Harsolia, et al. (2007) reported on a series of 172 patients, 93 treated with 
IMRT and 79 with conventional radiation. They showed that IMRT results in a significant 
decrease in acute dermatitis, edema, and hyperpigmentation and a reduction in the 
development of chronic breast edema compared with conventional wedge-based 
radiation.  In one randomized trial from the United Kingdom reported by Donovan et al of 
standard radiotherapy versus IMRT/3DCRT in early-stage breast cancer, 240 of 306 
patients were able to be evaluated by photographs for change in breast appearance 
(Donovan 2007).  There was a negative change in breast appearance in 58% of patients 
randomized to 2D conventional treatment compared to 40% randomized to IMRT.  In a 
second randomized trial from Canada of 358 patients, Pignol, et al.(2008) compared 
standard wedge compensated conventional radiation to IMRT/3DCRT and found that 
IMRT was associated with improved dose homogeneity and reduced moist desquamation 
(31% vs. 48%, p=0.0019). 
 
These randomized trials demonstrated reduced toxicity from standard fractionation WBI 
delivered with IMRT/3DCRT compared to 2D delivery methods.  An important question is 
whether similar results as IMRT can be achieved with 3DCRT methods that give 
comparable coverage of the entire breast volume and exclusion of normal tissues on CT.  
To fully evaluate this, it is first necessary to establish target doses, normal tissue 
constraints, acceptable heterogeneity, and appropriate quality assurance for the delivery 
of WBI with CT-based volumes with 3DCRT and IMRT. These parameters are not 
precisely known today. 

 
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14 
 
1.5 
Hypofractionation and Concurrent Boost 
There are 3 recent Phase I/II trials showing the safety and short-term efficacy of 
hypofractionated radiation therapy with a concurrent boost: 
 
1) Freedman, et al. (2007) have reported a clinical study of hypofractionation using IMRT 
and an incorporated breast boost in early-stage breast cancer. Seventy-five patients were 
treated on study.  The whole breast was treated to a dose of 2.25 Gy per day for 20 
fractions for a total of 45 Gy.  The incorporated boost gave simultaneously the tumor bed 
2.8 Gy per fraction for 20 days for a total of 56 Gy.  This use of hypofractionation of the 
whole breast volume, and simultaneously the boost volume, results in a 4-week overall 
treatment time.  The maximum acute skin toxicity by the end of treatment was grade 0 in 
9 patients (12%), grade 1 in 49 (65%), and grade 2 in 17 (23%).  There was no grade 3 
or higher skin toxicity.  The maximum skin toxicity varied by breast size: Small 100% 
grade 1 (n=12); medium 6% grade 0, 80% grade 1 and 14% grade 2 (n=35); and large 
4% grade 0, 48% grade 1 and 48% grade 2 (n=23).  After radiation, all grade 2 toxicity 
had resolved by 6 weeks.  Hematologic toxicity was grade 0 in most patients except for 
grade 1 neutropenia in 2 patients and grade 1 anemia in 11 patients.  With a median 
potential follow-up of 54 months, the 5-year local recurrence rate was 1.4%.  There were 
no significant differences in baseline versus 32 month post-treatment patient-reported or 
physician-reported cosmetic scores.   
 
2) Formenti, et al. (2007) have also reported a trial of IMRT, hypofractionation, and 
concomitant boost.  A dose of 40.5 Gy was delivered in 15 fractions with a concomitant 
boost of 0.5 Gy per day for a total tumor bed dose of 48 Gy.  The results in 91 patients 
treated were reported with a median follow-up of 12 months.  The major acute toxicity 
was reversible grade 1-2 dermatitis in 67%.  There were no treatment breaks.  There 
were 2 acute grade 3 toxicities, 1 skin and 1 fatigue.  There were no late grade 3 
toxicities.  Late fibrosis was reported grade 1 in 48%, grade 2 3%.  Grade 1 pigmentation 
change was noted in 70%.  Breast pain was grade 1 in 8% and grade 2 in 2%.  Skin 
telangiectasias were grade 1 in 3% and grade 2 in 2%.  There was 1 regional node 
recurrence.   
 
3) Chadha, et al.(2009) have reported a trial of conventional whole breast irradiation with 
a concomitant boost over 3 weeks for early stage breast cancer.  The whole breast dose 
was 2.7 Gy per fraction for 15 fractions to a dose of 40.5 Gy.  The concomitant boost to 
the lumpectomy site was a total of 3 Gy per fraction for 15 fractions to a total dose of 45 
Gy. The results of 105 patients were reported at a median follow-up of 24 months.  There 
was no acute grade 3 or 4 toxicity.  There were no reported late soft tissue toxicities.  
There was no significant negative effect reported on cosmesis. 
 
1.6  
Radiobiologic Rationale for Proposed Trial of Hypofractionation and Concurrent Boost 
The radiobiology co-investigators for this trial were participants of the UK START trials 
and Formenti trials.  They developed the dose regimens used in the proposed trial.  
Based on the best available estimates of the fractionation sensitivity, quantified by the 
α/βratio of the linear-quadratic (LQ) model, for subclinical breast cancer and changes in 
breast appearance derived from the UK fractionation trials, it is possible to estimate the 
biologically equivalent doses in 2-Gy fractions delivered to the whole breast and the 
tumor bed.  The two START trials, the Royal Marsden-Cheltenham pilot trial and the 
OCOG trial randomized more than 7,000 women to moderately hypofractionated 
schedules, confirming the validity of the LQ model effect estimates at least up to 3.3 Gy 
per fraction. 
  1.6.1  
Whole Breast Volume 
The WBI fractionation schedule in the control arm is 50 Gy in 25 fractions over five 
weeks for the whole breast irradiation.  This is also the control arm in the ongoing 
NSABP B-39 / RTOG 0413 phase III trial.  42.5 Gy in 16 fractions as used in the 

 
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15 
Canadian hypofractionated trial is also permitted.  The WBI dose-fractionation in the 
experimental arm is identical to the schedule used in the UK START B trial in the 
hypofractionation arm, 40 Gy in 15 fractions, 2.67 Gy per fraction over 3 weeks.   
 
There is evidence that the tumor control effect of the WBI in the experimental arm will 
be noninferior to the WBI dose fractionation used in the control arm.  In the START B 
trial (2008), the WBI dose fractionationation produced a 5-year estimate of local-
regional relapse of 2.0% with hypofractionation compared with 3.3% in the standard 2 
Gy control arm of that trial . This is consistent also with the 10-year estimates of local 
relapse of 6.2% for 42.5 Gy in 3 weeks and 6.7% for 50 Gy in 5 weeks in the Canadian 
hypofractionation trial (Whelan 2010).   
 1.6.2 
Boost 
The sequential tumor bed boost in the control arm is minimally 12Gy in 6 fractions, or 
minimal total of 62 Gy to the tumor bed or maximally 14 Gy in 7 fractions, or a maximal 
total of 64 Gy to the tumor bed.  The concurrent boost dose-fractionation in the 
experimental arm is 48.0 Gy in 15 fractions of 3.2 Gy.   
 
 
A concurrent boost to the tumor bed delivering a total dose of 48.0 Gy in 15 fractions 
with 3.2 Gy per day would result in an equivalent tumor bed dose (assuming an alpha 
beta ratio of 4, and correcting for proliferation effects) in 2-Gy per fraction of 
approximately 63-66 Gy in 2 Gy fractions (with the range due to an estimate for 
increased biologic effectiveness due to the fewer weeks of treatment with a concurrent 
rather than sequential boost).  This dose for the concurrent boost was developed with 
the input of our radiobiology co-investigators Soren M. Bentzen, PhD, DSc and Barry 
Rosenstein, PhD who have both been involved in prior trials of breast 
hypofractionation. 
 
1.7  
Other Questions That Remain About Whole-Breast Hypofractionated Radiation 
Despite the prior randomized trials, many questions still remain regarding the use of WBI 
hypofractionated schedules. 
1.7.1  
Length Of Treatment 
The length of treatment varied in these prospective trials of hypofractionation. The 
Ontario Clinical Oncology Group (OCOG) study finished in 3 weeks but no boost was 
used.  The trials by the United Kingdom used every other day fractionation in order to 
keep the overall treatment time for the WBI component constant at 5 weeks, which is 
not used in the United States. The exception is the START B trial where WBI was 
finished in 3 weeks in the hypofractionation arm, but then followed by a boost of 10 Gy 
in 5 fractions over an extra week in some 40% of the cases according to departmental 
policy or physician preference.  A prospective cooperative group trial of 3 week 
fractionation that includes a boost has not been completed. 
 
1.7.2 
Breast Size 
Few studies treated large breast sizes to any significant degree. Only the OCOG study 
provided an objective measurement of breast size using the patient chest wall 
separation, and then used this cut-off as an exclusion criterion.  There was no doubt a 
concern that with conventional radiation used in these trials, the baseline risk of acute 
dermatitis or late fibrosis would be greater in large breasted women. Radiation 
dermatitis is most directly related to increased dose inhomogeneity, which itself is most 
directly related to increasing breast size or chest wall diameter (Pignol 2008; Das 
1997). And moist desquamation is more common in women with large breasts than 
those with small breasts (Freedman 2006; Fisher 2000). So enrolling physicians may 
have felt that if this baseline was higher with conventional radiation, then how much 
more so could it have been with hypofractionated radiation? However, since the 
outcomes of these studies have now shown comparable acute and late long-term 
outcomes, further study is needed to determine whether this is only applicable to 
women mostly with small or medium-sized breasts included in these studies. 
 

 
RTOG 1005; version date December 16, 2021 
 
16 
 
1.7.3  
Radiation Sequencing With Chemotherapy 
The trials of whole-breast hypofractionation consisted of mostly lower-risk patients so 
that the number treated with systemic chemotherapy was low (11-36%).  As a result, 
the applicability and safety of fractionation schedules used in these trials to the majority 
of patients that are now treated with adjuvant systemic chemotherapy is not well 
known.  Potential for added complications of radiation in chemotherapy-treated patients 
include fatigue, cytopenias, and infection. Use of chemotherapy has also been 
associated with a worse long-term fibrosis and cosmetic outcome in some 
studies,(Abner 1991) mostly with concurrent rather than sequential sequencing (Abner 
1991;Toledano 
2006). 
 
However, 
these 
older 
studies 
used 
predominately 
cyclphosphamide-methotrexate-5-fluorouracil-based regimens (CMF), and the results 
may not be applicable to patients treated with the anthracycline- and taxane-based 
regimens now in use today.  The potential for added acute or late toxicity with 
hypofractionated radiation in women treated with modern chemotherapy regimens 
needs further study. 
1.7.4  
High-Risk Patients 
There are several clinical and pathologic factors that have been associated with an 
increased risk for local recurrence after breast-conserving surgery and radiation. These 
include young patient age (Fisher 2001;Taghian 2004; Freedman 2002;) a positive or 
close (< 2mm) margin (Veronesi 1995b; Freedman 1999; Park 2000), the presence of 
an extensive intraductal component (EIC) -positive tumor  (Veronesi 1995b; Freedman 
1999; Park 2000; Veronesi 1995) estrogen receptor-negative tumors (Wapnir 2006), 
and lymphovascular invasion (Veronesi 1995; Borger 1994). It is in these patients that 
the potential benefit of a radiation boost is greatest. For example, younger age was 
associated with a greater observed absolute risk reduction at 10 years in one 
randomized trial 14.  The risk of local recurrence was reduced from 23.9% to 13.5% in 
those aged ≤ 40 years, from 12.5% to 8.7% in the 41- to 50-year age group, from 7.8% 
to 4.9% in the 51- to 60-year age group, and from 7.3% to 3.8% in those older than 60 
years.  There was relatively low enrollment of patients with young age, positive nodes 
or close margins on the available randomized trials of whole-breast hypofractionation. 
Since most of these trials either treated lower-risk patients exclusively or did not stratify 
randomization based upon risk, it is also uncertain how the results of these trials can 
been applied to the majority of patients seen and treated with BCT. This trial is to have 
an eligibility criterion that will selectively enroll patients at an increased risk for local 
recurrence.  The estimate of 5-year local recurrence in the control arm of 2 Gy per 
fraction is 6%.  Table 2 shows data from recent prospective trials containing results in 
subgroups of high-risk patients similar to the expected enrollment of this trial.   
 
Table 2: 5-Year Local Recurrence after BCS + RT in prospective randomized trials 
 
Trial 
Years 
Subgroup 
5-Year IBTR 
(%) 
2 Gy 
fractionation 
5-Year IBTR 
(%) 
 Alternate 
fractionation 
Whelan  (OCOG) 
1993 - 1996 
All WBI 
Age < 50 
T-2 size 
3.2 
7.2 
5.4 
2.8 
3.6 
6.4 
Yarnold (START A) 
1998 - 2002 
All WBI + 60% boost 
Age < 50 
Grade 3 
Node positive 
Age < 50 OR grade 3 OR 
node positive 
3.6 
7.4 
7.3 
6.6 
5.5 
3.5† 
2.9 
4.6 
6.7 
4.4 
5.2† 
7.1 
6.9 
4 
6.1 
Yarnold  (START B) 
1999 - 2001 
All WBI + 60% boost 
Age < 50 
3.3 
4.8 
2.2 
4.1 

 
RTOG 1005; version date December 16, 2021 
 
17 
Grade 3 
Node positive 
Age < 50 OR grade 3 OR 
node positive 
7.6 
7.7 
5.6 
3.9 
4.4 
3 
Owen/Yarnold  
(RMH/GOC) 
1986 - 1998 
All WBI + 74% boost 
7.9 
7.1† 
9.1† 
Bartelink  (EORTC) 
1989 - 1996 
Age ≤ 40 
Age 41-50 
Grade 3 
10 
6 
7 
- 
Anderson  (NSABP) 
1981 - 2007 
All node negative 
Node negative and age ≤ 49 
Node negative and ER 
negative 
3 
5 
5 
- 
Holli  (Helsinki) 
1990 - 1999 
Age ≤ 50 
17 
- 
Bear (NSABP B-27) 
1995 - 2000 
With AC chemotherapy 
With AC and T chemotherapy 
7 
3-4 
- 
Wapnir (NSABP) 
1984 - 1994 
All node positive 
Node positive and age ≤ 49 
Node positive and ER 
negative 
6 
8 
8 
- 
Sartor  (CALGB) 
1994 - 1997 
With AC chemotherapy 
With AC and T chemotherapy 
10 
4 
- 
Veronesi (Milan) 
1985 - 1987 
Age ≤ 45 
Age 46 – 55 
Extensive in-situ component 
Margins positive 
8 
13 
30 
15 
- 
Fisher (NSABP) 
1988 – 1993 
All patients 
Age ≤ 49 
7.9 
12.9 
- 
EBCTCG  
1976 – 1998 
Node negative and age < 50 
Node negative and grade 3 
Node negative and T2 
Node negative and ER poor 
11 
12 
14 
12 
- 
 
† = results for the 2 hypofractionated trial arms shown 
References: (Veronesi 1990; Veronesi 1995; Fisher 1998; Mariani 1998; Bartelink 2001; Whelan 2002; Early Breast Cancer Trialists' 
Collaborative Group 2005; Sartor. 2005; Yarnold 2005; Bear et al. 2006; Owen 2006; Wapnir 2006; Bartelink 2007; The START 
Trialists' Group 2008; The START Trialists' Group 2008; Anderson 2009; Holli 2009; Jones 2009; Whelan 2010; Yarnold 2010) 
 
 
1.7.5  
Cardiac Toxicity  
The randomized trials of breast hypofractionated radiation do not have sufficient follow-
up to detect differences in late cardiac mortality.  A large meta-analysis revealed a 
small but negative impact of RT on non-breast mortality but this effect took 10 or more 
years to become evident 5.  The risk of radiation-related cardiac mortality has generally 
decreased over time (Giordano 2005), so that modern studies limited to patients 
treated with postlumpectomy radiation have not generally found differences in cardiac 
mortality between left- and right-sided irradiation  (Borger 2007;Harris 2006).  In a study 
of hypofractionation comparing ≤ 2 Gy to > 2 Gy fraction sizes, no difference in cardiac 
mortality was seen with a median follow-up of 7.9 years (Marhin 2007).  This needs to 
be confirmed with longer follow-up of hypofractionation particularly in higher risk 
patients also receiving cardiotoxic chemotherapy regimens, such as dose-dense 
doxorubicin, taxanes and traztuzumab. 
 
Nonfatal cardiac events have not been sufficiently reported in the randomized trials with 
hypofractionation either.  Previous studies of conventional radiation fractionation have 
shown an increase in the number of nonfatal cardiac events associated with left breast 

 
RTOG 1005; version date December 16, 2021 
 
18 
irradiation.  In a study of patients treated in the Netherlands between 1980 to 1993, 
there was a non-significant increase of the relative risk of cardiovascular disease of 
1.57 (95% confidence interval, 0.83-3.0) after left-sided radiation (Borger 2007).  A 
study from the University of Pennsylvania showed that 10% of patients treated to the 
right breast had developed coronary artery disease by 20 years after treatment, 
compared to 25% of patients with left-sided cancers (Harris 2006).  A group at the 
University of Michigan studied patients treated from 1984 to 2000 and observed a 
cumulative incidence of myocardial infarction/coronary artery disease requiring 
intervention of 2.7% at 10 years (Jagsi 2007). 
 
Because of the relatively small numbers of cardiac events expected in this trial, 
limitation of cardiac risk to women with left-sided treatment, and difficulty in trial 
feasibility to obtain the long-term follow-up necessary to observe cardiac toxicity after 
5-10 years, surrogate measures are needed to assess cardiac risk.  NTCP calculations 
have been previously used to model cardiac risk in patients treated with external beam 
irradiation for breast cancer (Gagliardi 1996; Hurkmans 2002; Muren 2002; Hiatt 2006).  
In this study, we propose to use NTCP calculations from planning CT scans to collect 
data on the potential risk of cardiac complications for hypofractionated versus 
conventionally fractionated radiation. 
 
1.8  
Standardization of IMRT and 3DCRT for WBI 
One of the most important issues concerning IMRT and 3DCRT for breast cancer is the 
accurate definition of target volumes.  Conventional radiation techniques for breast 
cancer have been based solely on clinical palpation of breast tissue and bony chest wall 
anatomy.  In contrast to standard techniques, IMRT and 3DCRT requires a volume-based 
target to create conformal dose distributions.  Since there may be a significant variation 
among physicians regarding the definitions of breast tissue target and regional nodal 
volumes, efforts to define accurately the location of boundaries of the breast tissue and 
lymph nodes are needed.  A consensus committee within the RTOG has developed 
guidelines for the definition of clinical target volumes and normal structures on CT for 
radiation treatment planning.  This atlas will be adopted for the definitions used in 
radiation treatment planning for this study (Li 2009; White 2010). 
 
IMRT will also require the development of acceptance criteria for judging the adequacy of 
any given treatment plan.  Conventional 2D radiation was judged by a single transaxial 
isodose distribution through patient isocenter that under-represented the total breast 
volume or coverage of anatomy on a 2D port film.  IMRT requires standardized 
benchmarks for assessment of dose-volume histograms for coverage of the targeted CT 
breast volumes and exclusion of normal structure volumes, e.g. lung and heart.  Lastly, 
there is considerable variation in what constitutes IMRT in the technical aspects of 
delivery.  Although the limited single institutions’ results of using IMRT for breast cancer 
are promising, acceptable IMRT techniques need to be standardized and validated in a 
multi-institutional setting. 
 
1.9  
Tissue Banking for Future Translational Research 
Blood samples will be banked for correlative studies to identify gene expressions 
predictive of radiation toxicity.  Tumor samples will be banked to correlate genes that may 
be predictive for cancer recurrence, and for use in comparison studies with adjacent 
normal breast tissue to correlate with late toxicity. 
1.9.1 
Single Nucleotide Polymorphisms (Snps) 
Late toxicity from WBI including fibrosis, skin atrophy and telangiectasia can occur in 
up to 20% of cases from standard fractionation (Meric 2002).  Certain treatment factors, 
such as large fraction size, use of bolus and total dose, as well as, patient factors 
including breast size and patient body mass, are well recognized to be associated with 
higher late toxicity rates.  It is a compelling hypothesis that certain genotypes are 
associated with more toxicity from radiation (Ho 2006).  Gene polymorphisms of 

 
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19 
transforming growth factor ß1 (TGF ß1) have been correlated with more severe fibrosis 
in breast cancer patients (Quarmbly 2003; Giotopoulos 2007) although independent 
validation studies are much needed.  We hypothesize that certain gene expressions will 
correlate with individuals who are prone to late toxicity from WBI and/or will have a 
worse/better outcome from hypofractionated regimens.   
 
