NSABP B-51/RTOG 1304 PROTOCOL SUMMARY OF CHANGES

For Protocol Amendment #1 to: NSABP B-51/RTOG 1304

NCI Protocol #: NSABP B-51/RTOG 1304

Local Protocol #: NSABP B-51/RTOG 1304

NCI Version Date: January 11, 2013

Protocol Date: July 10, 2013
Protocol Title: A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy Chestwall and
Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT in Patients with Positive Axillary
Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After
Neoadjuvant Chemotherapy
Please provide a list of changes from the previous CTEP approved version of the protocol. The list shall
identify by page and section each change made to a protocol document with hyperlinks to the section in
the protocol document. All changes shall be described in a point-by-point format (i.e., Page 3, section
1.2, replace ‘xyz’ and insert ‘abc’). When appropriate, a brief justification for the change should be
included. Specific text additions and changes are highlighted and in bold.
Please refer to the NSABP B-51/RTOG 1304 Sample Consent Form dated July 10, 2013, for a
summary of the consent form changes.

# Section Page(s) Change

Version dated January 11, 2013 Version dated July 10, 2013
1. NSABP 1 Version Date: January 11, 2013 Version Date: July 10, 2013
PROTOCOL (Replaces all other versions)
B-51/RTOG
PROTOCOL
1304
2. Protocol 3 N/A The Protocol Revision Record has
Revision been added and includes changes
Record made in Amendment #1.
3. Information 8 http://rpc.mdanderson.org/rpc http://rpc.mdanderson.org/rpc
Resources E-mail:
Row 7, Col 3 RPC@MDAnderson.org
Phone: 713-745-8989
4. Information 8 http://atc.wustl.edu http://atc.wustl.edu
Resources E-mail: itc@wustl.edu
Row 8, Col 3 Phone: 314-747-5415

i
# Section Page(s) Change
Version dated January 11, 2013 Version dated July 10, 2013
5. 3.2.5 26 Second primary cancer (SPC) Rationale: The endpoint term was
Aim: To compare the rates of revised to reflect the standard
second primary cancer by STEEP system definition.
treatment arm. Second primary invasive cancer
Endpoint: SPC, defined as the Aim: To compare the rates of
time from randomization to the second primary invasive cancer
development of a second primary by treatment arm.
invasive cancer of any site Endpoint: Second primary
excluding squamous and basal cell invasive cancer, defined as the
carcinoma of the skin. time from randomization to the
development of a second primary
invasive cancer of any site
excluding squamous and basal
cell carcinoma of the skin.
6. 10.3.2 45 Post lumpectomy whole breast + Rationale: Section heading
regional nodal irradiation (Arm revised to appropriately describe
2/Group 2A) treatment regimen.
Post lumpectomy whole breast
irradiation + regional nodal
irradiation (Arm 2/Group 2A)
7. 10.3.3 45 Post-mastectomy radiation (Arm Rationale: Section heading
2/Group 2B) revised to appropriately describe
treatment regimen.
Post-mastectomy irradiation +
regional nodal irradiation (Arm
2/Group 2B)
8. 10.7 55 ≤ 50% of the volume of Chestwall Rationale: Text added for
Chestwall or or Breast PTV Eval will receive clarification of compliance
breast: ≥ 54 Gy criteria.
≤ 50% of the volume of
Chestwall or Breast PTV Eval
will receive ≥ 54 Gy when a
boost is included in the
composite plan DVH

ii
# Section Page(s) Change
Version dated January 11, 2013 Version dated July 10, 2013
9. 10.10 57 Per Protocol: ≤ 50% of the Rationale: Text added for
Chestwall or volume of Breast PTV Eval will clarification of compliance
Breast PTV receive 108% (≥ 54 Gy) of the criteria.
Eval: prescribed dose of 50 Gy Per Protocol: ≤ 50% of the
Variation Acceptable: ≤ 50% of volume of Breast PTV Eval will
the volume of Breast PTV Eval receive 108% (≥ 54 Gy) of the
will receive 112% (≥ 56 Gy) of prescribed dose of 50 Gy when a
the prescribed dose of 50 Gy boost is included in the
composite plan DVH
Variation Acceptable: ≤ 50% of
the volume of Breast PTV Eval
will receive 112% (≥ 56 Gy) of
the prescribed dose of 50 Gy
when a boost is included in the
composite plan DVH
10. 10.10 59 Variation Acceptable: Maximal Rationale: Protocol revised to
Supraclavi- dose point is ≤ 57.5 Gy which is correct a calculation error. The
cular (SCL) 120% of the SCL prescribed dose maximal dose point of 57.5 Gy is
PTV: of 50 Gy 115% of 50 Gy and not 120% as
originally indicated.
Variation Acceptable: Maximal
dose point is ≤ 57.5 Gy which is
115% of the SCL prescribed dose
of 50 Gy
11. 10.10 59 Variation Acceptable: Maximal Rationale: Protocol revised to
Axillary dose point is ≤ 57.5 Gy which is correct a calculation error. The
PTV: ≤120% of the axillary prescribed maximal dose point of 57.5 Gy is
dose of 50 Gy 115% of 50 Gy and not 120% as
originally indicated.
Variation Acceptable: Maximal
dose point is ≤ 57.5 Gy which is
≤115% of the axillary prescribed
dose of 50 Gy
12. 10.10 59 Variation Acceptable: Maximal Rationale: Protocol revised to
Internal dose point is ≤ 57.5 Gy which is correct a calculation error. The
mammary ≤ 120% of the IMN prescribed maximal dose point of 57.5 Gy is
nodal (IMN) dose of 50 Gy 115% of 50 Gy and not 120% as
volumes: originally indicated.
Variation Acceptable: Maximal
dose point is ≤ 57.5 Gy which is
≤ 115% of the IMN prescribed
dose of 50 Gy