Although there may be dosimetric explanations or underlying medical conditions 
responsible for the development of acute and chronic normal tissue toxicities following 
radiotherapy for breast cancer, this explanation is not the case for many patients. 
Often, the adverse response is simply ascribed to unknown individual variations, but 
evidence in support of genetic factors being responsible for individual variation in 
radiosensitivity between patients has been obtained (Safwat 2002). The development 
of an in vitro radiosensitivity assay capable of predicting the extent of normal tissue 
damage in radiotherapy patients therefore represents a long sought after goal (Fletcher 
1988). Despite limited success, the effort to achieve this objective continues since an 
assay capable of predicting susceptibility for the development of adverse radiation 
effects would allow customization of radiotherapy protocols on an individual basis. By 
doing so, it has been estimated that a significant improvement in the therapeutic index 
could be achieved (Tucker 1996; Mackay 1999). The goal of this field of research, 
which has been termed “radiogenomics”, is therefore to develop a robust, specific 
assay for cancer patients eligible for radiotherapy to enable individual dose adjustment 
based upon the response of each patient to this test (Tucker 1996; Mackay 1999; 
Mackay 1998; Agren 1990). Of equal importance, knowledge of the genes whose 
alteration is associated with the development of radiation-induced normal tissue 
toxicities may provide important evidence as to the molecular pathways involved in the 
development of these radiation effects.  
 
Substantial work has been performed in recent years in an effort to identify the genetic 
markers associated with an altered response to a standard radiotherapy protocol. 
Single nucleotide polymorphisms (SNPs) represent common genetic alterations found 
in human populations in which an alternate base pair is substituted for the normally 
observed base pair. A widely accepted threshold for a SNP is that the minor allele must 
be present in at least 1% of the population. However, many SNPs are present at a 
lower frequency and are sometimes referred to as rare variants. SNPs occur 
approximately once every 1,000 nucleotides in the human genome. Thus, it is roughly 
estimated that there are approximately 10 million SNPs present in human populations. 
The term “association”, as used in this context, indicates that possession of the minor 
allele for the SNP is associated with either an increase or decrease in the incidence of 
the normal tissue toxicity compared with subjects that harbored the major allele for the 
particular SNP.  
 
The results of approximately 50 candidate gene studies to identify SNPs associated 
with a variety of radiation-induced normal tissue toxicities have been published 
(Andreassen 2009; Barnett 2009; Popanda 2009). Through this work, statistically 
significant associations with SNPs in the following genes with normal tissue toxicities 
following breast radiotherapy have been identified; ABCA1, APE1, ATM, CD44, eNOS, 
GSTA1, GSTP1, IL12RB2, LIG3, MAD2L2, MPO, PTTG1, RAD9A, SOD2, TGFB1, 
TP53, XRCC1 and XRCC3.  
 
It should be noted that among this list of genes, ATM and TGFB1 have been the focus 
of multiple studies, whereas the other genes have been screened in only one or two 
studies. We are therefore proposing a novel “alpha-spending function” approach to the 
statistical analysis of these data for association. Thus, we will test TGFB1 and ATM 
SNPs at a significance level of 0.02. This would provide close to the same power as a 
study targeting just those SNPs in isolation. For the next 16 genes, we will test at the 

 
RTOG 1005; version date December 16, 2021 
 
20 
0.0007 level. Using this data analytic strategy, the total type I (false-positive) error 
probability becomes 5%. 
 
We assume, conservatively, that 1,200 patients will be genotyped. Assume further that 
the prevalence of the genotype of interest is 17% and that the incidence of late toxicity 
is 20% in the non-carriers. Testing at a nominal level of 0.0007 provides 90% power to 
detect an odds ratio of 3.5. Testing at a nominal level of 0.02 provides 90% power to 
detect an odds ratio of 1.9. 
 
Although a series of candidate gene SNP studies has already been performed and 
several genome wide association studies are underway, a significant limit on the 
progress in radiogenomics is the lack of validation studies for SNPs that are identified 
in preliminary studies. Thus, the subjects to be screened in this study serve an 
important purpose as a validation population, the results of which will either act to 
confirm or refute the findings of initial studies.  
 
The subjects in this study will be genotyped using the SNPlex assay which uses the 
Applied Biosystems oligonucleotide ligation assay (OLA) to achieve allelic 
discrimination and target amplification. The chemistry is made possible through the use 
of a set of universal core reagent kits and a set of SNP-specific ligation probes. Each 
assay includes three SNP-specific ligation probes: Two of the probes are allele-specific 
oligos (ASOs). These are designed specifically for the detection of SNPs by having the 
discriminating nucleotide on the 3′ end. Each ASO probe sequence also contains one 
of 96 unique ZipCode™ sequences for ZipChute™ probe binding. The third probe is a 
locus-specific oligo (LSO). Its sequence is common to both alleles of a given locus and 
anneals adjacent to the SNP site on its target DNA. Genotyping will be accomplished 
for the 18 genes listed above for which an association with the development of normal 
tissue toxicity in breast cancer radiotherapy patients has been identified. Since the 
SNPlex assay is more efficiently performed for blocks of 48 SNPs, this total number of 
SNPs will be genotyped in these 18 genes. Thus, 2-3 SNPs will be genotyped for each 
gene, focusing upon the SNPs that initial reports have associated with radiation-
induced effects. 
 
1.9.2  
Breast Cancer Subtyping 
Gene expression profiling by microarray has been increasingly used to develop 
predictive assays and prognostic systems for breast cancer treatment and outcome. An 
example of this is the 21 gene assay (Oncotype Rx) that can predict risk of distant 
metastases and relative chemotherapy benefit in estrogen receptor positive, node 
negative breast cancer patients that undergo anti endocrine therapy (Paik 2004) and 
has recently been shown to predict local failure (Mamounas 2010).  In addition, the use 
of gene expression profiling and hierarchical clustering analyses has led to the 
classification of breast cancer into 5 groups based on patterns in gene expression: 
Luminal A, Luminal B, Basal Like, HER-2 enriched, and Normal like (Sorlie 2001).  
These subtypes have been correlated with distinct clinical phenotypes and to prognosis 
for overall and relapse free survival in various datasets (Sotiriou 2003; Carey 2006). 
The breast cancer subtypes have also been correlated with neoadjuvant chemotherapy 
response, with a higher likelihood of pathologic response associated with the basal-like 
and HER-2 enriched subtypes.  Much less is known for the association of these 
subtypes with local-regional relapse and the interaction with radiation. 
 
Estrogen 
(ER)/progesterone 
(PR) 
receptor, 
HER2, 
and 
cytokeratin 
(CK) 
immunohistochemistry (IHC) have been used as a surrogate for the molecular subtypes 
because of the technical limitations to date of performing microarray expression 
analysis on formalin fixed, paraffin embedded tissue.  The marker combinations that 
are used to match the breast cancer subtypes are:  luminal A:  ER+ and/or PR+, HER2 
-; luminal B: ER+ and/or PR+, HER2 +; basal-like: ER-, PR-, HER2 -, cytokeratin5/6+ 

 
RTOG 1005; version date December 16, 2021 
 
21 
and/or EGFR+; and HER2 enriched: ER-, PR-, HER2 +. Using markers as a surrogate, 
there have been a few studies that have retrospectively examined subtype to identify a 
relationship with local regional relapse demonstrating mixed results: 
 
1) Kyndi, et al. (2008, 2009) reported that breast cancer subtyping was correlated with 
local-regional recurrence. However, this study was in the postmastectomy setting, had 
more advanced stages of disease, and in retrospect suboptimal systemic therapy – all 
factors that limit applicability to the patient population to be included in this study. 
 
2) Millar, et al. (2009) used 5 biomarkers, ER, PR, HER2, CK 5/6 and EGFR IHC as 
surrogates for the intrinsic molecular subtypes to retrospectively examine 498 breast 
cancer patients who had undergone breast conservation therapy to identify any 
relationship with clinical outcomes.  No correlation of subtypes with in-breast cancer 
recurrence was found, but a significant difference was observed for overall survival.  
 
3) Freedman, et al. (2009) also did not find a correlation with local control and basal-
like breast cancer in patients treated with breast conservation including standard 
fractionated radiation. 
 
4) Nguyen, et al. (2008), retrospectively evaluated subtype, using ER, PR, and HER2 
biomarkers as surrogates, in 793 breast cancer patients who had undergone breast-
conserving therapy and found that the basal-like and HER2-enriched subtypes were 
significantly associated with increased rates of in-breast recurrence.   
 
These and other studies have evaluated the impact of intrinsic breast cancer subtype 
only in patients treated with standard radiation fractionation of 2 Gy per day.  A subset 
analysis of the 10 year outcomes from the Ontario Clinical Oncology Group randomized 
trial comparing standard fractionation to hypofractionation revealed that breast cancer 
patients with Grade III histology had significantly worse in-breast cancer recurrence 
rates in the hypo fractionated arm (4.7 % vs. 15.6%) (Whelan 2010). This suggests that 
the alpha/beta ratio and the effect of hypo fractionation may vary across different breast 
cancer cohorts, including intrinsic subtypes. 
 
The development of RT-PCR based approaches that will permit subtyping from paraffin 
embedded specimen blocks, such as the recently reported PAM50 assay that identified 
a 50 gene subset to reliably classify into the previously described 5 breast cancer 
subtypes (Parker 2009), will more readily allow for future analysis for intrinsic subtype 
in studies like this one.  Future correlative studies for this concept include an analysis 
by subtype to evaluate for an association with in-breast cancer recurrence by standard 
versus hypofractionated breast radiation.  Dr Frazer Symmans, breast pathologist and 
expert in this field, will assist with the design and analysis of these future studies using 
the tumor blocks to be submitted. Final design will depend on the number of blocks 
collected as well as the number of events. 
 
1.10  
Breast-Related Symptoms and Side Effects 
We intend to collect patient and physician-reported outcome data for the purpose of 
further understanding the differences in breast-related symptoms and side effects of 
hypofractionation compared to conventional fractionation.  Our hypothesis is that 
cosmetic results and breast-related symptoms 3 years after hypofractionated breast 
radiation with concomitant boost will not be inferior to that obtained 3 years after whole 
breast irradiation with sequential boost 
 
The Breast Cancer Treatment Outcome Scale (BCTOS) assesses symptoms and side 
effects associated with breast cancer treatment.  This tool is also being used in the 
RTOG 0413/NSABP B-39 so will facilitate comparisons with the outcomes from this 
study.  The BCTOS is a 22-item measure of perceived aesthetic (e.g., breast shape) and 

 
RTOG 1005; version date December 16, 2021 
 
22 
functional status (e.g., pain, mobility) after breast-conserving surgical treatment (BCT) 
and radiotherapy (Stanton 2001).  This validated scale was assessed in 185 women who 
underwent BCT and radiotherapy for Stage 0-II disease with 3 months to 18 years of 
follow-up. The BCTOS produced a factor structure with three internally consistent 
subscales (i.e., cosmetic status, functional status, and breast specific pain) that 
demonstrated predictive validity. With patient age, diagnosis duration, and other BCTOS 
subscales controlled, greater breast specific pain predicted greater depressive symptoms 
(P < 0.01) and lower QOL related to mental health (P < 0.05) and physical health (P < 
0.05). Cosmetic status predicted QOL related to physical health (P < 0.05). The relations 
of breast specific pain with QOL indicators varied somewhat as a function of diagnosis 
duration. 
 
Physician reported cosmetic outcome will be assessed using a 4 point scale (Harvard/ 
EORTC).  This scale has been used in prior RTOG studies including the ongoing Phase 
III study (NSABP B-39/RTOG 0413) comparing standard fractionated WBI to PBI. 
 
1.11  
Conclusions 
Prospective randomized trials have established the principle that hypofractionation may 
be used for whole breast radiation with acceptable toxicity and equal local control as 
conventional 50 Gy/ 2 Gy fractionation.  However, numerous questions remain to be 
answered before hypofractionation is accepted for use widely in the United States.   
▪ 
Phase III trials did not consistently employ a boost so that a three-week fractionation 
schedule would be reserved for lower risk or elderly patients felt not to require a 
boost.  Given the lack of data on combining hypofractionation with a boost, 
hypofractionation will not be used in high risk and younger patients in whom a boost 
is felt to be necessary.   
▪ 
There may be selection bias against women with larger breast sizes as well since 
they were not routinely included in hypofractionated trials due to requirements for 
limitation of dose inhomogeneity in treatment plans.   
▪ 
There were a relatively low percentage of patients treated with systemic 
chemotherapy on those trials, which could limit the ability to detect differences in 
complications with hypofractionation.   
▪ 
Data on use of a hypofractionated dose schedule with biological equivalence to the 
cumulative tumor bed dose from the boost is absent from these trials.  A sequential 
boost grafted onto a three-week hypofractionated regimen will only minimally affect 
the time and cost savings. 
▪ 
Phase III trials of hypofractionation have not assessed the long-term risk of cardiac 
toxicity with hypofractionation using NTCP models or long-term clinical follow-up 
beyond 10 years which is needed to observe differences in cardiac morbidity and 
mortality.   
 
To address this issue, the American Society of Radiation Oncology convened a task 
force of experts to make recommendations for fractionation of whole breast irradiation 
(WBI). After a review of the current literature, there was consensus that hypo-fractionated 
(HF) WBI is suitable in the following patients:  breast cancer patients with pT1-2, N0 
disease, >50 years old who do not receive chemotherapy. In regards to boost the task 
force concluded: “There were few data to define the indications for and toxicity of a tumor 
bed boost in patients treated with HF-WBI …. The task force agreed that the use of HF-
WBI alone (without a boost) is not appropriate when a tumor bed boost is thought to be 
indicated. When a boost is indicated, there was lack of consensus regarding the 
appropriateness of HF-WBI (Smith 2010).” 
 
The current study proposes to establish a hypofractionation schedule (with a concurrent 
boost) that delivers a dose in only 3 weeks that can be applied to a broader patient 
population than enrolled in the existing hypofractionation studies (high-risk, large 
breasted, and those requiring chemotherapy) seen routinely in everyday practice.  Patient 

 
RTOG 1005; version date December 16, 2021 
 
23 
inclusion criteria will be defined to include patients at higher than average risk for local 
recurrence who could most benefit from the addition of a tumor bed boost - age < 50 
years (even with DCIS), node positive breast cancer, lymphovascular space invasion, 
presence of an EIC with close (< 2mm) resection margins, focally positive margins, 
and/or non-hormone sensitive breast cancer.  If the proposed regimen were proven to 
provide equivalent low control even in these higher-risk patients, the impact on the 
treatment of the majority of breast cancer patients would be practice changing. 
 
The study also develops standards and tests the efficacy (for the first time for breast 
cancer) of clearly defined anatomic targets (employs the RTOG breast atlas), 3D-
conformal external beam radiation therapy and IMRT.  NTCP calculations will be used to 
assess differences in cardiac risk with hypofractionation versus conventional 2 Gy 
fractionation.  Exploratory correlative studies will include genes predictive of outcomes 
(efficacy and toxicity) related to radiation treatment, and the effects of hypofractionation 
and IMRT on health economic outcomes. 
 
2.0 OBJECTIVES 
2.1 
Primary 
 
 
To determine whether an accelerated course of hypofractionated WBI including a 
concomitant boost to the tumor bed in 15 fractions following lumpectomy will prove to be 
non-inferior in local control to a regimen of standard WBI with a sequential boost 
following lumpectomy for early-stage breast cancer patients. 
 
2.2 
Secondary 
2.2.1 
To determine whether breast-related symptoms and cosmesis from accelerated WBI 
that is hypofractionated (in only 3 weeks) with a concomitant boost is non-inferior to 
standard WBI with sequential boost; 
2.2.2 
To determine whether the risk of late cardiac toxicity in patients with left-sided breast 
cancer treated with hypofractionation will be non-inferior to conventional fractionated 
RT based upon analysis of radiation dosimetry from CT-based treatment planning and 
NTCP calculations; 
2.2.3 
To determine whether CT-based conformal methods IMRT and 3DCRT for WBI are 
feasible in a multi-institutional setting following lumpectomy in early-stage breast 
cancer patients and whether dose-volume analyses can be established to assess 
treatment adequacy and likelihood of toxicity; 
2.2.4 
To determine that cosmetic results and breast-related symptoms 3 years after 
hypofractionated breast radiation with concomitant boost will not be inferior to that 
obtained 3 years after whole breast irradiation with sequential boost; 
2.2.5  
To determine whether future correlative studies can identify individual gene 
expressions and biological host factors associated with toxicity and/or local recurrence 
from standard and hypofractionated WBI; 
2.2.6 
If shown to be non-inferior, to then determine if accelerated course of hypofractionated 
WBI including a concomitant boost to the tumor bed in 15 fractions following 
lumpectomy will prove to be superior in local control to a regimen of standard WBI with 
a sequential boost following lumpectomy for early-stage breast cancer patients; 
2.2.7 
To determine whether treatment costs for hypofractionated WBI with concomitant boost 
are not higher than that for WBI with sequential boost. 
 
3.0 PATIENT SELECTION  
 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
3.1 
Conditions for Patient Eligibility (10/21/13) 
For questions concerning eligibility, please contact  the study data manager 
3.1.1 
Pathologically proven diagnosis of breast cancer resected by lumpectomy and whole 
breast irradiation with boost without regional nodal irradiation planned 
3.1.2 
The patient must be female 

 
RTOG 1005; version date December 16, 2021 
 
24 
3.1.3 
The patient must meet at least one of the three following criteria: 
 
A. pStage I, II Breast Cancer AND at least one of the following: 
▪ 
Age < 50 years or 
▪ 
Positive axillary nodes or 
▪ 
Lymphovascular space invasion or 
▪ 
2 or more close resection margins (> 0 mm to ≤ 2 mm) or 
▪ 
1 close resection margin and extensive intraductal component (EIC) [Per 
College of American Pathologist (CAP) Recommendation] or 
▪ 
Focally positive resection margins or 
▪ 
Non-hormone sensitive breast cancer (ER and PR-negative) or 
▪ 
Grade III histology or 
▪ 
Oncotype recurrence score > 25 or 
 
B. pStage 0 breast cancer with nuclear grade 3 DCIS and patient age <50 years or 
 
C. ypStage 0, I, II breast cancer resected by lumpectomy after neoadjuvant systemic 
therapy 
3.1.4 
Study entry must be within 50 days from whichever comes later: last surgery (breast or 
axilla) or last chemotherapy NOTE: The day of surgery is Day “0” 
3.1.5 
If multifocal breast cancer, then it must have been resected through a single 
lumpectomy incision with negative margins 
3.1.6 
Breast-conserving surgery with margins defined as follows: (also see 3.1.3 for 
eligibility) 
▪ 
Negative margins defined as no tumor at the resected specimen edge.   
▪ 
Close resection margins > 0 mm to ≤ 2 mm. as follows:  
▪ 
One close resection margin and EIC (per College of American 
Pathologist (CAP) Recommendation) 
▪ 
 2 or more close resection margins. 
▪ 
A focally positive resection margin 
3.1.7 
For invasive breast cancer the axilla must be staged by one of the following: 
▪ 
Sentinel node biopsy alone (if sentinel node is negative, pN0, pN0(IHC-,+)); 
▪ 
Sentinel node biopsy alone, OR followed by axillary node dissection per 
investigator discretion, for clinically node negative patients as described below: 
o 
microscopic sentinel node positive (pN1mic) 
o 
one or two sentinel nodes positive (pN1) without extracapsular 
extension 
o 
negative sentinel node biopsy after neoadjuvant chemotherapy 
▪ 
Axillary node dissection is required following sentinel node biopsy with a 
minimum total of 6 axillary nodes if any of the following exist: 
o 
for > 2 positive SN 
o 
any positive SN biopsy after neoadjuvant chemotherapy 
o 
for clinically (by either imaging or examination) T3 disease 
o 
for extracapsular extension 
▪ 
Axillary dissection alone (with a minimum of 6 axillary nodes) 
3.1.8 
Age ≥ 18 
3.1.9 
CT-imaging of the ipsilateral breast within 28 days prior to study entry for the radiation 
treatment planning. Must be able to delineate on CT scan the extent of the target 
lumpectomy cavity for boost  
3.1.10 
Appropriate stage for protocol entry, including no clinical evidence for distant 
metastases, based upon the following minimum diagnostic workup:  
▪ History/physical examination, including breast exam (inspection and palpation of 
the breasts) and documentation of weight and Zubrod Performance Status of 0-
2 within 28 days prior to study entry; 
▪ Right and left mammography within 90 days of diagnostic biopsy establishing 
diagnosis   
3.1.11 
Patients must have had ER analysis performed on the primary breast tumor prior to 
study entry according to current ASCO/CAP Guideline Recommendations for hormone 
receptor testing.  If negative for ER, assessment of PgR must also be performed 

 
RTOG 1005; version date December 16, 2021 
 
25 
according to current ASCO/CAP Guideline Recommendations for hormone receptor 
testing (http://www.asco.org) 
3.1.12 
CBC/differential obtained within 14 days prior to study entry, with adequate bone 
marrow function defined as follows: 
▪ Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3 
▪ Platelets ≥ 75,000 cells/mm3 
▪ Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8.0 g/dl is acceptable.) 
3.1.13 
Women of childbearing potential must have a negative urine or serum pregnancy test 
within 14 days of study entry  
3.1.14 
Women of childbearing potential must be non-pregnant and non-lactating and willing to 
use medically acceptable form of contraception during radiation therapy 
3.1.15 
Patient must provide study specific informed consent prior to study entry 
3.1.16 
Breast implants allowed 
 
3.2 
Conditions for Patient Ineligibility (5/6/2013) 
3.2.1 
AJCC pathologic T4, N2 or N3, M1 pathologic stages III or IV breast cancer 
3.2.2 
Treatment plan that includes regional node irradiation 
3.2.3 
Prior invasive non-breast malignancy (except non-melanomatous skin cancer, 
carcinoma in situ of the cervix) unless disease free for a minimum of 5 years prior to 
study entry 
3.2.4 
Prior invasive or in-situ carcinoma of the breast (-prior LCIS is eligible) 
3.2.5 
Two or more breast cancers not resectable through a single lumpectomy incision 
3.2.6 
Bilateral breast cancer 
3.2.7 
DCIS only (without an invasive component) and age ≥ 50 years 
3.2.8 
DCIS nuclear grade 1 or 2 only (without an invasive component) and age < 50 years  
3.2.9 
Invasive breast cancer and low risk for 5-year in breast recurrence after lumpectomy 
with negative margins that does not meet one of the eligibility factors in 3.1.3. 
3.2.10 
Unable to delineate on CT scan the extent of the target lumpectomy cavity for boost 
(Placement of surgical clips to assist in treatment planning of the boost is strongly 
recommended, see Section 6.4.2 for details) 
3.2.11 
Suspicious unresected microcalcification, densities, or palpable abnormalities (in the 
ipsilateral or contralateral breast) unless biopsied and found to be benign 
3.2.12 
Non-epithelial breast malignancies such as sarcoma or lymphoma 
3.2.13 
Paget’s disease of the nipple 
3.2.14 
Male breast cancer 
3.2.15 
Prior radiotherapy to the breast or prior radiation to the region of the ipsilateral breast 
that would result in overlap of radiation therapy fields 
3.2.16 
Intention to administer concurrent chemotherapy for current breast cancer. 
3.2.17 
Severe, active co-morbidity, defined as follows: 
▪ 
Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months 
▪ 
Transmural myocardial infarction within the last 6 months 
▪ 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
▪ 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days before 
registration;  
▪ 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, 
however, that laboratory tests for liver function and coagulation parameters are not 
required for entry into this protocol 
▪ 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; 
note, however, that HIV testing is not required for entry into this protocol. The need 
to exclude patients with AIDS from this protocol is necessary because the 
treatments involved in this protocol may be significantly immunosuppressive 

 
RTOG 1005; version date December 16, 2021 
 
26 
3.2.18 
Pregnancy or women of childbearing potential who are sexually active and not 
willing/able to use medically acceptable forms of contraception 
3.2.19 
Active systemic lupus, erythematosus, or any history of scleroderma, dermatomyositis 
with active rash 
3.2.20 
Medical, psychiatric or other condition that would prevent the patient from receiving the 
protocol therapy or providing informed consent 
  
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT   
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment 
that do not affect eligibility. It is assumed that standard clinical judgment will be used to work-up 
patients who have physical or laboratory findings suggestive of metastatic disease, and 
appropriate evaluation will be performed as indicated.  Patients with metastatic disease are not 
eligible for protocol participation. 
 
4.1 
Required Evaluations/Management (5/6/2013) 
 
Note: that failure to perform one or more of these tests may result in assessment of a 
protocol violation.  
4.1.1 
For patients who have consented to participate in the Cosmesis/Quality of Life portion 
of the study, forms and photographs must be submitted (see Sections 11.0 and 12.0) 
4.1.2 
Bone scan (with plain film correlation if needed) for patients with invasive breast cancer 
when clinically warranted based on symptoms, and either abnormal physical 
examination, or abnormal (out of the normal reference range of the local site) alkaline 
phosphatase level within 180 days prior to study entry or within 90 days of last surgery 
(lumpectomy + axillary surgery) or initiation of neoadjuvant chemotherapy.  
4.1.3 
CT scans of the chest, abdomen and pelvis, or PET/CT when clinically warranted for 
patients with invasive breast cancer and new/unusual chest or abdominal symptoms, 
abnormal physical examination, or abnormal (out of the normal reference range of the 
local site) liver function tests within 180 days prior to study entry or within 90 days of 
last surgery (lumpectomy + axillary surgery) or initiation of neoadjuvant chemotherapy.   
4.1.4 
Chemistry panel that must include AST, ALT, alkaline phosphatase and bilirubin within 
14 days prior to study entry  
 
4.2 
Recommended Evaluations/Management (5/6/2013) 
4.2.1 
Bone scan (with plain film correlation if needed) is recommended but not required for 
patients with positive nodes within 180 days prior to study entry or within 90 days of last 
surgery (lumpectomy + axillary surgery) or initiation of neoadjuvant chemotherapy 
 
4.2.2  
Negative post-excision 
mammogram for patients with malignancy-associated 
calcifications after lumpectomy within 180 days prior to study entry 
 
5.0 REGISTRATION PROCEDURES (10/21/13) 
 
Access requirements for OPEN and TRIAD: 
 
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and 
Access Management (IAM) account. This is the same account (user id and password) used for 
the CTSU members' web site. To obtain an active CTEP-IAM account, go to https://eapps-
ctep.nci.nih.gov/iam.  
 
Note: See below for information on installing TRIAD for submission of digital RT data prior 
to enrolling patients 
 
5.1 
Pre-Registration Requirements for IMRT / 3D-CRT Treatment Approach (10/21/13) 
5.1.1 
In order to utilize either 3D-CRT or IMRT on this study, the institution must have met 
specific technology requirements and have provided baseline physics information. 
Instructions for completing these requirements are available on the Imaging and 
Radiation Oncology Core (IROC) Houston web site.  Visit 
http//irochouston.mdanderson.org and select “Credentialing”. 

 
RTOG 1005; version date December 16, 2021 
 
27 
 
 
This study will require each institution to complete a Benchmark case for credentialing.  
This applies for both the 3D-CRT and IMRT treatment modalities. The Benchmark case 
is a treatment planning exercise.  CT scans for each case will be made available for 
downloading from the  IROC Houston website (http//irochouston.mdanderson.org), and 
the institution is expected to use this dataset to demonstrate their ability to generate an 
acceptable dose distribution.  The CT datasets will include contours of the breast tissue 
together with contours of the boost volume.  The planning results will be submitted 
electronically via TRIAD for review. The results of this planning exercise will be 
examined and approved by the protocol Study Chairs before the first patient can be 
entered from a particular institution.  Upon successful completion and approval of the 
Benchmark case, IROC Philadelphia will notify the institution that they have completed 
this requirement. 
5.1.2 
The institution or investigator must complete a Facility Questionnaire or modify their 
existing questionnaire (on file at  IROC Philadelphia) and send it to IROC Philadelphia  
for review prior to entering any cases. The Facility Questionnaire can be found at the 
IROC Houston website (http//irochouston.mdanderson).  Updating an existing Facility 
Questionnaire can be accomplished by contacting:  IROC Philadelphia: 215-574-3219. 
In order to submit the benchmark credentialing case and all digital data for registered 
patients, the institution must have an IRB approval.  When submitting to TRIAD, select 
“Clinical Trials (NCI Oncology)”, then select “Benchmark” for submission type. IROC 
Philadelphia will notify the institution when all requirements have been met and the 
institution is RT credentialed to enter patients onto this study. 
 
5.2 
Digital RT Data Submission to RTOG Using TRIAD (10/21/13) 
TRIAD, the American College of Radiology’s (ACR) image exchange application, will be 
used for dosimetry digital treatment data.  
TRIAD Access Requirements: 
• 
Site physics staff who will submit images through TRIAD will need to be 
registered with The Cancer Therapy Evaluation Program (CTEP) and have a 
valid and active CTEP Identity and Access Management (IAM) account. Please 
refer to Section 5.0 of the protocol for instructions on how to request a CTEP-IAM 
account. 
• 
To submit images, the site physics user must have been assigned the 'TRIAD 
site user' role on the relevant Group or CTSU roster. NRG Oncology users 
should contact your site Lead RA to be added to your site roster.  Users from 
other cooperative groups should follow their procedures for assignment of roster 
roles. 
• 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be found on the NRG 
Oncology/RTOG website Core lab tab.    
 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password. 
 
If you have any questions regarding this information, please send an e-mail to the TRIAD 
Support mailbox at TRIAD-Support@acr.org. 
 
5.3 
Regulatory Pre-Registration Requirements (10/21/13) 
5.3.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 

 
RTOG 1005; version date December 16, 2021 
 
28 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.    Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the 
annual submission of a complete investigator registration packet (FDA Form 1572 with 
original signature, current CV, Supplemental Investigator Data Form with signature, 
and Financial Disclosure Form with original signature) to the Pharmaceutical 
Management Branch, CTEP, DCTD, NCI.  These forms are available on the CTSU 
registered member web site or by calling the PMB at 240-276-6575 Monday through 
Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
 
Requirements for RTOG 1005 site registration: 
 
Sites must be credentialed for either the IMRT or 3D-CRT Treatment Approaches.  
Please see protocol section 5.1 for details. 
 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
• 
CTSU RT Facilities Inventory Form (if applicable) 
 
NOTE: Per NCI policy all institutions that participate on protocols with a radiation 
therapy component must participate in the IROC Houston monitoring program.  For 
non-lead group institutions an RT Facilities Inventory From must be on file with CTSU.  
If this form has been previously submitted to CTSU it does not need to be resubmitted 
unless updates have occurred at the RT facility. 
5.3.2  
In addition to the requirements noted above, ALL institutions must fax copies of 
the documentation below to the CTSU Regulatory Office (215-569-0206); study-related 
regulatory 
documentation 
also 
may 
be 
e-mailed 
to 
the 
CTSU 
at 
CTSURegulatory@ctsu.coccg.org. This must be done prior to registration of the 
institution’s first case: 
▪ 
IRB/REB approved consent (English and native language versions*) 
*Note: Institutions must provide certification/verification of IRB/REB consent 
translation to NRG Oncology Headquarters (described below). 
▪ 
IRB/REB assurance number renewal information as appropriate. 
 
Non-English Speaking Canadian and Non-North American Institutions 
Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be 
provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved NRG Oncology will accept, at a minimum, a 
verified translation. A verified translation consists of the actual REB approved consent 
document in English and in the native language, along with a cover letter on 
organizational/letterhead stationery that includes the professional title, credentials, and 
signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and 
credentials of the neutral third party translator must be specified as well. 
5.3.3 
Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
 
 
For institutions that do not have an approved LOI for this protocol: 

 
RTOG 1005; version date December 16, 2021 
 
29 
International sites must submit an LOI to RTOG Headquarters to receive approval to 
participate in this trial. 
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to 
enrolling patients to this study. 
 
5.4 
OPEN Registration (10/21/13) 
5.4.1 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. All site 
staff will use OPEN to enroll patients to this study.  OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
  
• All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the group or CTSU web site 
as a tool to verify eligibility. 
• All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable).  
  
Access requirements for OPEN: 
 
▪ 
See Section 5.0 for obtaining a CTEP-IAM account. 
▪ 
To perform registrations, the site user must have been assigned the 'Registrar' 
role on the relevant Group or CTSU roster.  
▪ 
To perform registrations on protocols for which you are a member of the Lead 
Group, you must have an equivalent 'Registrar' role on the Lead Group roster.  
Role assignments are handled through the Groups in which you are a member  
▪ 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations) you must have the role of Registrar on the CTSU 
roster. Site and/or Data Administrators can manage CTSU roster roles via the 
new Site Roles maintenance feature under RSS on the CTSU members' web 
site. This will allow them to assign staff the "Registrar" role.  
 
NOTE: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your records.  
  
Further instructional information is provided on the open tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  
For any additional questions contact the CTSU help desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
5.4.2 
In the event that the OPEN system is not accessible, participating sites can contact 
web support for assistance with web registration: websupport@acr.org or call the 
Registration Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. 
ET. The registrar will ask the site to fax in the eligibility checklist and will need the 
registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration 
system (e.g. drug shipment and confirmation of registration) will occur.  
 

 
RTOG 1005; version date December 16, 2021 
 
30 
6.0 RADIATION THERAPY 
 
NOTE:  RAPID REVIEWS AND TIMELY REVIEWS ARE REQUIRED. RAPID REVIEWS NEED 
3 BUSINESS DAYS FOR PROCESSING.  SEE SECTION 6.8.2 
 
This trial is not utilizing the services of the ITC for dosimetry digital treatment data 
submission. See Section 5.2 for information on installing TRIAD for submission of digital 
RT data prior to enrolling patients. 
 
NOTE: Please see Appendix V for Contouring Guidelines and Appendix VI for DVH 
Constraints 
 
NOTE: Radiation therapy must begin within 9 weeks of last surgery or chemotherapy delivery 
 
6.1 
Dose Specifications 
6.1.1 
(Arm I) Standard Whole Breast Irradiation with Sequential Boost 
 
Breast: 50 Gy in 25 fractions of 2 Gy.  Optional: 42.7 Gy in 16 fractions of 2.67 Gy  
 
Lumpectomy Cavity: Total dose will be 12 Gy in 6 fractions or 14 Gy in 7 fractions 
per institutional discretion.  
6.1.2 
(Arm II) Hypofractionated Whole Breast Irradiation with Concurrent Boost 
 
Breast: 40.0 Gy in 15 fractions of 2.67 Gy fractions per day.   
 
Lumpectomy Cavity: Total dose of 48.0 Gy in 15 fractions of 3.2 Gy fractions per 
day.   
 
6.2 
Technical Factors  
6.2.1 
The guidelines for IMRT in this trial will conform to the policies set by the Advanced 
Technology Consortium (ATC) and the National Cancer Institute (NCI) 
(http://atc.wustl.edu/home/NCI/NCI_IMRT_Guidelines.html) 
6.2.2 
Each of the target volumes and normal structures listed below must be delineated on 
each slice from the 3D planning CT in which that structure exists. 
6.2.3 
Megavoltage photon beams with energies ≥ 6 MV and megavoltage electron beams 
are required.  Proton beams are not allowed. 
 
6.3 
Localization, Simulation, and Immobilization 
6.3.1 
Simulation and treatment may be performed with the patient in the supine or prone 
position. 
6.3.2 
Patients should be optimally positioned with alpha cradle casts, breast boards, wing 
boards and/ or other methods of immobilization at the discretion of the treating 
physician. 
6.3.3 
Methods to minimize the cardiac exposure to RT like heart block, gating or breathhold 
are allowed at the discretion of the treating physician  
6.3.4 
For large-breasted patients, including those with a large inframammary skin fold, 
devices to improve positioning of the breast are permissible. 
6.3.5 
A treatment planning CT scan in the treatment position will be required to define the 
clinical target volumes (CTV) and planning target volumes (PTV). 
▪ 
The CT required for generation of a virtual plan with 3DCRT or IMRT must be post-
lumpectomy  
▪ 
Radio-opaque markers must be placed on external landmarks at the acquisition of 
the CT scan to facilitate contouring segmentation of the CT data-set.  These 
markers should identify:  1) The lumpectomy incision 2) The outline of the palpable 
breast tissue circumferentially at least from 2 o’clock to 10 o’clock   3) The superior 
border of the breast tissue at 12 o’clock based on palpation.  Additional markers to 
define the borders of “clinical” tangent fields (e.g. based on the palpable breast 
tissue and boney landmarks) are often helpful. 
▪ 
The CT should extend cephalad to start at or above the mandible and extend 
sufficiently caudally (or inferiorly) to the inframammary fold to encompass the entire 
lung volume.  A CT scan image thickness of ≤ 0.5 cm should be employed. 

 
RTOG 1005; version date December 16, 2021 
 
31 
6.3.6 
External skin localizing marks, which may include permanent tattoos, are 
recommended for radiation daily localization and set-up accuracy. 
6.3.7 
For obese patients: while every effort should be made to include the full external 
contour in the planning CT, it is permissible to use CT with cutoff of a portion of the 
body image due to the limited field-of-view of the CT scanner only if: (1) the treated 
breast is fully included in the CT, (2) no treatment beam goes through the cutoff 
portion, and (3) maximum doses in cutoff  normal structures (e.g., contralateral lung, 
contralateral breast) can still be evaluated. 
 
6.4 
Treatment Planning/Target Volumes (10/21/13) 
6.4.1 
The definitions for the CTV, PTV and normal structures used in this protocol generally 
conform to the RTOG-endorsed consensus guidelines for delineation of target and 
normal 
structures 
for 
breast 
cancer 
(http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx) 
  
and the 1993 ICRU report #50: Prescribing, Recording and Reporting Photon Beam 
Therapy. 
6.4.2 
Target Volumes and Normal Structures 
 
Lumpectomy volumes: 
 
Lumpectomy GTV: Contour using all available clinical and radiographic 
information    including the excision cavity volume, architectural distortion, 
lumpectomy scar, seroma and/or extent of surgical clips (clips are strongly 
recommended).  Patients without a clearly identifiable lumpectomy bed are not 
eligible for protocol participation. 
 
Lumpectomy CTV: Lumpectomy GTV + 1 cm, 3D expansion.  Limit the CTV 
posteriorly at   anterior surface of the pectoralis major and anterolaterally 5 mm 
from skin and should not cross midline. In general, the pectoralis and/or serratus 
anterior muscles are excluded from the lumpectomy CTV unless clinically 
warranted by the patient’s pathology. 
 
 
Lumpectomy PTV: Lumpectomy CTV + 7 mm 3D expansion (excludes heart). 
 
Lumpectomy PTV Eval: Since a substantial part of the Lumpectomy PTV often 
extends outside the patient (especially for superficial cavities), the Lumpectomy 
PTV is then copied to a Lumpectomy PTV Eval which is edited. This 
Lumpectomy PTV EvaL is limited to exclude the part outside the ipsilateral breast 
and the first 5 mm of tissue under the skin (in order to remove most of the 
buildup region for the DVH analysis) and excluding the Lumpectomy PTV 
expansion beyond the posterior extent of breast tissue (chest wall, pectoralis 
muscles and lung) when pertinent. The lumpectomy PTV should not cross 
midline.  This Lumpectomy PTV Eval is the structure used for DVH constraints 
and analysis. This Lumpectomy PTV Eval cannot be used for beam aperture 
generation. 
 
 
Breast volumes: 
 
Breast CTV. Includes the palpable breast tissue demarcated with radio-opaque 
markers at CT simulation (see section 6.3), the apparent CT glandular breast 
tissue visualized by CT, consensus definitions of anatomical borders, and the 
Lumpectomy CTV from the breast cancer atlas (section 6.4).  The breast CTV is 
limited anteriorly within 5 mm from the skin and posteriorly to the anterior surface 
of the pectoralis, serratous anterior muscle excluding chestwall, boney thorax 
and lung. In general, the pectoralis and/or serratous anterior muscles are 
excluded from the breast CTV unless clinically warranted by the patient’s 
pathology. The breast CTV should generally follow consensus guidelines 
(http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.asp) 
Breast PTV:  Breast CTV + 7 mm 3D expansion (exclude heart and do not cross 
midline. 
 
Breast PTV Eval: Since a substantial part of the Breast PTV often extends 
outside the patient, the Breast PTV is then copied to a Breast PTV Eval which is 

 
RTOG 1005; version date December 16, 2021 
 
32 
edited. This Breast PTV Eval is limited anteriorly to exclude the part outside the 
patient and the first 5 mm of tissue under the skin (in order to remove most of the 
build up region for the DVH analysis) and posteriorly is limited no deeper to the 
anterior surface of the ribs (excludes boney thorax and lung). This Breast PTV 
Eval is the structure used for DVH constraints and analysis. This Breast PTV 
Eval cannot be used for beam aperture generation. 
 
 
 
Contralateral breast  
 
Includes the apparent CT glandular breast tissue visualized by CT and consensus 
definitions of anatomical borders from the RTOG Breast Atlas.  In general the 
borders are: 
 
• 
Posterior border: At the anterior surface of the pectoralis, serratous 
anterior muscles excluding chestwall, ribs, boney thorax and lung/heart;  
• 
Medial border: The sternal-costal junction, 
• 
Lateral border: Varies based on the size of the breast but typically is at 
the mid-axillary line and excludes the ipsilateral lattismus dorsi muscle.   
• 
Cephald border:   Should be similar to that of the ipsilateral breast CTV 
• 
Caudal border:  Inframammary fold and should be similar to that of the 
ipsilateral breast CTV.  
• 
Anterior border:  Skin minus 5 mm to minimize inaccuracy of dose 
calculation at the skin surface. 
 
Refer to the breast contouring atlas:  
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx 
 
 
Ipsilateral lung. This may be contoured with auto-segmentation with manual 
verification. 
 
Contralateral lung. This may be contoured with auto-segmentation with manual 
verification 
 
Heart 
 
This is to be contoured on all cases- not just the left sided cases. The heart should 
be contoured beginning just inferior to the level in which the pulmonary trunk 
branches into the left and right pulmonary arteries (PA). Above the PA, none of the 
heart’s 4 chambers are present. The heart should be contoured on every contiguous 
slice thereafter to its inferior most extent near the diaphragm.  The following 
structures if identifiable should be excluded from the heart contour: esophagus, 
great vessels (ascending and descending aorta, inferior vena cava).  One need not 
include pericardial fat, if present. Contouring along the pericardium itself, when 
visible, is appropriate.   
 