iii
# Section Page(s) Change
Version dated January 11, 2013 Version dated July 10, 2013
13. 11.5 66 Fax supporting documentation Rationale: A blank transmittal
that confirms the breast cancer form with the patient's study
recurrence or second primary number will be provided via e-
cancer diagnosis with the mail after a patient is enrolled.
transmittal form (provided by the Fax supporting documentation
online software and printed) to that confirms the breast cancer
412-622-2111. recurrence or second primary
cancer diagnosis with the
transmittal form (provided at the
time of enrollment) to 412-622-
2111.
14. 13.5.1 and Rationale: Instructions in the Due to the deletion, subsequent
13.5.2 January 11, 2013, version of the sections have been renumbered.
protocol deleted from the version
dated July 8, 2013. All
investigators will enroll patients
by accessing OPEN through the
CTSU Member Web site.
13.5.1 NSABP Investigators
Note: NSABP investigators who
also are registered with the CTSU
must enroll patients in B-51/1304
through the NSABP; they are not
permitted to enroll patients
through the CTSU.
Study entry instructions can be
found in the "Patient Entry
Guidelines" section of the
Members’ Area of the NSABP
Web site,
https://members.nsabp.pitt.edu.
13.5.2 CTSU Investigators
CTSU investigators can access
OPEN at https://open.ctsu.org or
from the OPEN tab on the CTSU
Members’ side of the Web site at
https://www.ctsu.org.

iv
# Section Page(s) Change
Version dated January 11, 2013 Version dated July 10, 2013
15. 15.2 75 Secondary efficacy endpoints Secondary efficacy endpoints
include overall survival (OS); include overall survival (OS);
loco-regional recurrence-free loco-regional recurrence-free
interval (LRRFI) (separately interval (LRRFI) (separately
analyzed for mastectomy patients analyzed for mastectomy patients
and for lumpectomy patients); and for lumpectomy patients);
distant recurrence-free interval distant recurrence-free interval
(DRFI); disease-free survival- (DRFI); disease-free survival-
ductal carcinoma in situ (DFS- ductal carcinoma in situ (DFS-
DCIS); second primary cancer DCIS); second primary invasive
(SPC); effect of XRT in cancer; effect of XRT in
mastectomy and lumpectomy mastectomy and lumpectomy
patients; and the frequency and patients; and the frequency and
severity of adverse events graded severity of adverse events graded
according to the CTCAE v4.0. according to the CTCAE v4.0.
16. Appendix C 106 No Boost No Boosta
Row 1, Col 5
17. Appendix C 106 Breast/Chestwall PTV Eval Breast/Chestwall PTV Eval
Row 2, Col 1 maximum dose maximum doseb
18. Appendix C 107 No Boost No Boosta
Row 1, Col 5
19. Appendix C 107 Lumpectomy PTV Eval maximum Lumpectomy PTV Eval
Row 5, Col 1 dose maximum doseb
20. Appendix C 108 Supraclavicular (SCL) PTV Supraclavicular (SCL) PTV
Row 3, Col 1 Maximal Point Dose Maximal Point Doseb
21. Appendix C 108 ≤ 120% of 50 Gy Rationale: Protocol revised to
Row 3, Col 4 correct a calculation error. The
maximal dose point of 57.5 Gy is
115% of 50 Gy and not 120% as
originally indicated.
≤ 115% of 50 Gy
22. Appendix C 108 Axillary (Ax) PTV Maximal Point Axillary (Ax) PTV Maximal
Row 5, Col 1 Dose Point Doseb
23. Appendix C 108 ≤ 120% of 50 Gy Rationale: Protocol revised to
Row 5, Col 4 correct a calculation error. The
maximal dose point of 57.5 Gy is
115% of 50 Gy and not 120% as
originally indicated.
≤ 115% of 50 Gy
24. Appendix C 108 IMN PTV Maximal Point Dose IMN PTV Maximal Point Doseb
Row 7, Col 1

v
# Section Page(s) Change
Version dated January 11, 2013 Version dated July 10, 2013
25. Appendix C 108 ≤ 120% of 50 Gy Rationale: Protocol revised to
Row 7, Col 4 correct a calculation error. The
maximal dose point of 57.5 Gy is
115% of 50 Gy and not 120% as
originally indicated.
≤ 115% of 50 Gy
26. Appendix C 109 No Boost No Boosta
Row 2, Col 6
27. Appendix C 110 No Boost No Boosta
Row 2, Col 6
28. Appendix C 110 a. Arm 2/Group 2B: No boost to Rationale: Text added for
Footnote a be delivered except in the case clarification.
of close invasive cancer a. Arm 2/Group 2B: No boost to
margins post-mastectomy. If be delivered post-
boost is delivered – it should mastectomy except in the
comply with these constraints. case of close invasive cancer
margins post-mastectomy. If
boost is delivered – it should
comply with the constraints
outlined in Section 10.6.5.3.

vi
 NSABP PROTOCOL B-51
RTOG PROTOCOL 1304

A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy

Chestwall and Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT
in Patients with Positive Axillary Nodes Before Neoadjuvant Chemotherapy
Who Convert to Pathologically Negative Axillary Nodes
After Neoadjuvant Chemotherapy
NATIONAL SURGICAL ADJUVANT BREAST AND BOWEL PROJECT

NSABP Operations Center NSABP Biostatistical Center

Four Allegheny Center – 5th Floor One Sterling Plaza
Pittsburgh, PA 15212-5234 201 North Craig Street, Suite 500
TELEPHONE: 412-330-4600 Pittsburgh, PA 15213
FAX: 412-330-4660 TELEPHONE: 412-624-2666
FAX: 412-624-1082
NSABP CLINICAL COORDINATING DIVISION: 1-800-477-7227
(For Clinical Questions Only)
RADIATION THERAPY ONCOLOGY GROUP
RTOG Headquarters RTOG Statistical Center
American College of Radiology American College of Radiology
1818 Market Street, Suite 1600 1818 Market Street, Suite 1600
Philadelphia, PA 19103 Philadelphia, PA 19103
TELEPHONE: 215-574-3189 TELEPHONE: 215-574-3203
FAX: 215-928-0153 FAX: 215-928-0153