Thyroid 
 
The thyroid is easily visible on a non-contrast CT due to its preferential absorption of 
Iodine, rendering it “brighter” or denser than the surrounding neck soft tissues. The 
left and right lobes of the thyroid are somewhat triangular in shape and often do not 
converge anteriorly at mid-line.  All “bright” thyroid tissue should be contoured. 
6.4.3 
Treatment Planning 
 
CT-based planning with tissue inhomogeneity correction is required 
 
IMRT or 3D-CRT are permitted 
The following definitions and conditions are applied concerning IMRT in this 
protocol: 
 
1. The treatment plan will be considered IMRT for the purposes of this 
protocol if an inverse planned optimization is used to determine the 
beam weights and apertures to meet the target and critical structure 
dose-volume constraints.  

 
RTOG 1005; version date December 16, 2021 
 
33 
 
2. The plan generated by direct aperture optimization that employs an 
inverse planning algorithm is considered as IMRT when the target and 
critical structure dose-volume constraints are met and at least 3 
apertures for each beam direction are used. 
 
3. If IMRT is combined with the standard open medial and lateral tangential 
fields for whole breast irradiation, the IMRT beam as defined in (1) above 
should deliver > 50% of the total number of monitor units for the beam 
orientation. 
 
4. Simultaneous integrated boost to deliver whole breast and boost doses 
at the same time with IMRT is allowed in ARM II. 
 
5. If an IMRT plan is used with another IMRT plan, forward-planning photon 
beams, and/or electron beam, the 3D composition dose distribution and 
DVHs should be generated.  
 
6. All standard IMRT planning and delivery systems using MLC (step-and-
shoot, dynamic MLC, slide-and-shoot, VMAT, tomotherapy) are allowed 
and classified as IMRT as long as target and critical structure dose-
volume constraints are met. 
 
7. IMRT planning and delivery systems using physical beam-intensity 
compensators designed by an inverse algorithm to modulate beam 
intensity so that the required dose constraints are met are also accepted 
as IMRT. 
 
8. The patient specific pre-treatment QA measurement is required prior to 
the first treatment for an IMRT plan.  
 
All plans that are not fit into the above definitions and conditions are classified as 
3D-CRT plans. Specifically: 
▪ 
The plans generated using forward-planning methods or segmental 
techniques such as “field-in-field” to meet dose-volume constraints are 
considered as 3D-CRT plans. These forward-planned or segmental 
treatment techniques are those intended to mainly improve the uniformity 
of the dose distribution, but not to produce steep dose gradients to 
protect critical structures (e.g., heart or lung). 
▪ 
The plans with the number of apertures < 3 for each beam direction are 
considered 3DCRT plans even if they were generated with inverse 
planning algorithms.  
 
 
Whole Breast Radiation Therapy 
The breast PTV is used to generate the beam apertures with an additional margin to 
take into account penumbra.  Fields should include all of the breast PTV and boost 
PTV.  The aperture margin generally needed beyond the PTV is 5 mm.  The goals of 
treatment planning are to encompass the breast PTV and minimize inclusion of the 
heart and lung.   
 
Field arrangements for 3D conformal and IMRT of the Breast PTV are at the 
discretion of the treating physician.  Multiple beam arrangements are to be designed 
during the treatment planning process to produce an optimal plan that meets the 
dose-volume constraints on the Breast PTV and normal tissues outlined below 
 
 
Boost Radiation Therapy 

 
RTOG 1005; version date December 16, 2021 
 
34 
The lumpectomy boost may be given by either electron beam or photon beams 
using either 3D-CRT or IMRT. A composite dose distribution and DVHs that include 
whole breast irradiation using either IMRT or 3D-CRT and lumpectomy cavity boost 
using electron beams, IMRT or 3D-CRT must be provided for review. Simultaneous 
integrated boost using IMRT is allowed in ARM II.   
 
Boost radiation must be planned from the initial CT for radiation planning.  Changes 
in patient positioning for the boost are not allowed.  The table position may move to 
optimize electron beam radiation. 
 
Brachytherapy boost is not allowed.  
 
In Arm I the boost will begin without a treatment break after completion of the 
treatment to the entire breast. 
 
If electron boost is used, there must be adequate dosimetric coverage of the 
lumpectomy PTV eval.  
 
Field arrangements for 3D-CRT and IMRT boosts are at the discretion of the treating 
physician. Multiple beam arrangements are to be designed during the treatment 
planning process to produce an optimal plan that meets the dose-volume constraints 
on the Lumpectomy PTV and normal tissues as outlined below. 
 
 
Treatment plans must meet Dose Volume Constraints (Section 6.4.3) for the 
contoured targets and normal structures (Section 6.4.2).  Various treatment 
approaches may be used to develop treatment plans and a composite plan 
combining WBI and boost plans must be generated. 
 
 
a. Approaches for ARM 1 Standard Whole Breast Irradiation (WBI) with sequential 
boost include: 
 
i. 3DCRT WBI with 3DCRT sequential boost 
ii. 3DCRT WBI with IMRT sequential boost 
iii. 3DCRT WBI with electron sequential boost 
iv. IMRT WBI with 3DCRT sequential boost 
v. IMRT WBI with IMRT sequential boost 
vi. IMRT WBI with electron sequential boost 
 
b. Approaches for ARM 2 Hypofractionated Whole Breast Irradiation with 
concurrent boost include: 
vii. 3DCRT WBI with 3DCRT concurrent boost 
viii.3DCRT WBI with IMRT concurrent boost 
ix. 3DCRT WBI with electron concurrent boost 
x. IMRT WBI with 3DCRT concurrent boost 
xi. IMRT WBI with IMRT concurrent boost 
xii. IMRT WBI with electron concurrent boost 
xiii.IMRT WBI with IMRT simultaneously integrated boost (SIB) 
 
NOTE: For Approach xiii (SIB), only one plan integrating both WBI and boost is 
generated. For all other approaches, two plans (one for WBI and another for boost) 
are generated 
 
 
Dose-volume histogram (DVH) analysis is required 
 
(See Appendix VI for summary table of dose volume constraints) 
 

 
RTOG 1005; version date December 16, 2021 
 
35 
For both ARM I and ARM II, the treatment plan for the whole breast and boost must 
be done prior to the start of radiation and meet the following dose-volume 
constraints defined below.  
All maximum doses should be defined in one dose calculation voxel, e.g., 3x3x3 
mm3. 
The conformity index is an optional constraint, but must be recorded and reported 
on all cases. All submitted DVHs will be evaluated for compliance with these 
parameters: 
 
 
ARM I Standard Whole Breast Irradiation with Sequential boost 
Breast PTV Eval:  
▪ 
Per Protocol: At least 95% of the breast PTV Eval will receive at least 95% 
(47.5 Gy) of the whole breast prescribed dose of 50 Gy (or 40.6 Gy if 
hypofractionation whole breast fractionation used).   
Variation Acceptable: At least 90% of the breast PTV Eval will receive at 
least 90% (45 Gy) of the whole breast prescribed dose of 50 Gy (or 38.4 Gy 
if hypofractionation whole breast fractionation used). 
▪ 
Per Protocol: No more than 30% of the breast PTV Eval will exceed 100% of 
the boost prescribed dose of 62-64 Gy (or 54.7-56.7 Gy if hypofractionated 
whole breast fractionation used).   
Variation Acceptable: No more than 35% of the breast PTV Eval will receive 
≥ 100% of the boost prescribed dose of 62-64 Gy (or 54.7-56.7Gy if 
hypofractionated whole breast fractionation used). 
▪ 
Per Protocol: No more than 50% of the volume of breast PTV Eval will 
exceed 54 Gy (or exceed 46.1 Gy if hypofractionated whole breast 
fractionation used).   
Variation Acceptable: No more than 50% of the volume of breast PTV Eval 
will exceed 56 Gy (or exceed 47.8 Gy if hypofractionated whole breast 
fractionation used). 
▪ 
Per Protocol: The maximal point dose will not exceed 115% of the 
prescription whole breast dose, e.g. will not exceed 57.5 Gy for a prescribed 
dose of 50 Gy  or will not exceed 49.1 Gy for a prescribed dose of 42.7 Gy if 
hypofractionation whole breast fractionation is used.   
Variation Acceptable: The maximal point dose will not exceed 120% (will not 
exceed 60 Gy for a prescription whole breast dose of 50 Gy or will not 
exceed 51.2 Gy if hypofractionated 42.7 Gy is used. The maximal dose may 
be evaluated without boost fields. 
▪ 
Optional constraint: Conformity Index (CI): defined as “the ratio of the 
volume covered by the 95% prescription isodose over the volume of Breast 
PTV Eval.  
Per Protocol: CI is no less than 0.95 and no more than 2.0.  
Variation Acceptable: CL is no less than 0.85 and no more than 2.5. 
 
Lumpectomy PTV Eval: 
▪ 
Per Protocol:  At least 95% of the Lumpectomy PTV Eval will receive at 
least 58.9-60.8 Gy which is 95% of the cumulative boost prescribed dose of 
62-64 Gy (or at least 52-53.9 Gy which is 95% of 54.7-56.7 Gy if 
hypofractionated whole breast fractionation used).   
Variation Acceptable: At least 90% of the Lumpectomy PTV Eval will receive 
at least 55.8— 57.6 Gy which is 90% of the cumulative boost prescribed 
dose of 62-64 Gy (or at least 49.2-51 Gy which is 90% of 54.7-56.7 Gy if 
hypofractionated whole breast fractionation used). 
▪ 
Per Protocol: No more than 5% of the Lumpectomy PTV Eval will exceed 
68.2-70.4 Gy which is 110% of the boost prescribed dose of 62-64 Gy (or 

 
RTOG 1005; version date December 16, 2021 
 
36 
exceed 60.2-62.4 Gy which is 110% of 54.7-56.7 Gy if hypofractionated 
whole breast fractionation used).   
Variation Acceptable: No more than 10% of the Lumpectomy PTV Eval will 
exceed  68.2-70.4 Gy which is 110% of the boost prescribed dose of 62-64 
Gy (or exceed 60.2-62.4 Gy which is 110% of 54.7-56.7 Gy if 
hypofractionated whole breast fractionation is used). 
▪ 
Per Protocol: The maximal point dose will not exceed 71.3-73.6 Gy which is 
115% of the boost prescribed dose of 62-64 Gy (or will not exceed 62.9-65.2 
Gy which is 115% of 54.7-56.7 Gy if hypofractionated whole breast 
fractionation is used).   
Variation Acceptable: The maximal dose point is will not exceed 74.4-76.8 
Gy which is 120% of the boost prescribed dose of 62-64 Gy (or maximal 
dose will not exceed 65.6-68 Gy which is 120% of 42.7 if hypofractionation 
is used). 
▪ 
Optional constraint: Conformity Index (CI): defined as “the ratio of the 
volume covered by the 95% prescription isodose over the volume of 
lumpectomy PTV Eval.  Per Protocol: Cl is no less than 0.95 and no more 
than 2.5.  
Variation Acceptable: CL is no less than 0.9 and no more than 3  
 Contralateral Breast 
▪ 
Per Protocol: The maximum dose to contralateral breast does not exceed 
310 cGy and no more than 5% exceeds 186 cGy.  
Variation Acceptable: The maximum dose does not exceed 496 cGy and no 
more than 5% exceeds 310 cGy   
 Ipsilateral Lung 
▪ 
Per Protocol: No more than 15% of the ipsilateral lung exceeds 20 Gy.  
Variation Acceptable: No more than 20% of the ipsilateral lung exceeds 20 
Gy. 
▪ 
Per Protocol: No more than 35% of the ipsilateral lung exceeds 10 Gy.   
Variation Acceptable:  No more than 40% of the ipsilateral lung exceeds 10 
Gy. 
▪ 
Per Protocol: No more than 50% of the ipsilateral lung exceeds 5 Gy.   
Variation Acceptable: No more than 55% of the ipsilateral lung exceeds 5 
Gy.  
       Contralateral Lung 
▪ 
Per Protocol: No more than 10% of the contralateral lung exceeds 5 Gy. 
Variation Acceptable: No more than 15% of the contralateral lung exceeds 5 
Gy  
Heart 
▪ 
Per Protocol: No more than 5% of the whole heart exceeds 20 Gy for left-
sided breast cancers and 0% of the heart exceeds 20 Gy for right-sided 
breast cancers.  
Variation Acceptable:  No more than 5% of the whole heart exceeds 25 Gy 
for left-sided breast cancers, and 0% of the heart exceeds 25 Gy for right-
sided breast cancers. 
▪ 
Per Protocol: No more than 30% of the whole heart exceeds 10 Gy for left 
sided breast cancers and no more than 10% of the heart exceeds 10 Gy for 
right-sided breast cancers.   
Variation Acceptable: No more than 35% of the whole heart exceeds 10 Gy 
for left-sided breast cancers and no more than 15% of the heart exceeds 10 
Gy for right-sided breast cancers. 
▪ 
Per Protocol: The mean heart dose does not exceed 400 cGy.  
Variation Acceptable: The mean heart dose does not exceed 500 cGy.  
  
Every attempt should be made to make the cardiac exposure to radiation as 
low as possible. 

 
RTOG 1005; version date December 16, 2021 
 
37 
 
Thyroid 
ARM 1 if prescribed 62-64 Gy:  
▪ 
Per Protocol: The maximum point dose does not exceed 2% of the 
prescribed dose (Maximum point dose does not exceed1.24-1.28 Gy).   
Variation Acceptable:  The maximum point dose does not exceed 3% of the 
prescribed dose (Maximum point dose does not exceed 1.86-1.92 Gy).  
.  
ARM 1 if prescribed 54.7-56.7 Gy:  
▪ 
Per Protocol: The maximum point dose does not exceed 2% of the 
prescribed dose (Maximum point dose does not exceed 1.09-1.13 Gy).   
Variation Acceptable: The maximum point dose does not exceed 3% of the 
prescribed dose (Maximum point dose does not exceed 1.64-1.70 Gy  
 
 
ARM II Hypofractionated Whole Breast Irradiation with Concomitant Boost 
Breast PTV Eval 
▪ 
Per Protocol: At least 95% of the breast PTV Eval will receive at least 95% 
(38 Gy) of the whole breast prescribed dose of 40 Gy.   
Variation Acceptable: At least 90% of the breast PTV Eval will receive at 
least 90% (36 Gy) of the whole breast prescribed dose. 
▪ 
Per Protocol: No more than 30% of the breast PTV Eval will exceed 100% 
of the boost prescribed dose of 48 Gy.   
Variation Acceptable: No more than 35% of the breast PTV Eval will exceed 
100% of the boost prescribed dose of 48 Gy. 
▪ 
Per Protocol: No more than 50% of the volume of breast PTV Eval will 
exceed 43.2 Gy. 
Variation Acceptable: No more than 50% of the volume of breast PTV Eval 
will exceed ≥ 44.8 Gy 
▪ 
Per Protocol: The maximal point dose will not exceed 115% (which is 46 
Gy) of the whole breast prescribed dose of 40 Gy.   
Variation Acceptable: The maximal point dose will not exceed 120% (which 
is 48 Gy) of the whole breast prescribed dose of 40 Gy.  
For simultaneously integrated boost, acceptability on the maximum dose in 
breast_PTVeval [i.e., not exceeding 46Gy per protocol or not exceeding 48 
Gy variation acceptable] should be judged that no disconnected isodose 
lines of 48 Gy are seen in the regions outside the lumpectomy PTV. In other 
words, it is acceptable if no isolated hot spots of more than 48 Gy are found 
in the regions outside the lumpectomy PTV. For all other treatment options, 
the maximum dose may be evaluated by turning off the boost fields. 
▪ 
Optional constraint: Conformity Index (CI): defined as “the ratio of the 
volume covered by the 95% prescription isodose over the volume of Breast 
PTV Eval.  
Per Protocol: CI is no less than 0.95 and no more than 2.0.  
Variation Acceptable: CI is no less than 0.85 and no more than 
 
Lumpectomy PTV Eval 
▪ 
Per Protocol: At least 95% of the Lumpectomy PTV Eval will receive at least 
95% (at least 45.6 Gy) of the boost prescribed dose of 48 Gy.   
Variation Acceptable: At least 90% of the Lumpectomy PTV Eval will 
receive at least90% (43.2 Gy) of the boost prescribed dose of 48 Gy. 
▪ 
Per Protocol: No more than 5% of the Lumpectomy PTV Eval will exceed 
110% (will not exceed 52.8 Gy) of the boost prescribed dose of 48 Gy.   
Variation Acceptable: No more than 10% of the Lumpectomy PTV Eval will 
exceed 110% (will not exceed 52.8 Gy) of the boost prescribed dose of 48 
Gy. 
▪ 
Per Protocol: The maximal point dose will not exceed 115% (will not 
exceed55.2 Gy) of the boost prescribed dose of 48 Gy.   

 
RTOG 1005; version date December 16, 2021 
 
38 
Variation Acceptable: The maximal point dose will not exceed 120% (will not 
exceed 57.6 Gy). 
▪ 
Optional constraint: Conformity Index (CI): defined as “the ratio of the 
volume covered by the 95% prescription isodose over the volume of 
lumpectomy PTV Eval. Per Protocol: CI is no less than 0.95 and no more 
than2.5.  
Variation Acceptable: CI is no less than 0.9 and no more than 3  
Contralateral Breast 
▪ 
Per Protocol: The maximum dose to contralateral breast does not exceed 
240 cGy and no more than 5% exceeds 144 cGy.  
Variation Acceptable: The maximal dose to contralateral breast does not 
exceed384 cGy and no more than 5% exceeds 240cGy. 
Ipsilateral Lung 
▪ 
Per Protocol: No more than 15% of the ipsilateral lung exceeds 16 Gy.   
Variation Acceptable: No more than 20% of the ipsilateral lung exceeds 16 
Gy. 
▪ 
Per Protocol: No more than 35% of the ipsilateral lung exceeds 8 Gy.   
Variation Acceptable:  No more than 40% of the ipsilateral lung exceeds 8 
Gy. 
▪ 
Per Protocol: No more than 50% of the ipsilateral lung exceeds 4 Gy.   
Variation Acceptable: No more than 55% of the ipsilateral lung exceeds 4 
Gy. 
▪ 
Contralateral Lung 
▪ 
Per Protocol: No more than 10% of the contralateral lung exceeds 4 Gy. 
Variation Acceptable: No more than 15% of the contralateral lung exceeds 4 
Gy. 
Heart 
▪ 
Per Protocol: No more than 5% of the whole heart exceeds 16 Gy for left-
sided breast cancers, and 0% of the heart exceeds 16 Gy for right-sided 
breast cancers.  
Variation Acceptable: No more than 5% of the whole heart exceeds 20 Gy 
for left-sided breast cancers, and 0% of the heart exceeds 20 Gy for right-
sided breast cancers. 
▪ 
Per Protocol: No more than 30% of the whole heart exceeds 8 Gy for left 
sided breast cancers and no more than 10% of the heart exceeds 8 Gy for 
right-sided breast cancers.   
Variation Acceptable: No more than 35% of the whole heart exceeds 8 Gy 
for left-sided breast cancers and no more than 15% of the heart exceeds 8 
Gy for right-sided breast cancers. 
▪ 
Per Protocol: The mean heart dose does not exceed 320 cGy.  
Variation Acceptable: The mean heart dose does not exceed 400 cGy.  
 
Every attempt should be made to make the cardiac exposure to radiation as 
low as possible. 
     Thyroid 
▪ 
Per Protocol: The maximum point dose does not exceed 2% of the 
prescribed dose (Maximum point dose does not exceed 0.96 Gy).   
Variation Acceptable:  The maximum point dose does not exceed 3% of the 
prescribed dose (Maximum point dose does not exceed 1.44 Gy). 
   
 
Skin bolus is not allowed. 
 
6.5 
Critical Structures (10/21/13) 
Note: All required structures must be labeled for digital RT data submission as listed 
below in the table.  Resubmission of data may be required if labeling of structures does 
not conform to the standard dicom name listed. 

 
RTOG 1005; version date December 16, 2021 
 
39 
 
The following table outlines the naming of the various normal and critical structures for 
submission to TRIAD:  
Standard Name 
Description 
BREAST_CNTR 
Contralateral breast 
SURG_BED 
Surgical bed 
CTV_WB 
CTV for the whole breast 
volume 
HEART 
Heart 
LUNG_IPSI 
Ipsilateral Lung 
LUNG_CNTR 
Contralateral Lung 
PTV_WB 
PTV for whole breast 
PTV_WB_EVAL 
PTV volume used to 
evaluate coverage 
SKIN 
External Patient Contour 
THYROID 
Thyroid 
BREAST_IPSI 
Ipsilateral  Breast 
CTV_SURG_BED 
CTV for the Surgical Bed 
Volume 
PTV_SURG_BED 
PTV Surgical Bed for 
CTV growth 
PTV_SURG_BED_EVAL 
PTV volume used to 
evaluate coverage 
 
6.6 
Treatment Verification  
6.6.1 
Before first treatment 
Portal films or images of each 3DCRT beam and an orthogonal pair for all patients 
must be obtained and approved by a physician prior to initiation of treatment. 
6.6.2 
Subsequent images or films 
Subsequent treatment images may be obtained every fraction. At the minimum, 
orthogonal pair films or treatment images must be obtained prior to fraction number 5 
and every 5 fractions subsequently. The imaging modality and process should be 
performed based on the institutional guidelines. 
 
6.7 
Documentation Requirements (10/21/13) 
All films or images are to be maintained at the local facility. (Please refer to Section 12.2 
for data submission) 
 
6.8 
Compliance Criteria (5/11/12) 
DVHs for the breast PTV Eval and lumpectomy PTV Eval and designated normal 
structures will be compared to determine protocol compliance according to the following 
rules: 
6.8.1 
Per Protocol: All specified DVH requirements identified as IDEAL in Section 6.4.3 have 
been met. 
6.8.2  
Variation Acceptable: Specified DVH requirements in Section 6.4.3 between Ideal and 
Acceptable. 
6.8.3 
Deviation Unacceptable: Specified DVH requirements for Variation Acceptable in 
Section 6.4.3 are not met. 
6.8.4 
Treatment Interruption (elapsed/break days);  
Treatment interruptions should be clearly documented in the patient’s medical record: 
 
Per Protocol: No breaks except weekends and holidays. 
Acceptable variation:  Arm 1 1-10 days, Arm 2 1- 5 days: 
Unacceptable variation:  Arm 1 > 10 days, Arms 2 > 5 days.   
 

 
RTOG 1005; version date December 16, 2021 
 
40 
6.9 
R.T. Quality Assurance Reviews (10/21/13) 
6.9.1 
Each case will be submitted digitally to TRIAD where it will be processed and made 
available for review by study chairs or designees  
6.9.2 
Review Process for Arm I Standard Whole Breast Irradiation with Sequential Boost 
The first 3D-CRT case and the first IMRT case enrolled by each radiation oncology 
facility will undergo timely review.  In this process, the finalized treatment plan is 
electronically submitted and reviewed. Each of these cases may proceed to treatment 
following planning without waiting for review and approval. Treatment plans must be 
submitted within one week of treatment initiation. These cases will be reviewed in a 
timely manner with feedback given to the submitting radiation oncology facility. 
Corrections and resubmission of data will be requested for cases that do not meet 
contouring and quality assurance criteria.  
 
6.9.3 
Review Process for Arm II Hypofractionated Whole Breast Irradiation with Concomitant 
Boost 
Rapid Review 
The first 3D-CRT case and the first IMRT case enrolled onto the trial from each 
radiation oncology facility will undergo rapid review.  In this process, the finalized 
treatment plan must be electronically submitted, reviewed, and approved prior to the 
start of treatment. Additional patients may not be enrolled until approval from the rapid 
review case is received.  Allow 3 business days for the results of the rapid review 
process.  Cases that are submitted on a Friday will not be processed until the following 
Monday.  The rapid review process will not start until all required data is received by 
the  IROC Philadelphia.  Cases that do not meet contouring and quality assurance 
criteria will not be approved and corrections will need to be made to obtain approval for 
accrual and treatment. If corrections or additional documentation is requested, the 
subsequent submission of the case will be given priority review. 
Timely Review   
After the first 3D-CRT and IMRT cases are submitted for rapid review, the subsequent 
first 3 cases of 3D-CRT and the first 3 cases of IMRT from each radiation oncology 
facility will undergo a timely review.  Each of these cases may proceed to treatment 
following planning without waiting for review and approval. The treatment plan must be 
submitted within one week of treatment initiation. These cases will be reviewed in a 
timely manner with feedback given to the submitting radiation oncology facility. 
Corrections and resubmission of data will be requested for cases that do not meet 
contouring and quality assurance criteria. 
Feedback regarding treatment guideline compliance will be forwarded to the radiation 
oncology facility. During the period of timely review, the radiation oncology facility will 
be permitted to continue accrual. If the review of cases 3 or 4 demonstrates a treatment 
plan that is unacceptable, the radiation oncology facility will be required to repeat the 
rapid review and timely review process. Additional patients may not be enrolled until 
approval for the rapid review case is received. 
6.9.4 
Review of all IMRT and 3DCRT conformal cases 
All cases enrolled on trial will be reviewed, including those submitted after successful 
completion of the rapid/timely review process.  Corrections and resubmission of data 
will be requested for cases that do not meet contouring and quality assurance criteria. If 
protocol non-compliance is documented at any time subsequent to completing the 
timely review process, the radiation oncology facility will be required to repeat the 
timely review process and successfully complete planning of (3 consecutive cases) in 
order for the facility is to continue enrollment. The radiation oncology facility will be 
permitted to continue accrual. 
6.9.5 
The Radiation Oncology Chairs Frank Vicini, MD, Gary Freedman, MD, Julia White, 
MD, and Douglas Arthur, MD will perform an RT Quality Assurance Review on all 
cases enrolled on an ongoing basis. The final cases will be reviewed within 3 months 
after this study has reached the target accrual or as soon as complete data for all 
cases enrolled has been received at  IROC Philadelphia, whichever occurs first. These 

 
RTOG 1005; version date December 16, 2021 
 
41 
reviews will be on going and performed at the NRG Oncology semi-annual meetings as 
well as at IROC Philadelphia. 
 
6.10 
Radiation Therapy Adverse Events  
6.10.1 
All Radiation Therapy AEs will be scored according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 
6.10.2 
Short Term 
Fatigue is an anticipated systemic reaction to radiation treatment. Skin erythema, 
desquamation, breast edema, breast tenderness and myositis are potential local 
reactions. 
6.10.3 
Long Term 
 
Long term effects possibly include radiation pneumonitis, rib fractures, and for left-sided 
lesions cardiac complications 
 
6.11 
Radiation Therapy Adverse Event Reporting (4/4/14) 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at                           
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm   
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be 
reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via 
the CTEP web site (https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613). 
 
6.11.1 
Adverse Events (AEs) and Serious Adverse Events (SAEs) Reporting 
Requirements  
 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.  Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product (attribution of 
unrelated, unlikely, possible, probable, or definite). (International Conference on 
Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements. 
February 
29, 
2012; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]
Routine 
adverse 
event 
reporting 
guidelines 
are 
available 
at: 
(http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx).  
 
 
Definition of an SAE: Any adverse experience occurring during any part of protocol 
treatment and 30 days after that results in any of the following outcomes: 
• 
Death; 
• 
A life-threatening adverse experience; 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant disability/incapacity; 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that do not result in death, are not life threatening, 
or do not require hospitalization may be considered an SAE, when, based 
upon medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in the 
definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic 
agents, the pregnancy of a study participant must be reported via CTEP-AERS 
in an expedited manner 

 
RTOG 1005; version date December 16, 2021 
 
42 
 
 Serious adverse events (SAEs) that meet expedited reporting criteria defined in the 
table below will be reported via CTEP-AERS.  SAEs that require 24 hour CTEP-AERS 
notification are defined in the expedited reporting table below.  Contact the CTEP-
AERS Help Desk if assistance is required. 
 
 
CTEP-AERS REPORTING REQUIREMENTS 
 
All serious adverse events that meet expedited reporting criteria defined in the 
reporting table below will be reported via CTEP-AERS, the Adverse Event Expedited 
Reporting 
System, 
accessed 
via 
the 
CTEP 
web 
site, 
https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and 
satisfies NRG Oncology requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy (RT)-only pathway for events experienced 
that involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to NRG Oncology by phone, (1-800-227-5463, and ext.4189). An electronic 
report must be submitted immediately upon re-establishment of the Internet connection. 
 
• 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
• 
Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected.  If supporting source documentation accompanies an CTEP-AERS report, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and 
fax supporting documentation the NRG Oncology dedicated SAE FAX, 215-717-0990. 
• 
A serious adverse event that meets expedited reporting criteria outlined in the following table 
but is assessed by the CTEP-AERS System as “expedited reporting NOT required” must still 
be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT 
Required” assessment; the CTEP-AERS System allows submission of all reports regardless 
of the results of the assessment.  
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies within 30 Days of the Last Administration of Intervention 1, 2 

 
RTOG 1005; version date December 16, 2021 
 
43 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last intervention and have an 
attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the intervention was last administered.  
Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 

 
RTOG 1005; version date December 16, 2021 
 
44 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials: 
The following are exceptions to expedited reporting:  grade 1 and grade 2 adverse events.  Routine AE reporting 
processes fulfill safety reporting obligations for these events. 
 
6.11.2 Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in 
patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system 
within 30 days of AML/MDS diagnosis.  
 
Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 
 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
 
7.0 DRUG THERAPY (5/11/2012) 
7.1 
Chemotherapy 
Chemotherapy may be given at the discretion of the patient’s medical oncologist. The use 
of chemotherapeutic agents during radiation therapy is not allowed. Chemotherapy is 
permitted both as an adjuvant or neoadjuvant to surgery.  All adjuvant chemotherapy will 
be given prior to radiotherapy.  Initiation of radiotherapy should be at least 2 weeks after 
the last cycle of adjuvant chemotherapy. 
 
7.2 
Hormonal Therapy 
Patients with ER-positive and / or PR-positive tumors should be treated with hormonal 
therapy for a minimum of 5 years. The dose and schedule of the drug(s) should be 
consistent with the instructions in the drug package inserts.  Hormonal therapy may be 
initiated before, during or after completion of radiotherapy at the discretion of the 
investigator.    
 
7.3 
Trastuzumab 
Trastuzumab or other anti-HER2 agent is permitted at the investigator’s discretion for 
patients whose tumors are HER2 positive.  The dose and schedule of these agents 
should be per standard treatment protocol. The use of Trastuzumab during radiotherapy 
is permitted. 
 
8.0 SURGERY (5/11/2012) 
Oncoplastic surgery is permitted as long as clear definition of the surgical cavity by clips or by 
postoperative changes at CT treatment planning is achievable. 

 
RTOG 1005; version date December 16, 2021 
 
45 
 
9.0 OTHER THERAPY (5/11/2012) 
9.1 
Permitted Therapies 
9.1.1 
Anti endocrine therapy (Tamoxifen, aromatase inhibitors, etc.) are allowed at any time 
(see Section 7.2) 
9.1.2 
Chemotherapy (see Section 7.1) 
9.1.3 
Targeted therapy (trastuzumab) (see Section 7.3) 
9.1.4 
Oncoplastic breast conserving surgery (see Section 8.0) 
 
9.2 
Non-permitted Therapies 
9.2.1 
The use of chemotherapeutic agents during radiation therapy is not allowed.  
 
10.0 
TISSUE/SPECIMEN SUBMISSION   
NOTE: Patients must be offered the opportunity to participate in the correlative 
components of the study, such as tissue/specimen submission or cosmesis/quality of life 
assessment. If the patient consents to participate in the tissue/specimen component of the study, 
the site is required to submit the patient’s specimens as specified in Section 10.0 of the protocol.  
Note: Sites are not permitted to delete the tissue/specimen component from the protocol or from 
the sample consent. 
 
10.1 
Tissue/Specimen Submission  
 
The NRG Oncology Biospecimen Bank at the University of California San Francisco 
acquires and maintains high quality specimens from NRG Oncology trials. Tissue from 
each block is preserved through careful block storage and processing. NRG Oncology 
encourages participants in protocol studies to consent to the banking of their tissue. The 
NRG Oncology Biospecimen Bank provides tissue specimens to investigators for 
translational research studies. Translational research studies integrate the newest 
research findings into current protocols to investigate important biologic questions. The 
NRG Oncology Biospecimen Bank also collects tissue for Central Review of pathology. 
Central Review of tissue can be for eligibility and/or analysis.  
 
 
In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the 
purpose of tissue banking and future translational research. 
 
Future correlative studies for this trial include a plan to genotype subjects for selected 
genes for which an association with the development of normal tissue toxicity in breast 
cancer radiotherapy patients has been identified (see Introduction section 1.9.1 for 
rationale and examples).  Future correlative studies for this protocol also include plans for 
an analysis by subtype as determined by gene expression analysis (see section 1.9.2).  
The goal is to evaluate for an association with subtype and in-breast cancer recurrence 
by standard versus hypofractionated breast radiation.  
 
The final design of these studies will depend on the number of specimens collected; the 
number of events observed in the trial, the state of scientific knowledge and the capability 
of the technology available at the time accrual to the trial is complete. Future correlative 
studies will be submitted for separate scientific and institutional review board review 
before they are implemented. 
 
 
10.2 
Specimen Collection for Tissue Banking and Translational Research  (10/21/13) 
For patients who have consented to participate in the tissue/blood component of 
the study. 
The following must be provided in order for the case to be evaluable for the NRG 
Oncology Biospecimen Bank:  
10.2.1 
One H&E stained slide of the tumor (this must be either the invasive portion of the 
tumor and/or the grade 3 DCIS portion if no invasive component;(slide can be a 
duplicate cut stained H&E; it does not have to be the diagnostic slide). 

 
RTOG 1005; version date December 16, 2021 
 
46 
• 
A corresponding paraffin-embedded tissue block (preferred) of the tumor or a 2 mm 
diameter core of tumor tissue punched from the tissue block containing the invasive 
tumor (or the grade 3 DCIS if no invasive tumor present) with a punch tool and 
submitted in a plastic tube labeled with the surgical pathology number and block ID. 
The block or punches must be submitted with the H&E from the same block.  
NOTE: A kit with the punch, tube, and instructions can be obtained free of charge 
from the Biospecimen Resource. Block or core must be clearly labeled with the 
pathology identification number and block ID that corresponds to the Pathology 
Report. 
NOTE: If sites are unable to submit a block or punch from the block then they 
may instead submit 1 H&E and 10-15 unstained slides from the tumor block. 
The unstained slides must be cut from the same block as the H&E and must be 
labeled with the pathology number and block ID. 
• 
If available, a corresponding paraffin-embedded tissue block (preferred) of normal 
breast tissue taken from adjacent to tumor (or a 2 mm diameter core of this tissue 
punched from the tissue block containing the normal with a punch tool and submitted 
in a plastic tube labeled with the surgical pathology number). NOTE: A kit with the 
punch, tube, and instructions can be obtained free of charge from the NRG Onoclogy 
Biospecimen Bank. Block or core must be clearly labeled with the pathology 
identification number and block ID that corresponds to the Pathology Report. 
NOTE: If sites are unable to submit a block or punch from the block then they 
may instead submit 1 H&E and 10-15 unstained slides from the normal tissue 
block. The unstained slides must be cut from the same block as the H&E and must 
be labeled with the pathology number and block ID 
10.2.2 
A Pathology Report documenting that the submitted block or core contains tumor. The 
report must include the NRG ONcology protocol number and patient’s case number. 
The patient’s name and/or other identifying information should be removed from the 
report. The surgical pathology numbers and information must NOT be removed from 
the report. 
10.2.3 
A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG 
Oncology Biospecimen  Bank; if for translational research, this should be stated on the 
form. The form must include the NRG Oncology protocol number and patient’s case 
number.  
 
Plasma and whole blood collection: For detailed processing and shipping instructions, 
see Appendix IV. 
10.2.4 
Plasma and Whole Blood for Tissue Banking 
The following materials must be provided to the NRG Oncology Biospecimen  Bank: A 
Specimen Transmittal Form documenting the date of collection of the biospecimen; the 
NRG Oncology protocol number, the patient’s case number, time point of study, and 
method of storage, for example, stored at -80° C, must be included. The specimens to 
be provided are: 
• 
5-10 mL of anticoagulated whole blood in EDTA tube #1 (purple/lavender top) 
taken from patient and processed for collection of plasma. This sample is to be 
obtained only once prior to treatment. No additional samples are to be obtained 
during follow-up visits following treatment. 
• 
5-10 mL of anticoagulated whole blood in EDTA tube #2 (purple/lavender top) 
taken from patient for collection of DNA. This sample is to be obtained once prior 
to treatment. However, if the site missed this collection time point, they may 
collect whole blood at any time point or during a follow-up visit. No additional 
samples are to be obtained. 
10.2.5 
Storage Conditions 
 
Store frozen biospecimens at -80 C (-70C to -90C) until ready to ship. If a -80C 
Freezer is not available:  

 
RTOG 1005; version date December 16, 2021 
 
47 
• Samples can be stored short term in a -20 C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday). 
OR: 
• Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
• Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time 
stored 
 
 
 
 
 
 
 
 
10.2.6 Specimen Collection Summary   
Specimens for Tissue Banking/Translational Research 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E stained 
slides of the primary tumor 
(this must be either the 
invasive portion of the tumor 
and/or the grade 3 DCIS 
portion if no invasive 
component). 
Prior to protocol treatment  
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
A corresponding paraffin-
embedded tissue block 
(preferred) of the primary 
tumor taken before initiation 
of treatment or a 2 mm 
diameter core of tissue, 
punched from the tissue 
block with a punch tool  
Prior to protocol treatment 
Paraffin-embedded 
tissue block or punch 
biopsy (must match the 
H&E slide being 
submitted)   
 
Note: For sites unable to 
submit the block or 
punch then 10-15 
unstained slides is an 
acceptable substitute 
Block or punch shipped 
ambient 
 
If available: representative 
H&E stained slides of 
Normal tissue adjacent to 
the tumor (>1cm from 
lesion) 
Prior to protocol  treatment 
 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
 
If available: A paraffin-
embedded tissue block of 
adjacent normal tissue  
(>1cm from lesion) taken 
before initiation of treatment 
or a 2 mm diameter core of 
tissue, punched from the 
tissue block with a punch tool  
Prior to protocol treatment 
Paraffin-embedded 
tissue block or punch 
biopsy  
Note: For sites unable to 
submit the block or 
punch then 10-15 
unstained slides is an 
acceptable substitute 
Block or punch shipped 
ambient 
 
PLASMA: 5-10 mL of 
anticoagulated whole blood in 
EDTA 
Prior to protocol treatment 
Frozen plasma samples 
containing 0.5 mL per 
aliquot in 1 mL cryovials 
Plasma sent frozen on dry 
ice via overnight carrier 
(Mon-Wed) 

 
RTOG 1005; version date December 16, 2021 
 
48 
tube#1(purple/lavender top) 
and centrifuge  
(five to ten) 
Whole blood for DNA: 5-10 
mL of anticoagulated whole 
blood in EDTA tube #2 
(purple/lavender top) and mix 
Prior to protocol treatment. 
(Note: If site missed this 
collection time point they 
may collect whole blood for 
DNA at any time point or 
follow up visit but must 
note this on the ST). 
Frozen whole blood 
samples containing 1ml 
per aliquot in 1 mL 
cryovials (three to five) 
Whole blood sent frozen 
on dry ice via overnight 
carrier (Mon-Wed) 
 
10.2.7 
Submit materials for Tissue Banking and Translational Research as follows: 
 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen 
Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
Questions: 415-476- 7864/FAX 415-476-5271; RTOG@ucsf.edu 
 
10.3 
Reimbursement (4/4/14) 
 
Please note that with the start of the new NCI National Clinical Trials Network (NCTN) 
Program, NCI funds for reimbursement for protocol-specified biospecimen materials will 
be distributed per the requirements/methods specified by the new NCTN Program. This 
information will be made available with the other registration materials in the Oncology 
Patient Enrollment Network (OPEN) portal system. OPEN will serve as the registration 
system for all patient enrollments onto NCI-sponsored NCTN trials, including this study, 
which will be transitioned into the new Program from the NCI-sponsored Cooperative 
Group Clinical Trials Program. 
 
10.4 
Confidentiality/Storage  
 
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.asp
x for further details.) 
10.4.1 
Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the 
patient’s case number only. The NRG Oncology Biospecimen Bank database only 
includes the following information: the number of specimens received, the date the 
specimens were received, documentation of material sent to a qualified investigator, 
type of material sent, and the date the specimens were sent to the investigator. No 
clinical information is kept in the database. 
10.4.2 
Specimens for tissue banking will be stored for an indefinite period of time. Trial 
participants will be invited to donate specimens for tissue banking and to consent to 
store these indefinitely for future translational studies. If at any time the patient 
withdraws consent to store and use specimens, the material will be returned to the 
institution that submitted it. 
 

 
RTOG 1005; version date December 16, 2021 
 
49 
11.0 
PATIENT ASSESSMENTS (5/6/2013) 
11.1 
Study Parameters  
See Appendix I for a summary of assessments and time frames.  Note: Clarifications of 
or exceptions to the study parameters are indicated in Appendix I with an asterisk (*) and 
are discussed below: 
11.1.1 
A breast assessment will be conducted weekly during radiation and at the last day of 
radiation.  This assessment will include inspection of the breast being treated and 
toxicity assessment.  Palpation of the breast during this assessment is optional at the 
discretion of the treating physician. 
11.1.2 
A breast examination will be conducted within 28 days prior to study entry, at 1 month, 
at 6 months and subsequent interval visits where the history and physical examination 
is required.  An examination is inspection and palpation of both breasts and toxicity 
assessment 
 
11.2 
Cosmetic and Quality of Life Outcomes (1/9/14) 
 
NOTE: Non-chemotherapy Cosmesis subset closed to accrual 3/8/13; 
chemotherapy Cosmesis subset closed to accrual 1/9/14 
 
NOTE: Patients must be offered the opportunity to participate in the correlative 
components of the study, such as quality of life assessment. 
 