KEY STUDY PERSONNEL

Group Chairmen: Norman Wolmark, MD (NSABP)
Walter J. Curran, MD (RTOG)
Protocol Chairs: Eleftherios Mamounas, MD, MPH (NSABP)
Julia White, MD (RTOG)
Radiation Oncology Co-Chairs: Atif Kahn, MD (NSABP)
Simona Shaitelman, MD (RTOG)
Mylin Torres, MD (RTOG)
Frank Vicini, MD (NSABP)
Protocol Officer: Thomas Julian, MD (NSABP)
Behavioral and Health Outcomes Officer: Patricia Ganz, MD (NSABP)
Behavioral and Health Outcomes Co-Officer: Susan McCloskey, MD (NSABP)
Protocol Statistician: Hanna Bandos, PhD (NSABP)
Protocol Pathologist: Soonmyung Paik, MD (NSABP)
Protocol Physicist: Nilendu Gupta, PhD (RTOG)
STUDY PARTICIPANTS: NSABP, CTSU
Version Date: July 10, 2013 (Replaces all other versions)
This protocol was designed and developed by the NSABP and the RTOG of the American College of Radiology (ACR).
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 the NSABP or the RTOG nor does the NSABP or the RTOG assume any responsibility for
unauthorized use of this protocol.

NSABP B-51/RTOG 1304 – Page 1

 [BLANK PAGE]

07/10/13 NSABP B-51/RTOG 1304 Page 2

 PROTOCOL REVISION RECORD

Original Version: January 11, 2013

Amendment #1: July 10, 2013

NSABP B-51/RTOG 1304 Protocol amended prior to Protocol Activation.

Sections Changed/Deleted:
Cover Page
Information Resources
Section 3.0: 3.2.5
Section 10.0: 10.3.2, 10.3.3, 10.7, 10.10
Section 11.0: 11.5
Section 13.0: 13.5.1, 13.5.2 have been deleted and subsequent sections renumbered
Section 15.0: 15.2
Appendix C: Pages 106-110
Sample Consent Form

07/10/13 NSABP B-51/RTOG 1304 Page 3

 [BLANK PAGE]

07/10/13 NSABP B-51/RTOG 1304 Page 4

 TABLE OF CONTENTS

INFORMATION RESOURCES................................................................................................................... 8
CANCER TRIALS SUPPORT UNIT (CTSU) .......................................................................................... 10
GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS .................................................. 11

1.0 SUMMARY OF STUDY DESIGN ............................................................................................... 13

2.0 BACKGROUND ........................................................................................................................... 15
2.1 Introduction....................................................................................................................... 15
2.2 Evidence for using adjuvant XRT in patients with early-stage breast cancer................... 16
2.3 Rationale for neoadjuvant chemotherapy ......................................................................... 17
2.4 The NSABP experience on rates and patterns of loco-regional recurrence in patients
treated with neoadjuvant chemotherapy ........................................................................... 17
2.5 Using neoadjuvant chemotherapy in order to tailor the use of loco-regional XRT .......... 22
2.6 Issues with post-mastectomy breast reconstruction and the use of post-mastectomy
chestwall XRT .................................................................................................................. 23
2.7 Standardization of IMRT and 3DCRT for regional nodal XRT and dose volume
analysis.............................................................................................................................. 23
3.0 STUDY AIMS AND ENDPOINTS .............................................................................................. 25
3.1 Primary aim and endpoint ................................................................................................. 25
3.2 Secondary aims and endpoints .......................................................................................... 25
4.0 RADIATION ONCOLOGY FACILITY CREDENTIALING AND QUALITY
ASSURANCE ................................................................................................................................ 27
4.1 Pre-registration requirements for 3DCRT/IMRT treatment approach .............................. 27
4.2 Facility questionnaire and data submission ...................................................................... 27
4.3 Quality assurance for standard whole breast irradiation with boost
(Arm 1/Group 1A) ............................................................................................................ 28
4.4 Quality assurance for regional nodal irradiation + breast XRT or chestwall XRT
(Arm 2/Groups 2A and 2B) .............................................................................................. 28
4.5 Radiation therapy Quality Assurance Review .................................................................. 29
5.0 PATIENT ELIGIBILITY AND INELIGIBILITY ........................................................................ 30
5.1 Patient selection guidelines ............................................................................................... 30
5.2 Conditions for patient eligibility ....................................................................................... 30
5.3 Conditions for patient ineligibility .................................................................................... 32
6.0 REQUIREMENTS FOR ENTRY, TREATMENT, AND FOLLOW-UP ..................................... 33
7.0 PATHOLOGY AND CORRELATIVE SCIENCE STUDIES ...................................................... 35
7.1 Overview of requirements................................................................................................. 35
7.2 Use of specimens .............................................................................................................. 35
7.3 Specimen submission and identification procedures ........................................................ 35
7.4 Hypotheses ........................................................................................................................ 36
8.0 BEHAVIORAL AND HEALTH OUTCOMES CORRELATIVE SCIENCE STUDY ............... 39
8.1 Overview........................................................................................................................... 39
8.2 Aims and hypotheses ........................................................................................................ 40
8.3 Administration of B-51/1304 patient-completed questionnaires ...................................... 41
8.4 BAHO patient population ................................................................................................. 42
9.0 TREATMENT REGIMEN ............................................................................................................ 43
9.1 Arm 1/Group 1A ............................................................................................................... 43