Breast Cancer Treatment Outcome Scale (BCTOS) - a 22-item measure of perceived 
aesthetic (e.g., breast shape) and functional status (e.g., pain, mobility) after breast-
conserving surgical treatment (BCT) and radiotherapy.  
 
This brief self-report instrument has high reliability and validity, and it has been used in a 
variety of previous studies on recovery from breast cancer treatment. These endpoints 
will be assessed at baseline prior to start of RT, end of radiation, 1 month and 6 months 
after radiation, and 1, 2 and 3 years after completion of radiation.  This tool was also 
used and at these same time points to facilitate comparisons with the outcomes from 
RTOG 0413/NSABP B39.  This tool includes items that focus specifically on 
radiotherapy-relevant symptoms (e.g., reports of skin problems, tenderness in the breast, 
hardness in the breast due to enhanced fibrosis, and pain). 
 
Physician reported cosmetic outcome has been consistently reported from prospective 
studies evaluating new methods for breast radiation.  It is important to demonstrate that 
physician reported cosmetic outcomes are non-inferior with this novel method as well.  
Physician assessed cosmetic outcome will be assessed at baseline prior to start of RT 
but after surgery, 1 year and 3 years using a 4 point scale (Harvard/ EORTC).  This scale 
has been used in prior RTOG studies assessing PBI, and is currently used on the 
ongoing Phase III study (NSABP B-39/RTOG 0413) comparing standard fractionated 
WBI to PBI. 
 
11.2.1 
Finally, digital images (photographs) will be taken of the treated and untreated breasts, 
again using RTOG-established protocol. For practical reasons, these digital images will 
only be taken at three points in time, at baseline (prior to the start of radiation but after 
surgery) and at the 1-year and 3-year (final) assessment points. Two digital images will 
be taken at each of these assessment points. One will be a close up of the treated 
breast alone, in order to provide detailed information regarding the treatment effects. 
The second digital image will be a straight frontal view of both breasts taken in either a 
standing or seated position with the patient's hands symmetrically placed on her hips, 
taking care to exclude her face and framing and focusing on both the treated and 
untreated breast to allow optimal comparison of the breasts for symmetry.  
 
These photographs will then be uploaded as  

 
RTOG 1005; version date December 16, 2021 
 
50 
J-peg files @ https://silver1.phila.acr.org/clinical_rtog/pgsitetools.html. 
(See Appendix VII)  
 
These digital images will later be evaluated for cosmetic results by a panel of 
physicians using diagnostic criteria established in previous RTOG trials (e.g., degree of 
scarring, extent of pock marks and/or dimpling, degree of symmetry between the 
breasts, extent of changes to the skin). We think it is of interest and important to obtain 
multiple measures of cosmetic outcome, in order to assess the degree of 
correspondence between physician-generated and patient-generated outcomes. Prior 
research, taken together with data generated from previous NSABP trials, suggests 
that physician-generated ratings often underestimate the degree of dissatisfaction 
experienced and problems perceived by the patient. Our plan is to use the patient's 
self-report as our primary cosmetic endpoint. 
 
11.3 
Measurement of Response  
 
 Not applicable to this study  
 
 
11.4 
Criteria for Discontinuation of Protocol Treatment 
11.4.1 
Progression of disease 
11.4.2 
A delay in protocol treatment, as specified in Section 6.0 
 
If study therapy is stopped but she still allows the study doctor to follow her care, she 
should continue to be followed according to the study schedule. Follow up and data 
collection will continue as specified in the protocol. 
 
12.0 
DATA COLLECTION 
Data should be submitted to: 
NRG Oncology* 
 1818 Market Street, Suite 1600 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will 
be used (first-last). Last names with apostrophes will be identified by the first letter of the last 
name. 
 
12.1 
Summary of Data Submission (1/9/14) 
Item 
Due 
Demographic Form (A5) 
Within 2 weeks of study entry 
Initial Evaluation Form (I1) 
 
Pathology Report (P1)  
 
 
Slides/Blocks (P2)  
 
See Section 10.0 
 
 
 
Surgical Pathology Report (S5) 
Surgical Operative report (S2) 
 
 
 
Within 2 weeks of study entry. Also at time of 
progression/relapse if applicable. 
 
 
 
Digital Images(Photographs) 
Photograph Submission Notification Form(T7) 
 
Baseline prior to RT but after surgery);1 and 3 
years post RT completion  
(for patients registered prior to 1/9/14) 
 
 

 
RTOG 1005; version date December 16, 2021 
 
51 
Cosmesis Questionnaires: 
Patient Reported Cosmesis Questionnaire 
(BQ) (for patients registered prior to 1/9/14) 
Baseline prior to RT but after surgery);at the 
completion of RT; 1 and 6 months post RT 
completion; 1, 2 and 3 years post RT 
completion 
 
 
 
Physician Reported  Cosmesis Questionnaire 
(QP) (for patients registered prior to 1/9/14) 
 
 
 
Baseline (prior to RT start but after surgery);1 
and 3 years post RT completion 
 
 
 
 
 
Follow-up Form (F1) 
 
At 1 and 6 months post RT; at 1 year post RT, 
then annually. Also at progression /relapse 
and death 
 
Comorbidities & Other Conditions Form (CF) 
Baseline (prior to study entry); at 6 months 
post RT completion; at 1 year post RT 
completion ,then annually  
 
 
 
 
12.2 
Summary of Dosimetry Digital Data Submission (10/21/13) 
(Submit to TRIAD; see Section 5.2 for account access and installation instructions.) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital Data Submission – Treatment Plan submitted 
to TRIAD by Physicist 
Within 1 week of start of RT 
Digital data submission includes the following: 
• 
CT 
data, critical normal structures, all GTV, CTV, 
and PTV contours  
• 
Digita
l beam geometry for initial and boost beam 
sets 
• 
Dose
s for initial and boost sets of concurrently 
treated beams 
• 
Digital DVH data for all required critical normal 
structures, GTV, CTV, and PTVs for total dose 
plan 
• 
All required structures MUST be labeled per 
the table in Section 6.5. 
• 
The “RTOG 1005 Datasheet” is available in 
the Forms section of the of the NRG 
Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTabl
e/StudyDetails.aspx?study=1005.  
Submit via TRIAD with the digital data listed above. 
Upon submission of the digital data via TRIAD, 
complete an online digital data transmission form 
(DT) located in the Forms section on the NRG 
Oncology/RTOG web site at 
 

 
RTOG 1005; version date December 16, 2021 
 
52 
    
http://www.rtog.org/ClinicalTrials/ProtocolTable/Study
Details.aspx?study=1005 
 
 
Note: All simulation and portal films and/or digital film 
images will be kept by the institution and only 
submitted if requested. 
 
 
 
Final Dosimetry Information 
Within 1 week of RT end 
Radiotherapy Form (T1) [copy to HQ] 
Daily Treatment Record (T5) [copy to HQ] 
Modified digital patient data as required through 
consultation with Image-Guided Therapy QA Center 
 
 
13.0 
STATISTICAL CONSIDERATIONS  
13.1  
Study Endpoints 
13.1.1 
Primary Endpoint 
  
Local failure (failure: the first occurrence of a local-in breast failure) 
13.1.2 
Secondary Endpoints 
▪ 
Overall survival (failure: death due to any cause); 
▪ 
Disease-free survival (failure: local-regional disease recurrence or distant 
metastases or second primary or death due to any cause); 
▪ 
Distant disease-free survival (failure: distant metastases or second primary 
or death due to any cause); 
▪ 
Adverse events related to treatment; 
▪ 
Changes in breast-related symptoms and side effects and cosmesis; 
▪ 
Correlation between dose-volume data and both adverse events and 
efficacy; 
▪ 
Translational research of single nucleotide polymorphisms (SNPs) in TGFB1 
and ATM genes. 
▪ 
Treatment costs 
 
13.2 
Study Design (16-DEC-2021) 
13.2.1  
Stratification Variables 
Patients will be stratified before randomization with respect to age (< 50 vs. ≥ 50), 
chemotherapy use (no vs. yes),histologic grade (1, 2 vs. 3)and ER status (+ vs. –). The 
treatment allocation scheme described by Zelen (1974) will be used because it 
balances patient factors other than institution. 
13.2.2    Sample Size Derivation 
The sample size calculations are based on the primary hypothesis that the local failure 
rate in the hypofractionated arm (Arm 2) will not be significantly worse than in the 
standard treatment arm (Arm 1). The null hypothesis (H0) of this test is that the hazard 
rate of Arm 2 (2) is significantly worse than the hazard rate of Arm 1 (1). The 
alternative hypothesis (HA) is that the hazard rate of Arm 2 is not significantly worse 
than the hazard rate of Arm 1. 
H0:   ≥ 0       vs.         HA:  < 0 
 
where    = -ln ( 2/1 ) and 0 is a non-inferiority margin. 
 
The estimated rate of local recurrence at 5 years for the control arm of whole breast 
radiation with sequential boost for this trial is 6%.  The justification based upon 
prospective trials is shown in Table 2 (in Section 1.7.4).  Table 3 below shows the 
estimates for patient enrollment of high-risk subgroups.  It is expected the percentage 
of high risk features to be significantly higher in this trial than previous hypofractionation 

 
RTOG 1005; version date December 16, 2021 
 
53 
trials from Canada (Whelan 2002) and the United Kingdom (START) because these 
groups are specifically targeted by this study’s eligibility.  The following patient 
enrollment is assumed: 65% N0, and 35% N1.  The enrollment of node positive 
patients in the UK START A trial was 29% and START B trial 23%.  It is assumed that 
approximately 50% of patients will be ≤ 50 years of age.  In the UK START A 23% were 
age ≤ 50 and UK START B 21% age ≤ 50 years.  In the Whelan study, 25% were ≤ 50 
years of age.  Because this protocol specifically is limiting eligibility to high risk patients, 
and excludes low-risk patients > 50 years, node negative patients will be 
disproportionately younger in order to be eligible, while node positive patients will be 
expected to have a more typical age distribution.  It is assumed that 45% of patients will 
be grade 3.  
 
The enrollment of grade 3 patients on the UK START A was 28% and START B 23%, 
and 19% in the trial by Whelan et al.  The percentage enrollment on the UK START 
trials of age < 50, grade 3 or node positive was 56% for trial A and 48% for trial B.  It is 
also assumed that 60% of patients will be ER-positive, and 40% ER-negative.  In the 
Whelan study, the enrollment of ER-negative patients was 27%. 
 
 
 
 
 
Table 3: Patient Enrollment Estimates 
Cohort 
Protocol enrollment 
N0 
65% 
N1 
35% 
 
 
Age ≤ 50 
50% 
Age > 50 
50% 
 
 
Grade 3 
45% 
 
 
ER negative 
40% 
 
 
Neoadjuvant chemo 
5% 
 
The protocol will specifically exclude the following patients which have a very low risk of 
5-year local recurrence: 
 
1) DCIS and age ≥ 50 years. 
2) DCIS and age < 50 years and grade 1 or 2 
3) Invasive breast cancer and ≥ 70 years old, T1, N0, ER/PR positive  
4) Invasive breast cancer and ≥ 50 years old, T1, N0, Grade 1-2, ER/PR positive.   
 
Based on a control arm 5-year local failure rate of 6%, Table 4 below shows the non-
inferiority margin and corresponding sample sizes for 5-year local failure rates for the 
hypofractionated arm of 9 and 9.5%. 
 
Table 4: Sample Size Calculations 
 
5-Year 
Control Arm 
Local Failure 
Rate 
5-Year 
Experimental 
Arm Local 
Failure Rate 
Hazard 
Ratio 
(Hypo/Control) 
Non-
Inferiority 
Margin 
Required  
Sample Size 
Evaluable (Total) 
6% 
9% 
1.52 
0.42 
2150 (2312) 

 
RTOG 1005; version date December 16, 2021 
 
54 
6% 
9.5% 
1.61 
0.48 
1900 (2044) 
 
The required sample size for the primary endpoint of local failure is based on the 
following conditions: 
▪ 
Local- failure times are exponentially distributed with (at least approximately) 
constant hazards in both treatment arms 
▪ 
The control (standard) arm will have a 5-year local failure rate of 6% (yearly 
crude hazard of 0.01238) 
▪ 
The experimental arm will have a 5-year local failure rate of no more than 9% 
(yearly crude hazard of 0.01886) 
▪ 
0 = 0.42 (non-inferiority margin) 
▪ 
Upper limit on hazard ratio (experiment/control) = 1.52 
▪ 
One-sided test at  = 0.025 
▪ 
Statistical power of 90% to conclude non-inferiority if HR = 1 
▪ 
4 years of accrual with 5 years of follow-up 
▪ 
Two interim significance tests and a final test are planned 
 
With 90% statistical power to conclude non-inferiority if the HR = 1, a one-sided 
significance level of 0.025 and the parameters above, 2150  patients will be accrued 
uniformly over 4 years to reach the required 245 local failure events. Guarding against 
an ineligibility or lack-of-data rate of up to 7%, the final targeted accrual for this study 
will be 2312 patients. 
 
Given the impact of treatment crossovers on non-inferiority trials, the rate of treatment 
crossovers will be closely monitored.  Table 5 shows the impact for 5% and 10% 
crossover rates.  If the crossover rate falls between 5% and 10%, the RTOG will 
discuss with NCI the potential of amending the trial in order to adjust for this crossover 
so as to maintain the original study parameters.  If the crossover rate reaches or 
exceeds 10%, RTOG will discuss with NCI the feasibility of continuing the trial. 
 
Table 5: Impact of Crossover 
 
 
 
Crossover 
Rate 
Adjusted 5-yr 
Control Rate 
Adjusted 5-yr 
Hypo Rate 
Type I Error 
(0.025 by 
Design) 
Increase in Accrual Time 
to Maintain Original 
Parameters 
 
 
5% 
0.0615 
0.0885 
0.05 
0.82 years 
 
 
10% 
0.0631 
0.0870 
0.08 
2.16 years 
 
 
Redesign (2021) 
 
The redesign was done in accordance with the NCI Policy for Major Design Amendments 
for Ongoing Randomized Clinical Trials and redesign specifics performed by a statistician 
independent from the trial.  
 
The statistical design and analysis plan is revised based on the following changes to the 
assumptions made in the original design, using the completed accrual.  These 
adjustments will allow for timely reporting of the trial results, while maintaining statistical 
integrity and reflecting current knowledge of the observed local failure rate in the control 
arm. 
 
1) Change the upper limit on the hazard ratio and the corresponding 
non‐inferiority margin 
 
Based on the currently observed local failure rate in the control arm (Arm 1), the 
redesign is based on a 5‐year local failure rate of 1.59% (yearly hazard = 

 
RTOG 1005; version date December 16, 2021 
 
55 
0.0032). Since this is much lower than the original estimate of 6%, the redesign 
for the non-inferiority primary endpoint hypothesis will use a larger hazard ratio 
(HR) upper limit of 2.12 (yearly hazard = 0.0068, corresponding to a 
non‐inferiority margin = 0.75), while maintaining a smaller absolute difference in 
5‐year local failure rates. The 5‐year event rate for the experimental arm (Arm 2) 
under the null hypothesis of inferiority would be no more than 3.33%, an absolute 
increase of 1.74% from the control arm, compared to the original design of no 
more than 9%, which was an absolute increase of 3%. 
 
2) Change the power and significance level to 80% and 0.05, respectively. 
 
The original sample size calculations were based on statistical power of 90% to 
conclude non‐inferiority if HR=1 and a one‐sided significance level of 0.025. The 
redesign is revising these to 80% and 0.05, respectively, to allow for more timely 
reporting so that the trial may maintain clinical relevancy. 
 
3) Omit the originally planned interim analyses. 
 
 
Summary:   
Assuming a 5‐year local failure rate of 1.59% in Arm 1, an upper bound HR of 2.12 for 
the non-inferiority alternative hypothesis and using a 1‐sided significance level of 0.05, an 
analyzable sample size of at least 2150 patients will provide >80% power to conclude 
non‐inferiority if the HR is 1 when at least 46 IBR events are observed. 
 
If the alternative hypothesis of noninferiority is accepted based on the proposed 
analyses, a test of superiority also will be conducted to determine if the 
hypofractionated treatment (Arm 2) is superior to the standard treatment (Arm 1).  With 
2150 analyzable patients and a one-sided type I error of 0.05, there will be 71% power 
to detect a reduction in the 5-year local failure rate from 1.59% to 0.8% based on an 
intention to treat analysis.   
 
13.3 
Accrual 
Patient accrual is projected to be 45 cases per month, with a ramp-up period in the first 6 
months.  The expected monthly accrual in months 1 through 3 and months 4 through 6 
following the study being broadcast to RTOG membership and placed on the CTSU 
menu are 0 and 20, respectively. If the total accrual during months 13 through 18 of the 
study is ≤ 20% of the targeted accrual (< 55 cases in total), then the protocol will be 
discontinued per NCI-CTEP accrual guidelines for phase III studies. If the total accrual 
during months 13 through 18 is between 21% and 49% (55 to 133 cases), then the 
protocol will continue to accrue subjects and will be evaluated again at the end of month 
24. If the accrual during months 22 through 24 is at least 50% of the targeted accrual (≥ 
68 cases in total), the NCI-CTEP accrual guidelines for phase III studies will have been 
met and the study will continue accrual; otherwise, the study will be discontinued. 
 
13.4  
Analysis Plan (16-DEC-2021) 
13.4.1  
Statistical Methods 
Local failure time will be measured from the date of randomization to the date of first 
local failure or last follow-up. 
 
The primary hypothesis will be tested using the logrank test comparing the crude (i.e. 
cause-specific) hazard of local failure between treatment groups. The Cox proportional 
hazards regression model will be used to estimate the treatment hazard ratio and 
investigate additional factors that may be related to local failure. 
 

 
RTOG 1005; version date December 16, 2021 
 
56 
The cumulative probability of local failure in the presence of competing failure events 
will be estimated by the cumulative incidence method. (Kalbfleish 1980) The cumulative 
incidence distributions between the two arms will be compared using Gray’s test 
(1988). We note that because competing failure types are not expected to differ 
between treatment arms, it is anticipated that results from comparing cause-specific 
hazards or cumulative incidence functions should yield similar inferential results. 
 
Overall survival, disease-free survival, and distant disease-free survival will be 
estimated by the Kaplan-Meier method (Kaplan 1958) and distributions between the 
two arms will be compared using the log-rank test (Mantel 1966). 
13.4.2  
Interim Analysis to Monitor the Study Progress 
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented/published. In general, the interim reports will 
contain the following information: 
▪ 
patient accrual rate with a projected completion date (while the study is still 
accruing) 
▪ 
total patients accrued  
▪ 
distributions of important pretreatment and prognostic baseline variables  
▪ 
the frequencies and severity of adverse events by treatment arm 
▪ 
compliance rates of treatment delivery 
 
The interim reports will not contain the results from the treatment comparisons with 
respect to the primary endpoint, overall survival, or any secondary endpoints, with the 
exception of reporting of adverse events. 
 
Additionally, the rate of treatment crossovers will be evaluated on a quarterly basis, 
until the last patient has completed treatment.  If this rate exceeds 10%, the study will 
be evaluated for a potential sample size increase to adjust for the crossover effect. 
13.4.3 
CDUS Reports 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly by electronic means. Reports are 
due January 31, April 30, July 31, and October 31. 
13.4.4 
Data Monitoring Committee (DMC) Review 
To monitor the safety and efficacy of this study, it will be officially reviewed by the NRG 
Oncology DMC twice a year in conjunction with the NRG Oncology semi-annual 
meeting and in between meetings as needed. 
13.4.5 
Significance Testing for Early Termination and/or Reporting 
 
Primary Endpoint: Local Failure 
Two interim analyses will be performed when 33% and 67% of the local failure 
events have occurred, corresponding to 81 and 165 local failure events.  At each 
look, if the experimental arm is significantly better than the standard arm (at 
p<0.001) then accrual will be stopped (if applicable) and the trial results will be 
reported with the conclusion that the hypo-fractionated WBI arm is non-inferior to the 
standard fractionated WBI arm with respect to local failure.  For the study, a hazard 
ratio up to 1.52 (hypo/standard) will still result in a conclusion of non-inferiority.  At 
the interim looks, if the lower bound of the 95% confidence interval for the hazard 
ratio (hypo/standard) is greater than 1.52, then accrual will be stopped (if applicable) 
and the trial results will be reported, with the conclusion that the hypo-fractionated 
WBI arm is inferior to the standard fractionated WBI arm with respect to local failure. 
 
In addition to accrual, distributions of pretreatment characteristics, frequency and 
severity of adverse events, and compliance with protocol treatment, at the first 
RTOG DMC meeting following the required number of deaths for each planned 
interim analysis, blinded efficacy results will be reported to the NRG Oncology DMC. 
 