07/10/13 NSABP B-51/RTOG 1304 Page 5

 9.2 Arm 1/Group 1B ............................................................................................................... 43
9.3 Arm 2/Group 2A ............................................................................................................... 43
9.4 Arm 2/Group 2B ............................................................................................................... 43
9.5 Breast surgery ................................................................................................................... 43
9.6 Adjuvant endocrine therapy .............................................................................................. 43
9.7 Anti-HER2 therapy ........................................................................................................... 44
9.8 Non-protocol therapy ........................................................................................................ 44
9.9 Participation in other clinical trials ................................................................................... 44
10.0 RADIATION THERAPY .............................................................................................................. 45
10.1 Radiation therapy for Arm 1/Group 1A ............................................................................ 45
10.2 Radiation therapy for Arm 2 ............................................................................................. 45
10.3 Dose specifications ........................................................................................................... 45
10.4 Technical factors ............................................................................................................... 46
10.5 Localization, simulation, and immobilization................................................................... 46
10.6 Target volumes/treatment planning .................................................................................. 47
10.7 Required dose-volume histogram (DVH) analysis ........................................................... 55
10.8 Skin bolus ......................................................................................................................... 57
10.9 Treatment verification....................................................................................................... 57
10.10 Compliance criteria ........................................................................................................... 57
11.0 ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 62
11.1 Adverse event characteristics............................................................................................ 62
11.2 Adverse events and serious adverse events....................................................................... 62
11.3 Expedited reporting of adverse events .............................................................................. 62
11.4 Routine reporting of adverse events ................................................................................. 66
11.5 Reporting breast cancer recurrence and second primary cancer ....................................... 66
12.0 DOCUMENTATION OF BREAST CANCER RECURRENCE AND SECOND
MALIGNANCIES ......................................................................................................................... 67
12.1 General instructions .......................................................................................................... 67
12.2 Local recurrence ............................................................................................................... 67
12.3 Regional recurrence .......................................................................................................... 67
12.4 Distant recurrence ............................................................................................................. 68
12.5 Contralateral breast cancer................................................................................................ 69
12.6 Second primary cancer...................................................................................................... 69
12.7 Documentation requested following death ....................................................................... 69
13.0 REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES .......................... 70
13.1 Investigator requirements.................................................................................................. 70
13.2 Patient consent form ......................................................................................................... 70
13.3 Required submission of tumor samples ............................................................................ 70
13.4 Patient enrollment ............................................................................................................. 70
13.5 Oncology Patient Enrollment Network (OPEN)............................................................... 71
13.6 Investigator-initiated discontinuation of study therapy .................................................... 71
13.7 Patient-initiated discontinuation of study therapy ............................................................ 72
13.8 Patient-initiated withdrawal from the study...................................................................... 72
14.0 REQUIRED DATA COLLECTION ............................................................................................. 73
14.1 Data collection .................................................................................................................. 73
14.2 Instructions for completion of B-51/1304 forms and materials ........................................ 73
14.3 Instructions for submission of B-51/1304 data, forms, and materials .............................. 73
14.4 Data reporting to CTEP .................................................................................................... 74

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 14.5 Dosimetry digital data submission .................................................................................... 74
15.0 STATISTICAL CONSIDERATIONS ........................................................................................... 75
15.1 Primary endpoint............................................................................................................... 75
15.2 Secondary endpoints ......................................................................................................... 75
15.3 Stratification and randomization ....................................................................................... 75
15.4 Sample size calculation ..................................................................................................... 75
15.5 Statistical analysis ............................................................................................................. 76
15.6 Interim analyses ................................................................................................................ 76
15.7 Statistical considerations for BAHO ................................................................................. 77
15.8 Issues relating to racial and ethnic differences ................................................................. 78
16.0 PUBLICATIONS INFORMATION .............................................................................................. 80
17.0 REFERENCES .............................................................................................................................. 81

Figure 1 NSABP B-51/RTOG 1304 Schema .................................................................................. 14

Figure 2 10-year cumulative incidence of LRR in patients ≥ 50 years of age treated with
mastectomy plus breast XRT ............................................................................................ 20
Figure 3 10-year cumulative incidence of LRR in patients < 50 years of age treated with
lumpectomy plus breast XRT ........................................................................................... 20
Figure 4 10-year cumulative incidence of LRR in patients with ≤ 5 cm tumors treated with
mastectomy ....................................................................................................................... 21
Figure 5 10-year cumulative incidence of LRR in patients with > 5 cm tumors treated with
mastectomy ....................................................................................................................... 21
Figure 6 Survival of patients with residual disease after neoadjuvant chemotherapy according
to Ki67 status .................................................................................................................... 36
Figure 7 LRR of patients from NSABP trial B-20 based on Recurrence Score.............................. 37
Figure 8 Gene expression algorithms and proliferation activity ..................................................... 37

Table 1 Multivariate analysis of independent predictors of 10-year locoregional

recurrence (LRR) according to type of surgery ................................................................ 19
Table 2 Tests, exams, and other requirements prior to randomization .......................................... 33
Table 3 Tests, exams, and other requirements during therapy and follow-up for
Arm 1 and Arm 2 .............................................................................................................. 34
Table 4 Summary of B-51/1304 tumor sample submission requirements ..................................... 35
Table 5 Expedited reporting requirements for adverse events that occur within 30 days
of the last dose of radiation therapy .................................................................................. 64
Table 6 Proposed interim monitoring boundaries .......................................................................... 76
Table 7 Expected racial and ethnic composition of NSABP B-51/RTOG 1304 ........................... 79

Appendix A Assessment of performance status and activities of daily living ...................................... 85

Appendix B Contouring Guidelines ...................................................................................................... 86
Appendix C Compliance Criteria Table .............................................................................................. 105