Analysis for Reporting the Initial Treatment Results 

 
RTOG 1005; version date December 16, 2021 
 
57 
The primary hypothesis of this study is that the local failure rate in the 
hypofractionated arm (Arm 2) will not be significantly worse than in the standard 
treatment arm (Arm 1). This major analysis will occur after at least 46 local failures 
have been observed. It will include: 
▪ 
tabulation of all cases entered and those excluded from the analyses with the 
reasons for exclusion given 
▪ 
distributions of important prognostic baseline variables  
▪ 
the frequencies and severity of adverse events by treatment arm 
▪ 
compliance rate of treatment delivery 
▪ 
observed results with respect to the primary and secondary endpoints 
All eligible patients randomized will be included in the comparison and will be 
grouped by assigned treatment in the analysis. The primary hypothesis of non-
inferiority will be tested using the logrank test statistic, comparing the cause-specific 
hazards, with a 1-sided significance level of 0.05. Additional analyses of treatment 
effect will be performed using the Cox proportional hazard model with the 
stratification factors included as fixed covariates, as well as any factors that show an 
imbalance between the arms. Where feasible, treatment comparisons with respect 
to the primary endpoint (local failure) will be compared within ethnic and racial 
categories. 
 
13.5  
Quality of Life 
13.5.1  
Design 
The primary endpoint for the breast-related symptoms and side effects of the trial is 
self-reported cosmesis, using the BCTOS cosmesis scale (Stanton 2001). Patients that 
do and do not receive chemotherapy will be recruited and analyzed separately to 
address this cosmesis endpoint. The BCTOS will be collected at baseline, after 
informed consent has been obtained, end of radiation, 1 month and 6 months after 
radiation, and 1, 2 and 3 years after completion of radiation; with the primary endpoint 
focusing on mean change from baseline to 3 years.  The goal is to establish that self –
reported cosmesis results for the experimental arm are non-inferior to those of the 
control arm.  
 
Two-hundred and sixty-six evaluable patients provide 90% power, with a one-sided 
alpha of 0.025, to test the null hypothesis that the mean change in cosmesis score in 
the experimental arm will be at least 0.4 standard deviations worse than in the control 
arm.  To answer this hypothesis separately in patients that do and do not receive 
chemotherapy and to allow for up to a 10% attrition rate for the 3-year assessment, 296 
patients receiving chemotherapy and 296 patients not receiving chemotherapy will be 
recruited for the QoL substudy, for a total of 592 patients. 
 
Physician reported cosmesis will also be evaluated at baseline, and 1 & 3 years after 
completion of radiation, as well as photos being collected at the same time points. 
13.5.2  
Analysis 
The t-test will be used for the primary QoL comparison of mean change in cosmesis 
score (baseline to 3 years), measured by BCTOS between the treatment arms.   In 
addition to cosmesis, the pain and functional status subscales from the BCTOS will be 
compared, focusing on change from baseline to 1 year from the completion of radiation.  
The t-test will also be used to compare the treatment arms for these subscales.  Within 
each of the chemotherapy and non-chemotherapy groups, 266 patients will provide 
90% and 85% power to detect effect sizes of 0.4 and 0.37 respectively, with 1-sided 
alpha levels of 0.025, for these subscales.   
 
Secondary longitudinal analyses, using all of the time points collected, will be evaluated 
for the three subscales of the BCTOS. 
 

 
RTOG 1005; version date December 16, 2021 
 
58 
Using photographs collected at baseline, and 1 and 3 years after completion of 
radiation,  
   cosmesis will be evaluated by an independent panel using the same scoring scale as 
reported by the physicians; and will be reported separately for chemotherapy and non-
chemotherapy patients. 
13.5.3  
Missing Quality of Life Data 
Processes such as e-mail alerts will be in place to prospectively remind sites about 
upcoming QoL assessments in order to help minimize the amount of missing data. 
The distributions of quality of life data collection patterns over all collection points in 
each treatment arm will be described.  To inspect the missing data mechanism at least 
a graphical method will be used.  A missing completely at random (MCAR) mechanism 
exists when missing values are randomly distributed across all observations. A missing 
at random (MAR) mechanism exists when values are not randomly distributed across 
all observations, rather than one or more sub-samples.  
 
 
If the cause of missing data is MCAR, list wise deletion (complete case analysis) will be 
done. If the MAR assumption is supported by the data, then an imputation method such 
as multiple imputation will be applied to impute missing data.  
 
 
If the MAR assumption is not supported by the data, then adjusting for covariates (such 
as the baseline quality of life score) might reduce the conditional association between 
outcomes and missing values. If missing data patterns look similar when stratified by 
such covariate(s), then an analysis that adjusts for such covariate(s) will be conducted 
and an imputation method such as multiple imputation will be applied.  If approximate 
conditional independence cannot be obtained with any set of covariates, then MNAR 
(missing not at random) must be addressed by an explicit model for the missing data 
mechanism (Donaldson 2005) and then an imputation method such as multiple 
imputation will be applied. All results from the imputed analysis using the multiple 
imputation will be compared to the complete case analysis results to assess any 
potential biases. 
 
13.6 
Treatment Costs 
The shorter duration of accelerated WBI with concurrent boost can be expected to lead to 
lower costs for those procedures based on the time of a patient's treatment compared to 
standard WBI with sequential boost, but the type and intensity of procedures may differ 
between the two study arms. For example the distribution of treatment approaches, e.g. 
IMRT, 3DCRT, may differ between the study arms.  Patients treated with 
hypofractionated WBI with concomitant boost may be more likely to receive IMRT than 
patients treated with standard WBI with sequential boost and the difference in approach 
could lead to higher treatment costs.   A cost model will be developed for each study arm 
with each of the possible treatment approaches, and the procedures used in each 
approach.  The model will use the actual distribution of type of treatment approach in 
each study arm and Medicare relative value units and conversion factors to estimate and 
compare treatment costs for each study arm and each type of treatment.  The model will 
also include stratification and patient risk factors. The primary cost analysis will test 
whether hypofractionated WBI with concurrent boost is not higher in treatment cost than 
standard WBI with sequential boost.    
 
13.7 
Gender and Minorities  
Women of all races and ethnic groups are eligible for this study.  In conformance with the 
national Institutes of Health (NIH) Revitalization Act of 1993 with regard to inclusion of 
women and minorities in clinical research, possible interactions between race/ethnicity 
and treatment have been considered. Based on NSABP B-39/RTOG 0413, it is projected 
that 3% of the patients will be of Hispanic or Latino ethnicity and 97% will not; racial 
distribution are projected to be 91% white, 6% black or African American, 2.5% Asian and 
< 1% for both American Indian or Native Alaskan and Native Hawaiian or other pacific 

 
RTOG 1005; version date December 16, 2021 
 
59 
islander. The projected non-White and Hispanic/Latino accrual rates are too low for any 
meaningful treatment comparisons.  
 
 
The following table lists the projected accrual by gender, ethnic, and racial categories.   
 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
58 
N/A 
58 
Not Hispanic or Latino 
2254 
N/A 
2254 
Ethnic Category: Total of all subjects 
2312 
N/A 
2312 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
2 
N/A 
2 
Asian 
58 
N/A 
58 
Black or African American 
139 
N/A 
139 
Native Hawaiian or other Pacific Islander 
9 
N/A 
9 
White 
2104 
N/A 
2104 
Racial Category: Total of all subjects 
2312 
N/A 
2312 
 
  
 
 
 
 
 
 
 
 
 
 

 
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60 
 
 
 
 
 
 
 
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66 
Zelen M. The Randomization and Stratification of patients to clinical trials. J chron dis. 27:365-75, 
1974 
 
 
 
 
 
APPENDIX I (5/6/13) 
STUDY PARAMETER TABLES 
 
Pre-Treatment Assessments 
*See sections 4.0 and 11.1 for exceptions and details 
 
 
Assessments 
Within 180 days prior 
to study entry*  
Within 90 
days of 
diagnostic, 
biopsy of 
the affected 
breast 
establishing 
diagnosis  
Within 50 
days from 
study entry 
Within 28 
days prior 
to study 
entry  
Within 14 
days prior 
to study 
entry 
Last surgery 
(breast/axilla)/ last 
chemo  
 
 
X 
 
 
History and 
Physical, Zubrod 
and weight 
documentation 
 
 
 
X 
 
Breast Examination* 
 
 
 
X 
 
Right and Left 
Mammogram 
 
X  
 
 
 
CT scan  of 
ipsilateral breast  for 
treatment planning 
 
 
 
X* 
 
Performance status 
 
 
 
X  
 
CBC w/ diff & ANC 
 
 
 
 
X 
Chemistry panel  
 
 
 
 
X 
Determination of 
hormone receptor 
status 
 
Prior to study entry. See section 3.1.11 
Serum or urine 
pregnancy test (if 
applicable) 
 
 
 
 
X 
Bone scan 
X* 
 
 
 
 
CT of chest, ab, and 
pelvis or PET/CT 
X* 
 
 
 
 
Negative post-
excision 
mammogram  
Recommended* 
 
 
 
 

 
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67 
 
Assessments During Treatment (1/9/14) 
*See section 11.1 for details 
 
 
Follow-Up Assessments 
*See section 11.1 for details 
 
 
 
 
 
Assessments 
Prior to Start of 
RT 
Weekly During 
RT 
Last Day of RT 
History and Physical, Zubrod and 
weight documentation 
 
X 
X 
Breast Assessment * 
 
X 
X 
Performance status 
 
X 
X 
Adverse event evaluation 
 
X 
X 
Specimens for research-(if patient 
consents)  
X 
 
 
Cosmesis/QOLStudy (if patient 
consents) 
(for patients registered prior to 1/9/14) 
 
NOTE: Non-chemotherapy Cosmesis subset 
closed to accrual 3/8/13;chemotherapy 
Cosmesis subset closed to accrual 1/9/14 
▪ 
Doctor cosmetic assessment 
(questionnaire and photos) 
X 
 
 
▪ 
Patient questionnaire 
(BCTOS) 
X 
 
X 
Assessments 
1 Month After 
RT Completion 
6 Months After 
RT Completion 
1 Year After RT 
Completion 
Then Annually  
History and Physical, Zubrod and 
weight documentation 
X 
X 
X 
Breast Examination * 
X 
X 
X 
Bilateral or Right and Left 
Mammography 
 
 
X 
Ipsilateral  Mammography of the  
treated breast 
 
X 
 
Performance status 
X 
X 
X 
Adverse event evaluation 
X 
X 
X 
Cosmesis/QOLStudy (if patient 
consents) 
(for patients registered prior to 1/9/14) 
 
NOTE: Non-chemotherapy Cosmesis subset 
closed to accrual 3/8/13;chemotherapy 
Cosmesis subset closed to accrual 1/9/14 
▪ 
Doctor cosmetic assessment 
(questionnaire and photos) 
 
 
X (and @ year 3  
▪ 
Patient questionnaire 
(BCTOS) 
X 
X 
X (for 3 yrs) 

 
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68 
APPENDIX II 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light 
housework, office work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more 
of waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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69 
APPENDIX III 
 
 
AJCC STAGING SYSTEM 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
Breast 
 
Primary Tumor (T) 
The T classification of the primary tumor is the same regardless of whether it is based on clinical or 
pathologic criteria, or both.  Size should be measured to the nearest millimeter.  If the tumor size is 
slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be 
rounded to the millimeter reading that is closest to the cutoff.  For example, a reported size of 1.1 mm is 
reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm.  Designation should be made with the 
subscript “c” or “p” modifier to indicate whether the T classification was determined by clinical (physical 
examination or radiologic) or pathologic measurements, respectively.  In general, pathologic 
determination should take precedence over clinical determination of T size. 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor.   
Tis 
Carcinoma in situ 
Tis (DCIS) 
Ductal carcinoma in situ 
Tis (LCIS) 
Lobular carcinoma in situ 
Tis (Paget’s) 
Paget’s disease of the nipple NOT associated with invasive carcinoma and/or carcinoma 
in situ (DCIS and/or LCIS) in the underlying breast parenchyma.  Carcinomas in the 
breast parenchyma associated with Paget’s disease are categorized based on the size 
and characteristics of the parenchymal disease, although the presence of Paget’s 
disease should still be noted 
T1 
 
Tumor ≤20 mm in greatest dimension 
T1mi 
Tumor ≤1 mm in greatest dimension 
T1a 
Tumor >1 mm but ≤5 mm in greatest dimension 
T1b 
Tumor >5 mm but ≤10 mm in greatest dimension 
T1c 
Tumor >10 mm but ≤20 mm in greatest dimension 
T2 
Tumor >20 mm but ≤50 mm in greatest dimension 
T3 
Tumor >50 mm in greatest dimension 
T4 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or 
skin nodules). 
Note: Invasion of the dermis alone does not qualify as T4 
T4a 
Extension to the chest wall, not including only pectoralis muscle adherence/invasion 
T4b 
Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of 
the skin, which do not meet the criteria for inflammatory carcinoma  
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma (see “Rules for Classification”) 
Note: Inflammatory carcinoma is restricted to cases with typical skin changes 
involving a third or more of the skin of the breast. While the histologic presence of 
invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not 
required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a 
diagnosis of inflammatory breast cancer. 
 
Regional Lymph Nodes (N) Clinical 
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastases 
N1 
Metastases to movable ipsilateral level I, II axillary lymph node(s) 
N2 
Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in 
clinically detected* ipsilateral internal mammary nodes in the absence of clinically evident 

 
RTOG 1005; version date December 16, 2021 
 
70 
axillary lymph node metastases 
N2a 
Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to 
other structures 
N2b 
Metastases only in clinically detected* ipsilateral internal mammary nodes and in the 
absence of clinically evident level I, II axillary lymph node metastases 
N3 
Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, 
II axillary lymph node involvement; or in clinically detected* ipsilateral internal mammary 
lymph node(s) with clinically evident level I, II axillary lymph node metastases; or metastases 
in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary 
lymph node involvement 
N3a 
Metastases in ipsilateral infraclavicular lymph node(s) 
N3b 
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c 
Metastases in ipsilateral supraclavicular lymph node(s) 
*Note: Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by 
clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic 
macrometastasis based on fine needle aspiration biopsy with cytologic examination. Confirmation of 
clinically 
detected metastatic disease by fine needle aspiration without excision biopsy is designated with an (f) 
suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the 
absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the 
confirmation of the nodal status 
will be designated in site-specific factors as clinical, fine needle aspiration, core biopsy, or sentinel lymph 
node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in 
conjunction with a pathologic T assignment. 
 
Regional Lymph Nodes Pathologic (pN)* 
pNX 
Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for 
pathologic study) 
pN0 
No regional lymph node metastasis identified histologically 
*Note: Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or 
single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section. ITCs may be 
detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are 
excluded 
from the total positive node count for purposes of N classification but should be included in the total 
number of nodes evaluated. 
pN0(i-) 
No regional lymph node metastases histologically, negative IHC 
pN0(i+) 
Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC 
including ITC) 
pN0  
(mol-) 
No regional lymph node metastases histologically, negative molecular findings (RT-PCR) 
pN0 
(mol+) 
Positive molecular findings (RT-PCR),** but no regional lymph node metastases detected by 
histology or IHC 
pN1 
Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or in internal mammary 
nodes with metastases detected by sentinel lymph node biopsy but not clinically detected*** 
pN1mi 
Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 
2.0 mm) 
pN1a 
Metastases in 1-3 axillary lymph nodes, at least one metastasis greater than 2.0 mm 
pN1b 
Metastases in internal mammary nodes with micrometastases or macrometastases detected 
by sentinel lymph node biopsy but not clinically detected*** 
pN1c 
Metastases in 1-3 axillary lymph nodes and in internal mammary lymph nodes with 
micrometastases or macrometastases detected by sentinel lymph node biopsy but not 
clinically detected 
pN2 
Metastases in 4-9 axillary lymph nodes; or in clinically detected**** internal mammary lymph 
nodes in the absence of axillary lymph node metastases 

 
RTOG 1005; version date December 16, 2021 
 
71 
pN2a 
Metastases in 4-9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm) 
pN2b 
Metastases in clinically detected**** internal mammary lymph nodes in the absence of 
axillary lymph node metastases 
pN3 
Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph 
nodes; or in clinically detected**** ipsilateral internal mammary lymph nodes in the presence 
of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph 
nodes and in internal 
mammary lymph nodes with micrometastases or macrometastases detected by sentinel 
lymph node biopsy but not clinically detected***; or in ipsilateral supraclavicular lymph nodes 
pN3a 
Metastases in ten or more axillary lymph nodes (at least one tumor deposit greater than 2.0 
mm); or metastases to the infraclavicular (level III axillary lymph) nodes 
pN3b 
Metastases in clinically detected**** ipsilateral internal mammary lymph nodes in the 
presence of one or more positive axillary lymph nodes; or in more than three axillary lymph 
nodes and in internal mammary lymph nodes with micrometastases or macrometastases 
detected by sentinel lymph node biopsy but not clinically detected*** 
pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
*Notes: 
*Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy.  
Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node 
dissection is designated (sn) for “sentinel node,” for example, pN0(sn). 
**RT-PCR: reverse transcriptase/polymerase chain reaction 
***”Not clinically detected” is defined as not detected by imaging studies (excluding lymphoscintigraphy) 
or not detected by clinical examination. 
****”Clinically detected” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by 
clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic 
macrometastasis based on fine needle aspiration biopsy with cytologic examination. 
 
Distant Metastasis  (M) 
M0 
 
No clinical or radiographic evidence of distant metastases 
cM0(i+) 
No clinical or radiographic evidence of distant metastases, but deposits of molecularly or 
microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional 
nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of 
metastases 
M1 
Distant detectable metastases as determined by classic clinical and radiographic means 
and/or histologically proven larger than 0.2 mm 
 
Anatomic Stage/Prognostic Groups 
Stage 0 
Tis 
N0 
M0 
Stage IA 
T1* 
N0 
M0 
Stage IB 
T0 
T1* 
N1mi 
N1mi 
M0 
M0 
Stage IIA 
T0 
T1* 
T2 
N1** 
N1** 
N0 
M0 
M0 
M0 
Stage IIB 
T2 
T3 
N1 
N0 
M0 
M0 
Stage IIIA 
T0 
T1* 
T2 
T3 
T3 
N2 
N2 
N2 
N1 
N2 
M0 
M0 
M0 
M0 
M0 
Stage IIIB 
T4 
T4 
T4 
N0 
N1 
N2 
M0 
M0 
M0 

 
RTOG 1005; version date December 16, 2021 
 
72 
Stage IIIC 
Any T 
N3 
M0 
Stage IV 
Any T 
Any N 
M1 
*Notes: 
*T1 includes T1mi. 
**T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified 
Stage IB. 
M0 includes M0(i+). 
▪ 
The designation pM0 is not valid; any M0 should be clinical. 
▪ 
If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage 
IV and remains Stage IV regardless of response to neoadjuvant therapy. 
▪ 
Stage designation may be changed if postsurgical imaging studies reveal the presence of distant 
metastases, provided that the studies are carried out within 4 months of diagnosis in the absence 
of disease progression and provided that the patient has not received neoadjuvant therapy. 
▪ 
Post neoadjuvant therapy is designated with “yc” or “yp” prefix.  Of note, no stage group is 
assigned if there is a complete pathologic response (CR) to neoadjuvant therapy, for example, y 
 

 
RTOG 1005; version date December 16, 2021 
 
73 
APPENDIX IV (10/21/13) 
 
 
Appendices for NRG Oncology Biospecimen Collection 
 
NRG Oncology FFPE Specimen Plug Kit Instructions 
 
NRG Oncology Blood Collection Kit Instructions 
 
Shipping Instructions: 
US Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
❑ 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
❑ 
Check that the ST has the consent boxes checked off.  
❑ 
Check that all samples are labeled with NRG Oncology study and case number, and include date 
of collection as well as collection time point. 
 
❑ 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/ slide box. Place a small wad of padding in 
top of container If you can hear the slides shaking they are likely to break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do 
not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you 
shake the container the blocks are not shaking. If you can hear them shaking they might break 
during shipping.  
o Slides, Blocks or Plugs can be shipped ambient or with a cold pack either by USPS to the 
USPS address (94143) or by Courier to the Street Address (94115). Do NOT ship on Dry Ice. 
 
❑ 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified.  If possible keep serum, plasma, and whole blood submissions in 
separate bags. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at 
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of 
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two 
separate boxes.  Any Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
o Send frozen specimens on dry ice via overnight courier to the address above.  Specimens 
should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent 
thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples 
can be stored frozen at -80C until ready to ship. 
 
❑ 
For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank by email at: RTOG@ucsf.edu or (415)-476-7864 or fax (415)-476-5271. 
 

 
RTOG 1005; version date December 16, 2021 
 
74 
 
 
APPENDIX IV continued 
 
 
NRG Oncology FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen  
Bank. The plug kit contains a shipping tube and a punch tool.    
 