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 INFORMATION RESOURCES

NSABP Operations Center RTOG Headquarters

Four Allegheny Center – 5th Floor 1818 Market Street, Suite 1600
Pittsburgh, PA 15212-5234 Philadelphia, PA 19103
Phone: 412-330-4600 Phone: 215-574-3189
Fax: 412-330-4660 Fax: 215-928-0153
NSABP Biostatistical Center
Cooperative Group RTOG Statistical Center
One Sterling Plaza
contact information 1818 Market Street, Suite 1600
201 North Craig Street, Suite 500
Pittsburgh, PA 15213 Philadelphia, PA 19103
Phone: 412-624-2666 Phone: 215-574-3203
Fax: 412-624-1082 (General Fax: 215-928-0153
office)
http://www.nsabp.pitt.edu http://www.rtog.org
Questions/problems
NSABP Operations Center Phone: 412-330-4600
regarding IRB review &
Division of Regulatory Affairs Fax: 412-330-4661
informed consent
Phone: 1-888-823-5923
CTSU Regulatory Office Fax: 215-569-0206
Submission of IRB approval 1818 Market Street, Suite 1100 E-mail:
Philadelphia, PA 19103 CTSURegulatory@ctsu.coccg.org
Questions concerning
NSABP Operations Center Phone: 1-800-477-7227
eligibility and clinical aspects
Clinical Coordinating Division E-mail: ccd@nsabp.org
of the trial
Phone: 412-383-4900
Study entry information NSABP Biostatistical Center Refer to the Patient Entry Guidelines in
(see Section 13.0) Patient Entry Coordinator the Members' Area of the
NSABP Web site.
Questions regarding
RTOG RT Quality Assurance Phone: 215-574-3219
radiation therapy treatment
Radiation therapy http://rpc.mdanderson.org/rpc
Radiological Physics Center
credentialing E-mail: RPC@MDAnderson.org
(RPC)
Phone: 713-745-8989
Submission of electronic data http://atc.wustl.edu
Image-guided Therapy QA Center
for credentialing and case E-mail: itc@wustl.edu
(ITC)
reviews and treatment data Phone: 314-747-5415
Submission of tumor blocks NSABP Biostatistical Center Questions regarding receipt of
(see Section 7.1) One Sterling Plaza specimens:
201 North Craig Street, Suite 500 Phone: 412-624-2666
Pittsburgh, PA 15213 For all other questions:
Note: When sending blocks, or Phone: 412-359- 3312
other materials, please indicate Refer to the B-51/1304 Pathology and
on the package "Pathology Correlative Science Instructions in the
specimens Enclosed." Members' Area of the NSABP Web site.
Arrangement for return of NSABP Division of Pathology Phone: 412-359-3312
blocks that are not to be E-mail: pathology.questions@nsabp.org
stored or to request kits for
2 mm core sampling of
existing tumor/lymph node
block(s)

07/10/13 NSABP B-51/RTOG 1304 Page 8

 INFORMATION RESOURCES (continued)

Questions concerning NSABP Biostatistical Center Phone: 412-383-2641

expedited adverse event B-51/1304 AE Reporting Nurse Fax: 412-622-2113
reporting (see Section 11.3) E-mail: SAEReporting@nsabp.pitt.edu
Submission of patient- NSABP Biostatistical Center Phone: 412-624-2666
completed questionnaires B-51/1304 Data Manager Fax: 412-622-2115
(see Section 14.0) Refer to the B-51/1304 Forms and
Supporting Documents page in the
Members' Area of the NSABP Web site.
Questions concerning data NSABP Biostatistical Center Phone: 412-624-2666
management and Medidata B-51/1304 Data Manager
Rave

07/10/13 NSABP B-51/RTOG 1304 Page 9

 CANCER TRIALS SUPPORT UNIT (CTSU)
ADDRESS AND CONTACT INFORMATION

To submit site registration For patient Submit study data through

documents: enrollments: Medidata Rave unless otherwise
specified in the protocol:
Online Data Submission: B-51/1304
Patient enrollments will will use Medidata Rave for electronic
be conducted through the data submission. Access Rave using
Oncology Patient your active CTEP-IAM user id and
CTSU Regulatory Office Enrollment Network password at the following url:
1818 Market Street, Suite 1100 (OPEN). OPEN is the https://login.imedidata.com/selectlogin
Philadelphia, PA 19103 Web-based registration Refer to Section 14.3 for specific
Phone: 1-866-651-CTSU system for patient instructions.
Fax: 215-569-0206 enrollments onto
Submit patient-completed
E-mail: NCI-sponsored
questionnaires to the NSABP as
CTSURegulatory@ctsu.coccg.org Cooperative Group
directed on the worksheet.
clinical trials. Refer to
Section 13.5 for specific Do not submit study data or forms to
instructions. CTSU Data Operations. Do not copy
the CTSU on data submission.

The study protocol and all related forms and documents must be downloaded from the
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Sites must
use the current form version and adhere to the instructions and submission schedule outlined in the
protocol.
CTSU sites should follow procedures outlined in the protocol for Site Registration, Patient Enrollment,
Adverse Event Reporting, and Data Submission.
For patient eligibility and treatment-related questions, contact the Clinical Coordinating Division at
the NSABP Operations Center at 1-800-477-7227 or by e-mail at ccd@nsabp.org.
For data submission questions, contact the B-51/1304 Data Manager at the NSABP Biostatistical
Center by calling 412-624-2666.
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU
Help Desk by phone or email:
CTSU General Information Line – 1-888-823-5923 or ctsucontact@westat.com. All calls and
correspondence will be triaged to the appropriate CTSU representative.
For detailed information on the regulatory and monitoring procedures for CTSU sites, please
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU Member Web
site at https://www.ctsu.org.
The CTSU Web site is located at https://www.ctsu.org.

07/10/13 NSABP B-51/RTOG 1304 Page 10

 GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS

3DCRT three-dimensional conformal radiation therapy

AC doxorubicin and cyclophosphamide
AdEERS Adverse Event Expedited Reporting System
AE adverse event
ANOVA analysis of variance
ASCO American Society of Clinical Oncology
ATC Advanced Technology Consortium
BAHO Behavioral and Health Outcomes
BCTOS Breast Cancer Treatment Outcome Scale
BID twice a day
CAP College of American Pathologists
CI confidence interval
CPK creatine phosphokinase
CT computed tomography
CTCAE Common Terminology Criteria for Adverse Events
CTEP Cancer Therapy Evaluation Program
CTSU Cancer Trials Support Unit
CTV clinical target volume
DCIS ductal carcinoma in situ
DFS-DCIS disease-free survival-ductal carcinoma in situ
DRFI distant recurrence-free interval
DVA dose-volume analysis
DVH dose-volume histogram
ECOG Eastern Cooperative Oncology Group
ER estrogen receptor
FNA fine needle aspiration
GTV gross tumor volume
H&E hematoxylin and eosin
HER2 human epidermal growth factor receptor 2
HR hazard ratio
IBC-RFI invasive breast cancer recurrence-free interval
IHC immunohistochemistry
IMN internal mammary node
IMRT intensity modulated radiation therapy
IRB Institutional Review Board
ITC Image-guided Therapy Center
LCIS lobular carcinoma in situ
LRR loco-regional recurrence
LRRFI loco-regional recurrence-free interval
MOS SF-36 Medical Outcomes Study Short-Form 36
MRI magnetic resonance imaging
NCI National Cancer Institute
NCIC National Cancer Institute of Canada
NSABP National Surgical Adjuvant Breast and Bowel Project
NTCP normal tissue complication probability
OAR organs at risk

07/10/13 NSABP B-51/RTOG 1304 Page 11

 GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS (continued)

OPEN Oncology Patient Enrollment Network

OR overall response
OS overall survival
p probability
pCR pathologic complete response
PET positron emission tomography
PgR progesterone receptor
PO by mouth
PRO patient-reported outcome
PTV planning target volume
PTV EVAL planning target volume for evaluation
QA quality assurance
QOL quality of life
RPC Radiological Physics Center
RTOG Radiation Therapy Oncology Group
RTQA Radiation Therapy-Quality Assurance
SAE serious adverse event
SFTP Secure File Transfer Protocol
SPC second primary cancer
WBI whole breast irradiation
XRT external radiotherapy

07/10/13 NSABP B-51/RTOG 1304 Page 12

1.0 SUMMARY OF STUDY DESIGN
NSABP B-51/RTOG 1304, a Phase III, multicenter, randomized post neoadjuvant therapy trial,
will evaluate whether the addition of chestwall and regional nodal radiation therapy (XRT) after
mastectomy or breast and regional nodal XRT after breast conserving surgery will significantly
reduce the rate of events for invasive breast cancer recurrence-free interval in patients who
present with histologically positive axillary nodes but convert to histologically negative axillary
nodes following neoadjuvant chemotherapy.
Secondary aims include overall survival, loco-regional recurrence-free interval, distant
recurrence-free interval, disease-free survival-ductal carcinoma in situ, and second primary
cancer. The study will also look at quality of life issues related to arm function, arm and breast
edema, cosmesis, pain, fatigue, and restricted work and social activity.
Patient must have clinically T1-3, N1 breast cancer at the time of diagnosis and must have had
pathologic confirmation of axillary nodal involvement at presentation (before neoadjuvant
therapy) based on either a positive FNA (demonstrating malignant cells) or positive core needle
biopsy (demonstrating invasive adenocarcinoma).

Patients must have completed a minimum of 12 weeks of standard neoadjuvant chemotherapy

consisting of an anthracycline and/or taxane-based regimen. Patients with HER2-positive tumors
must have received neoadjuvant trastuzumab or other anti-HER2 therapy (either with all or with a
portion of the neoadjuvant chemotherapy regimen), unless medically contraindicated.
After patients complete their neoadjuvant chemotherapy, they will have either a lumpectomy or a
mastectomy. At the time of definitive surgery, all removed axillary nodes must be histologically
free from cancer. Note: Patients found to be pathologically node positive by sentinel node
biopsy alone should be approached regarding participation in the Alliance in Oncology study
A011202 if the study is open at the investigator's institution. All patients will receive additional
systemic therapy as planned (i.e., hormonal therapy for patients with hormone receptor-positive
breast cancer and trastuzumab or other anti-HER2 therapy for patients with breast cancer that is
HER2-positive).
Mastectomy patients will be randomized to no XRT or to receive comprehensive XRT, which is
radiation to the chestwall plus regional nodal areas. Lumpectomy patients will be randomized to
receive standard whole breast XRT (no regional nodal XRT) or to receive comprehensive XRT,
which is radiation to the breast plus regional nodal areas.
Tumor blocks must be submitted for correlative science studies, which will include examining the
role of proliferation measures as a prognosticator for patients with residual disease after
neoadjuvant chemotherapy and the development of predictors of the degree of reduction in
loco-regional recurrence. Submission of a tumor sample from the primary breast tumor is a study
requirement for all patients. A tumor block from any gross residual disease (> 0.5 cm) at the time
of surgery is also required.
The Behavioral and Health Outcomes population will include 736 enrolled patients. Targeted
patient-reported outcome instruments for arm function, arm and breast edema, cosmesis, pain,
and fatigue will be used. In addition, disruption in everyday function (work, childcare, disability
time) will be tracked, along with overall quality of life. Patients will complete assessments prior
to randomization and at 3, 6, 12, and 24 months from randomization.

The B-51/1304 study will enroll 1636 patients over a period of 5 years. It is anticipated that the
definitive analysis will be carried out approximately 7.5 years after study initiation.

07/10/13 NSABP B-51/RTOG 1304 Page 13

 Figure 1
NSABP B-51/RTOG 1304 Schema

Clinically T1–3, N1 Breast Cancer

Documented Positive Axillary Nodes by FNA
or by Core Needle Biopsy

Minimum of 12 Weeks of Standard Neoadjuvant Chemotherapy

Plus Anti-HER2 Therapy for Patients with HER2-Positive Tumors

Definitive Surgery with Histologic Documentation of Negative Axillary Nodes

(Either by Axillary Dissection or by Sentinel Node Biopsy ± Axillary Dissection)

STRATIFICATION
• Type of surgery (mastectomy, lumpectomy)
• Hormone receptor status (ER-positive and/or PgR-positive;
ER- and PgR-negative)
• HER2 status (negative, positive)
• Adjuvant chemotherapy (yes, no)
• pCR in breast (yes, no)

RANDOMIZATION

Arm 1 Arm 2
(Groups 1A and 1B)*, ** (Groups 2A and 2B)*, **
No Regional Nodal XRT Regional Nodal XRT
• Group 1A Lumpectomy: No • Group 2A Lumpectomy:
regional nodal XRT with WBI Regional nodal XRT with WBI
• Group 1B Mastectomy: No • Group 2B Mastectomy: Regional
regional nodal XRT and no nodal XRT and chestwall XRT
chestwall XRT
* Patients will be randomized to one of the following:
• Arm 1
− Radiation therapy for Group 1A
Whole breast irradiation + boost
− No radiation therapy for Group 1B
• Arm 2
− Radiation therapy for Group 2A
Whole breast irradiation + boost and regional nodal irradiation
− Radiation therapy for Group 2B
Chest wall and regional nodal irradiation
** All patients will receive additional systemic therapy as planned (i.e., hormonal therapy
for patients with hormone receptor-positive breast cancer and trastuzumab or other
anti-HER2 therapy for patients with breast cancer that is HER2-positive).