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at 
room temperature. Place the punch tool on the paraffin block over 
the selected tumor area. (Ask a pathologist to select area with 
tumor.) Push the punch into the paraffin block. Twist the punch tool 
once around to separate the plug from the block. Then pull the 
punch tool out of the block. The punch should be filled with tissue 
sample. 
 
 
 
Step 2 
Label the punch tool with the proper specimen ID.  DON’T remove 
specimen from the punch. 
 
 
Use a separate punch tool for every specimen. Call or e-mail us if 
you have any questions or need additional specimen plug kits. 
 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
 
 
 
   
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block 
and return the remaining block to your facility.  Please indicate on the submission form the request to 
perform the plug procedure and return of the block. 
 
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below: 
For Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please 
contact the NRG Oncology Biospecimen Bank by email at: RTOG@ucsf.edu or call 415-476-7864 
/FAX 476-5271; 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
75 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens or Trackable 
shipments 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
76 
 
 
 
APPENDIX IV continued 
 
 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS   
 
This Kit is for collection, processing, storage, and shipping of plasma and whole blood (as specified by 
the protocol): 
 
Kit contents: 
• One Purple Top EDTA tube for plasma (A) 
• One Purple Top EDTA tube for Whole Blood 
(B) 
• Twenty  (20) 1 ml cryovials 
• Styrofoam container (inner)  
• Cardboard shipping (outer) box 
• Kit Instructions 
• Specimen Transmittal Form 
• Absorbent shipping material (3) 
• Biohazard bags (3) 
• UN1845 DRY Ice Sticker 
• UN3373 Biological Substance Category B 
Stickers 
 
Preparation and Processing of Plasma and Whole Blood: 
 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED, and include collection time point on 
ST. 
 
A) Plasma): Purple Top EDTA tube #1 
 
❑ 
Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with 
the RTOG study and case number, collection date, time and time point, and clearly mark 
cryovials “plasma”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 
RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on 
the ST. 
3. If the interval between specimen collection and processing is anticipated  
 
to be more than one hour, keep specimen on ice until centrifuging   
 
is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are  
necessary for the plasma collected (5 to 10) labeled with RTOG study and  
case numbers, collection date/time, time point collected and clearly mark  
specimen as “plasma”.  Avoid pipetting up the buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C 
6. Store frozen plasma -70 to -90 C until ready to ship on dry ice.   
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED,  
and include collection timepoint on ST. 
 
B) Whole Blood For DNA: Purple Top EDTA tube #2  
                          
❑ 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them 
with the NRG Oncology study and case number, collection date/ time, and clearly mark 
cryovials  “blood”. 
 

 
RTOG 1005; version date December 16, 2021 
 
77 
Process: 
1. After collection, invert tube(s) multiple multiple times to ensure adequate mixing of EDTA. 
Blood can also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the 
blood collected (3 to 5) labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “blood”.  
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen -70 to -90 C until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED, and include collection time point on 
ST. 
 
Storage and Shipping: 
 
Freezing and Storage: 
 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
❑ 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
▪ 
Samples can be stored short term in a -20 C Freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only- Canada Mon-Tues). 
- OR: 
▪ 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only- Canada Mon-Tues). 
- OR: 
▪ 
Samples can be stored in lid. nitrogen vapor phase (ship out Monday-Wednesday only- 
Canada Mon-Tues). 
❑ 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
❑ 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from 
Canada) to prevent thawing due to delivery delays.  Saturday and holiday deliveries cannot 
be accepted.  
❑ 
Include all NRG Oncology paperwork in a sealed plastic and tape to the outside top of the 
Styrofoam box. 
❑ 
Wrap frozen specimens of same type (i.e., all plasma together and whole bloods together) in 
absorbent shipping material and place each specimen type in a separate biohazard bag.  
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg 
minimum).  Add padding to avoid the dry ice breaking the tubes.  
❑ 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 
and UN1895 stickers to outer cardboard box. 
❑ 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice 
from breaking the tubes. 
❑ 
For questions regarding collection, shipping or to order a Blood Collection Kit, please Email 
RTOG@ucsf.edu or call (415)476-7864.  
 
Shipping Address : 
 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476- 7864 or e-mail: RTOG@ucsf.edu 

 
RTOG 1005; version date December 16, 2021 
 
78 
APPENDIX V (5/6/13) 
 
RADIATION THERAPY SAMPLE TREATMENT PLANS  
 
CONTOURING GUIDELINES 
 
1 
Contouring Targets and Organs at Risk (OAR): 
Contouring accurately and consistently is essential for case evaluation and the data comparison 
necessary to achieve the primary and secondary endpoints of this protocol. The structures to be 
contoured are the same in both arms 1 and 2.  
 
The targets to be contoured in every case are:   
• 
Lumpectomy 
• 
Lumpectomy clinical target volume (CTV) 
• 
Lumpectomy planning target volume (PTV) 
• 
Lumpectomy planning target volume for evaluation (PTV-eval) 
• 
Breast CTV 
• 
Breast PTV 
• 
Breast PTV-eval 
The following OAR will be contoured on all cases: 
• 
Ipsilateral lung 
• 
Contralateral lung 
• 
Heart 
• 
Contralateral breast 
• 
Thyroid. 
 
2 
Contouring Targets: 
The targets to be contoured are listed in the protocol under section 6.4.2 are listed below 
with accompanying figures 1- 5. 
2.1 
Lumpectomy Target Volumes 
2.1.1 
Lumpectomy:  (Figure 1.) For this protocol the term “lumpectomy” will represent 
the surgical cavity from the breast conserving surgery. This is to replace the 
typical gross tumor volume designation (GTV) used in other disease sites or 
when the tumor is insitu. Contour using all available clinical and radiographic 
information including the excision cavity volume, architectural distortion, 
lumpectomy scar, seroma and/or extent of surgical clips (clips are strongly 
recommended).  Patients without a clearly identifiable excision cavity are not 
eligible for protocol participation.  
2.1.2 
Lumpectomy Clinical Target Volume (CTV):  (Figure 1.)  The Lumpectomy CTV 
consists of the contoured Lumpectomy plus a 1 cm 3D expansion with the 
following 3 limitations: 1. limit the CTV posteriorly at anterior surface of the 
pectoralis major; 2. limit anterolaterally 5 mm from skin; and 3. should not cross 
midline. In general, the pectoralis muscles and/or serratus anterior muscles are 
excluded from the lumpectomy CTV unless clinically warranted by the patient’s 
pathology.  
2.1.3 
Lumpectomy Planning Target Volume (PTV): (Figure 2.) The lumpectomy PTV is 
a 7 mm expansion on the Lumpectomy CTV and excludes the heart. This is the 
structure used for beam aperture generation. 
2.1.4 
Lumpectomy Planning Target Volume for evaluation (PTV_EVAL) (Figure 3.). 
This Lumpectomy PTV_EVAL is limited to exclude the portion of the PTV that 
extends outside the ipsilateral breast beyond skin or into the chest wall or thorax.  

 
RTOG 1005; version date December 16, 2021 
 
79 
The lumpectomy PTV-eval consists of the lumpectomy PTV excluding the first 5 
mm of tissue under the skin (in order to remove most of the buildup region for the 
DVH analysis) and excluding the Lumpectomy PTV expansion beyond the 
posterior extent of breast tissue (chest wall, pectoralis muscles and lung) when 
pertinent. This Lumpectomy PTV_EVAL is the structure used for DVH constraints 
and analysis. 
 
Figure 1.  Lumpectomy and Lumpectomy Clinical Target Volume 
(CTV)
 
 
 
Figure 2. Lumpectomy Planning Target Volume (PTV) 

 
RTOG 1005; version date December 16, 2021 
 
80 
 
 
Figure 3.  Lumpectomy Planning Target Volume for Evaluation 
(PTVeval)
 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
81 
2.2 
Breast Target Volumes 
2.2.1 
Breast Clinical Target Volume (CTV): (figure 4.), Consists  of and takes into 
account the clinical borders placed at the time of CT simulation, the apparent 
glandular and fatty breast tissue visualized by CT, consensus definitions of 
anatomical borders from the RTOG breast cancer atlas, and  should include the 
Lumpectomy CTV.  The breast CTV is limited anteriorly within 5 mm from the 
skin and posteriorly to the anterior surface of the pectoralis muscles, serratus 
anterior muscle/ chestwall, boney thorax and lung.  In general, the pectoralis and 
serratous anterior muscles/chestwall are excluded from the breast CTV unless 
clinically warranted by the patient’s pathology.  RTOG anatomy consensus 
guidelines are available at: 
(http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx) 
 
2.2.2 
Breast Planning Target Volume (PTV): (figure 4.): Consists of the Breast CTV 
generated above plus a 7 mm 3D expansion (excluding heart and not to cross 
midline). This is the structure used for beam aperture generation. 
2.2.3 
Breast Planning Target Evaluation for evaluation (PTV eval): (figure 5) This 
Breast PTV_EVAL is intended to exclude the portion of the breast PTV that 
extends outside the outside the patient or into the boney thorax and lungs.  This 
Breast PTV_EVAL consists of the breast PTV limited to exclude the part 
anteriorly outside the patient and the first 5 mm of tissue under the skin (in order 
to remove most of the buildup region for the DVH analysis) and posteriorly is 
limited no deeper to the anterior surface of the ribs (excludes boney thorax and 
lung). This Breast PTV_EVAL is the structure used for DVH constraints and 
analysis. 
 
Figure 4.  Breast Clinical Target Volumes (CTV) and Breast Planning Target Volumes (PTV) 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
82 
Figure 5. Breast Planning Target Volume for evaluation (PTV_eval) 
 
 
 
3 
Organs at Risk (OAR) 
The OAR to be contoured on all cases are the ipsilateral and contralateral lung, heart, thyroid and 
contralateral breast. 
3.1 
Ipsilateral and contralateral Lung: This may be contoured with auto-segmentation with 
manual verification. 
3.2 
Heart: This is to be contoured on all cases- not just the left sided ones. The heart should 
be contoured beginning just inferior to the level in which the pulmonary trunk branches 
into the left and right pulmonary arteries (PA). Above the PA, none of the heart’s 4 
chambers are present. The heart should be contoured on every contiguous slice 
thereafter to its inferior most extent near the diaphragm.  The following structures if 
identifiable should be excluded from the heart contour: esophagus, great vessels 
(ascending and descending aorta, inferior vena cava).  One need not include pericardial 
fat, if present. Contouring along the pericardium itself, when visible, is appropriate. 
3.3 
Thyroid: The thyroid is easily visible on a non-contrast CT due to its preferential 
absorption of Iodine, rendering it “brighter” or denser than the surrounding neck soft 
tissues. The left and right lobes fo the thyroid are somewhat triangular in shape and often 
do not converge anteriorly at mid-line.  All “bright” thyroid tissue should be contoured. 
3.4 
Contralateral Breast:  Includes contralateral breast as defined by clinical markers   
And the apparent CT glandular breast tissue visualized by CT and consensus definitions 
of anatomical borders from the RTOG Breast Atlas.  In general the borders are: 
Posterior border: At the anterior surface of the pectoralis, serratous anterior muscles 
excluding chest wall, ribs, boney thorax and lung/heart;  
Medial border: The sternal-costal junction, 

 
RTOG 1005; version date December 16, 2021 
 
83 
Lateral border: Varies based on the size of the breast but typically is at the mid-axillary 
line and excludes the ipsilateral lattismus dorsi muscle.   
Cephald border:   Should be similar to that of the ipsilateral breast CTV 
Caudal:border:  Inframammary fold and should be similar to that of the ipsilateral breast 
CTV.  
Anterior border:  Skin minus 5 mm to minimize inaccuracy of dose calculation at the skin 
surface. 
RTOG anatomy consensus guidelines are available at:   
(http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
84 
APPENDIX VI (5/6/13) 
 
DOSE VOLUME HISTOGRAM CONSTRAINTS 
 
 
 
 
 
All maximum doses should be defined in one dose calculation voxel, e.g., 3x3x3 mm3. 
 
The conformity index is an optional constraint, but must be recorded and reported on all cases 
 
 
Breast PTV Eval  
Breast  
PTV eval 
Description 
Constraint 
ARM I 
50 Gy in 25 
sequential 
12-14 Gy 
boost total 
62-64 Gy 
ARM I  
42.7 in 16 
sequential 12-
14 Gy boost 
total 54.7-56.7 
Gy 
ARM II 
40 Gy in 15 
concurrent 
boost to 48 
Gy 
Goal 
Volume 
Dose 
Breast PTV 
Eval 
receiving 
whole-
breast dose 
Per 
Protocol 
at least 
95% of the 
breast PTV 
Eval 
receives 
at least 95% of 
whole breast 
dose which is 
47.5 Gy 
40.6 Gy 
38 Gy 
Variation 
Acceptable 
at least 
90% of the 
breast PTV 
Eval 
receives 
at least 90% of 
whole breast 
dose which is 
45 Gy 
38.4 Gy 
36 Gy 
Breast PTV 
Eval 
receiving 
boost dose 
Per 
Protocol 
no more 
than 30% 
of the 
breast PTV 
Eval 
exceeds 100% 
of boost dose 
which is 
62-64 Gy 
54.7-56.7 Gy 
48 Gy 
Variation 
Acceptable 
no more 
than 35% 
of the 
breast PTV 
Eval 
exceeds 100% 
of boost dose 
which is 
62-64 Gy 
54.7-56.7 Gy 
48 Gy 
Breast PTV 
Eval 
receiving 
above the  
whole-
breast dose  
Per 
Protocol 
no more 
than 50% 
of the 
breast PTV 
Eval 
exceeds 108% 
of whole breast 
dose which is 
54 Gy 
46.1 Gy 
43.2 Gy 
Variation 
Acceptable 
no more 
than 50% 
of the of 
the breast 
PTV Eval  
 
exceeds 112% 
of whole breast 
dose which is 
56 Gy 
47.8 Gy 
44.8 Gy 
Breast PTV 
Eval 
maximum 
dose 
Per 
Protocol 
 
does not 
exceed 115% 
of prescription 
whole breast 
dose which is 
57.5 Gy 
49.1 Gy 
46 Gy 
Variation 
Acceptable  
 
does not 
exceed 120% 
of prescription 
60 Gy 
51.2 Gy 
48 Gy 

 
RTOG 1005; version date December 16, 2021 
 
85 
whole breast 
dose which is 
Conformity 
Index (Ratio 
of volume 
covered by 
95% 
prescription 
isodose / 
volume of 
Breast PTV 
Eval) 
Per 
Protocol 
 
no less than 
0.95 and no 
more than 2.0 
 
 
 
Variation 
Acceptable 
 
No less than 
0.85 and no 
more than 2.5 
 
 
 
 
 
Lumpectomy PTV Eval 
Lumpectomy    
PTV Eval 
Description 
Constraint 
ARM I 
50 Gy in 25 
sequential 
12-14 Gy 
boost total 
62-64 Gy 
ARM I  
42.7 in 16 
sequential 12-
14 Gy boost 
total 54.7-56.7 
Gy 
ARM II 
40 Gy in 15 
concurrent 
boost to 48 
Gy 
Goal 
Volume 
Dose 
Lumpectomy 
PTV Eval 
receiving 
boost dose 
Per 
Protocol 
at least 
95% of 
the 
lumpecto
my PTV 
Eval 
receives 
at least 95% of 
boost dose 
which is 
58.9-60.8 Gy 
52-53.9 Gy 
45.6 Gy 
 Variation 
Acceptable 
at least 
90% of 
the 
lumpecto
my PTV 
Eval 
receives 
at least 90% of 
boost dose 
which is 
55.8-57.6 Gy 
49.2-51 Gy 
43.2 Gy 
Lumpectomy
PTV Eval 
receiving 
above boost 
dose 
Per 
Protocol 
no more 
than 5% 
of the 
lumpecto
my PTV 
Eval 
exceeds 110% 
of boost dose 
which is 
68.2-70.4 Gy 
60.2-62.4 Gy 
52.8 Gy 
Variation 
Acceptable 
no more 
than 10% 
of the 
lumpecto
my PTV 
Eval 
exceeds 110% 
of boost dose 
which is 
68.2-70.4 Gy 
60.2-62.4 Gy 
52.8 Gy 
Lumpectomy 
PTV Eval 
maximum 
dose 
Per 
Protocol 
 
does not 
exceed 115% 
of boost dose 
which is 
71.3-73.6 Gy 
62.9-65.2 Gy 
55.2 Gy 
Variation 
Acceptable 
 
does not 
exceed 120% 
of boost dose 
which is 
74.4-76.8 Gy 
65.6-68 Gy 
57.6 Gy 

 
RTOG 1005; version date December 16, 2021 
 
86 
Conformity 
Index (Ratio 
of volume 
covered by 
95% 
prescription 
isodose / 
volume of 
Lumpectomy 
PTV Eval) 
Per 
Protocol 
 
No less than 
0.95 and no 
more than 2.5 
 
 
 
 
Variation 
Acceptable 
 
No less than 
0.9 and no 
more than 3 
 
 
 
 
 
Normal Tissue Constraints 
Description 
 
Volume 
ARM I 
ARM II 
Heart dose constraint 
1 
Per 
Protocol 
no more than 5% of the 
heart for left-sided 
cancer 
0% of the heart for 
right-sided exceeds 
20 Gy 
16 Gy 
Variation 
Acceptable 
no more than 5% of the 
heart for left-sided 
cancer 
0% of the heart for 
right-sided exceeds 
25 Gy 
20 Gy 
Description 
 
Volume 
ARM I 
ARM II 
Heart dose constraint 
2 
Per 
Protocol 
no more than 30% of 
the heart for left-sided 
cancer 
no more than 10% of 
the heart for right-sided 
exceeds 
10 Gy 
8 Gy 
Variation 
Acceptable 
no more than 35% of 
the heart for left-sided 
cancer 
no more than 15% of 
the heart for right-sided 
exceeds 
10 Gy 
8 Gy 
Heart dose constraint 
3 
Per 
Protocol 
Mean dose does not 
exceed 
400 cGy 
320 cGy 
Variation 
Acceptable 
Mean dose does not 
exceed 
500 cGy 
400 cGy 
Ipsilateral lung dose 
Per 
Protocol 
no more than 15% of 
the ipsilateral lung 
exceeds 
20 Gy 
16 Gy 
Variation 
Acceptable 
no more than 20% of 
the ipsilateral lung 
exceeds 
20 Gy 
16 Gy 
Ipsilateral lung dose 
constraint 1 
Per 
Protocol 
no more than 35% of 
the ipsilateral lung 
exceeds 
10 Gy 
8 Gy 
Variation 
Acceptable 
no more than 40% of 
the ipsilateral lung 
exceeds 
10 Gy 
8 Gy 
Ipsilateral lung dose 
constraint 2 
 
Per 
Protocol 
no more than 50% of 
the ipsilateral lung 
exceeds 
5 Gy 
4 Gy 

 
RTOG 1005; version date December 16, 2021 
 
87 
Variation 
Acceptable 
no more than 55% of 
the ipsilateral lung 
exceeds 
5 Gy 
4 Gy 
Contralateral Lung 
Per 
Protocol 
no more than 10% 
exceeds 
5 Gy 
4 Gy 
Variation 
Acceptable 
no more than 15% 
exceeds 
5 Gy 
4 Gy 
Contralateral Breast 
Per 
Protocol 
Dmax does not exceed 
/  no more than 5% 
exceeds 
310 / 186 
cGy 
240 / 144  cGy 
Variation 
Acceptable 
Dmax does not exceed 
/ no more than 5% 
exceeds 
 
496 / 
310cGy 
 
384 /  240 cGy 
Thyroid 
Per 
Protocol 
Max point dose does 
not exceed 2% of 
prescribed dose which 
is 
1.24-1.28 
Gy for 62-
64 Gy 
prescribed 
dose or 
1.09-1.13 
Gy for 
54.7-56.7 
Gy 
prescribed 
dose 
0.96 Gy 
 
Variation 
Acceptable 
Max point dose does 
not exceed 3% of 
prescribed dose which 
is  
1.86-1.92 
Gy for 62-
64 Gy 
prescribed 
dose or 
1.64-1.7 
Gy for 
54.7-56.7 
Gy 
prescribed 
dose 
1.44 Gy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
RTOG 1005; version date December 16, 2021 
 
88 
APPENDIX VII (5/6/13) 
 
INSTRUCTIONS FOR SUBMITTING COSMESIS PHOTOS 
 
 
To submit cosmesis photos: 
• 
Make sure photos are available in a JPEG format on the computer that you are using- 
Identify the photos as follows:  
             Baseline photos-Single_B forTreated Breast view Both_B for Both Breasts view 
             1-year photos -   Single_1 for Treated Breast view Both_2 for Both Breasts view 
             3-yearphotos-     Single_3 for Treated breast view Both_3 for Both Breasts view  
• 
Go to http://www.rtog.org/ 
• 
Click on site tools link at the top of the page 
• 
Click on RTOG Cosmesis Upload Tool 
• 
Click on RTOG 1005  
• 
Log in using your  personal ID and Password  
• 
Complete the required fields and upload the photos 
• 
Please be sure to upload one photo of the treated breast and one photo showing both 
breasts as instructed in Section 11.2.1 of the protocol