07/10/13 NSABP B-51/RTOG 1304 Page 14

2.0 BACKGROUND

2.1 Introduction

Decisions on the use of adjuvant chestwall + regional nodal radiotherapy (XRT) after mastectomy
or regional nodal XRT after breast conserving surgery + breast XRT (WBI) are generally based
on the pathologic nodal status at the time of surgical staging. Patients who have involved axillary
nodes are generally recommended to receive XRT to the chestwall + regional nodal basins (after
mastectomy) or to the breast + regional nodal basins (after lumpectomy). On the other hand,
XRT for patients with negative axillary nodes is not typically recommended after mastectomy,
and it is confined to the breast after breast conserving surgery.

In patients with large operable breast cancer, neoadjuvant chemotherapy has been consistently
shown to down-stage primary breast tumors allowing for conversion of mastectomy candidates to
candidates for breast conserving surgery. In addition, neoadjuvant chemotherapy has been shown
to down-stage involved axillary nodes. With modern chemotherapy regimens
(anthracycline- and taxane-containing regimens), it is estimated that about 40% of patients with
involved axillary nodes at presentation would have pathologically negative axillary nodes at the
time of surgery.1 This proportion is estimated to be even higher in patients with triple-negative
breast cancers and in those with HER-2 neu positive tumors who receive neoadjuvant
chemotherapy + trastuzumab.2,3

Several randomized clinical trials and non-randomized studies have consistently shown that
achievement of pathologic complete response (pCR) in the breast with negative axillary nodes is
associated with excellent long-term outcomes both in terms of loco-regional recurrence (LRR) as
well as distant recurrence.4–6 With the increasing use of neoadjuvant chemotherapy, a commonly
encountered clinical scenario involves patients who present with pathologically involved axillary
nodes, receive neoadjuvant chemotherapy, and are found to be pathologically node-negative at
the time of definitive surgery. For such patients, there is an active debate on the appropriate use
(and extent) of loco-regional XRT after mastectomy or breast conserving surgery. On one hand,
since these patients presented with known positive axillary nodes, they are at high-risk for LRR
and should receive XRT to the chestwall and regional nodal basins (after mastectomy) or to
regional nodal basins in addition to breast XRT (after lumpectomy). On the other hand,
sterilization of involved axillary nodes by neoadjuvant chemotherapy lowers the risk for LRR
making the need for XRT to the chestwall and regional nodal basins after mastectomy and to
regional nodal basins (after lumpectomy) questionable. The decision of whether to add chestwall
+ regional nodal XRT in patients who have undergone mastectomy is further complicated by the
desire of most patients to undergo immediate reconstruction at the time of mastectomy.

This active debate in the use of XRT is clearly shown in more recent NSABP neoadjuvant trials
(NSABP B-40/B-41) where the use of XRT was left at the discretion of the treating physician.
When we examined the rates of comprehensive loco-regional XRT used in these two NSABP
protocols, we found that only 60% of lumpectomy patients who presented with clinically positive
nodes and were found to have histologically negative nodes at the time of surgery received
comprehensive breast and regional nodal XRT. Similarly, only 50% of mastectomy patients who
presented with clinically positive nodes and were found to have histologically negative nodes at
the time of surgery received comprehensive chestwall and regional nodal XRT. These data
clearly highlight that there is no established standard of care for the use/extent of XRT in these
patients.

07/10/13 NSABP B-51/RTOG 1304 Page 15

 The proposed clinical trial formally tests the hypothesis of whether the addition of chest
wall + regional nodal XRT (after mastectomy) or regional nodal XRT (after lumpectomy), will
improve outcomes in patients with operable breast cancer and positive axillary nodes at
presentation whose axillary nodes convert to negative after neoadjuvant chemotherapy.

2.2 Evidence for using adjuvant XRT in patients with early-stage breast cancer

For patients with early-stage breast cancer who receive surgery as their initial treatment, there is
abundant information on rates and predictors of LRR, with or without adjuvant systemic
therapy.7–10 This information has been used for decisions about the use of loco-regional XRT
following mastectomy or the addition of regional nodal XRT following breast conserving
surgery.

For patients treated with mastectomy, based on the available evidence from several randomized
clinical trials and overview analyses,11–15 chestwall and regional XRT has been shown to
significantly reduce LRR and to significantly prolong overall survival for patients with positive
axillary nodes. However, for patients with negative axillary nodes, the absolute reduction in LLR
from post-mastectomy XRT was small, and there was no significant improvement in overall
survival (OS).

For patients treated with breast conserving surgery, the addition of post-lumpectomy breast XRT
has been shown to significantly reduce rates of breast cancer recurrence and to significantly
reduce breast cancer specific mortality.16 The effect of adding regional nodal XRT to breast
XRT has not been formally tested (until more recently). By extrapolation from the
post-mastectomy XRT trials, most clinicians would recommend adding regional nodal XRT to
breast XRT for patients with 4 or more positive nodes but not in those with negative nodes.
Debate exists on the need to add regional nodal XRT for patients with 1–3 positive nodes,
although more recently, results from the NCIC MA.20 trial demonstrated that in lumpectomy
patients with 1–3 positive nodes (some high-risk node-negative patients were also included), the
addition of regional nodal XRT to breast XRT significantly reduced regional nodal recurrence
and significantly prolonged disease-free survival (DFS) and distant disease-free survival (DDFS).
Also, a non-significant trend in prolonging OS was shown with the addition of regional nodal
XRT.17 On the basis of the above results, chestwall and regional nodal XRT are commonly
prescribed for mastectomy patients with positive axillary nodes, and regional nodal XRT in
addition to breast XRT is rapidly gaining momentum for the majority of node-positive patients
treated with lumpectomy.

The outcome data from the MA.20 trial challenge the traditional wisdom (as established by the
Oxford Overview analyses) of a 4:1 ratio between the reduction in LRR and the reduction in
distant recurrence. In the MA.20 trial, the addition of regional nodal radiation to breast radiation
significantly lowered the risk of LRR and the risk of distant recurrence. However, the number of
distant recurrence events prevented with the addition of regional nodal radiation (116-77=39) was
larger than the number of LRR events prevented by the use of regional nodal radiation
(48-29=19).17 This can be the result of the fact that at times LRR may go undetected or can be
detected only after distant recurrence has been diagnosed. The results of the MA.20 trial support
our approach of using invasive breast cancer recurrence-free interval as our primary endpoint for
the B-51/1304 trial.

07/10/13 NSABP B-51/RTOG 1304 Page 16

2.3 Rationale for neoadjuvant chemotherapy

Neoadjuvant chemotherapy is the gold standard for patients with locally advanced breast cancer
and a reasonable alternative to adjuvant chemotherapy in those with large operable disease. In
randomized clinical trials, neoadjuvant chemotherapy has been found to be equally effective to
adjuvant chemotherapy in prolonging DFS and OS and has some potential clinical advantages
such as the conversion of mastectomy candidates to candidates for breast conserving surgery and
the improvement in cosmesis by reducing the size of lumpectomy in patients who are breast
conserving surgery candidates but present with large tumors. In addition, the consistent
observation that achievement of pCR to neoadjuvant chemotherapy is associated with excellent
long-term outcomes has brought forward the hypothesis that neoadjuvant chemotherapy can be
used to reduce the extent of surgery in the axilla by down-staging involved axillary nodes and
performing sentinel node biopsy alone and to reduce the extent of (or need for) loco-regional
XRT by down-staging primary tumors and sterilizing involved axillary nodes. However, in
contrast to the abundant information on LRR rates for patients treated with surgery first followed
by adjuvant systemic therapy, there is limited information on rates and predictors of LRR in
patients who receive neoadjuvant chemotherapy. The reason for this paucity of data is two-fold.
First, considerably fewer patients with operable breast cancer are being treated with neoadjuvant
vs. adjuvant chemotherapy. Second, by the time neoadjuvant chemotherapy became established
as an alternative to adjuvant chemotherapy, the role of loco-regional XRT in patients with
positive nodes was well-established. Thus, most available databases of patients treated with
neoadjuvant chemotherapy include those who, at the discretion of the treating physician, were
treated with postoperative XRT (because they either had pathologically positive nodes at surgery
or because they were presumed to be node-positive before neoadjuvant chemotherapy). As a
result of this paucity of data on patterns and rates of LRR, there is considerable debate on how to
best treat with loco-regional XRT those patients who present with involved axillary nodes before
neoadjuvant chemotherapy, and who are found to have negative axillary nodes after the
neoadjuvant treatment.

2.4 The NSABP experience on rates and patterns of loco-regional recurrence in patients treated
with neoadjuvant chemotherapy

Until the late 1990s, all National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant
and neoadjuvant breast cancer clinical trials did not allow chestwall/regional nodal XRT after
mastectomy or regional nodal XRT after breast-conserving surgery. This was because up until
that time, there was no convincing evidence that XRT to those areas significantly improved OS,
while it did increase morbidity. In fact, as late as 1995, a systematic review of randomized trials
of XRT plus surgery vs. surgery alone for early breast cancer demonstrated that despite a three
times lower rate of LRR with XRT plus surgery compared to surgery alone, there was no
significant difference in 10-year survival.11 Similar results were demonstrated in the 2000 update
of the overview in which the long-term (10-year and 20-year) favorable and unfavorable effects
of XRT were examined.12 Only after a significant overall survival benefit with the addition of
post-mastectomy XRT was demonstrated in the late 1990s for patients with positive nodes
receiving adjuvant chemotherapy13–15 was the addition of chestwall and regional nodal XRT
after mastectomy and regional nodal XRT after breast conserving therapy allowed in subsequent
NSABP trials. Before this change, the NSABP conducted two trials of neoadjuvant
chemotherapy (NSABP B-18 and NSABP B-27). Data from these two trials provide us with the
opportunity to examine the rates and patterns of LRR in patients treated with neoadjuvant
chemotherapy as well as to identify independent predictors of LRR in this setting.

07/10/13 NSABP B-51/RTOG 1304 Page 17

 Between October 1988 and April 1993, 1523 patients in NSABP B-18 were randomized to
receive either 4 cycles of neoadjuvant doxorubicin and cyclophosphamide (AC x 4) or the same
chemotherapy given after surgery. Eligible patients had operable, palpable breast cancer
(T1–3, N0–1, M0) diagnosed by fine needle aspiration (FNA) or core needle biopsy. Between
December 1995 and December 2000, 2411 patients in NSABP B-27 were randomized to receive
either 4 cycles of neoadjuvant AC or 4 cycles of neoadjuvant AC followed by 4 cycles of either
neoadjuvant or adjuvant docetaxel. Eligible women had primary operable breast cancer
(T1c–3, N0, M0 or T1–3, N1, M0) diagnosed by core biopsy or FNA. Stratification variables for
both studies were age, clinical tumor size, and clinical nodal status. FNA results were used to
establish eligibility; hormone receptor status was not available at randomization and was not used
for stratification. In B-18, patients who were ≥ 50 years of age received tamoxifen (10 mg PO
BID for 5 years) starting after chemotherapy, regardless of hormone receptor status. In B-27, all
patients received tamoxifen (20 mg/day for 5 years) starting on the first day of chemotherapy
regardless of hormone receptor status. In both studies, patients undergoing lumpectomy received
breast XRT, but patients undergoing mastectomy received no XRT.

2.4.1 Incidence of LRR by protocol arm and in the B-18 and B-27 combined dataset

The 10-year cumulative incidence of LRR was 14.3% and 12.2% in the neoadjuvant AC
arms of B-18 and B-27, respectively (p=0.05). There was a significant reduction in the
10-year cumulative incidence of LRR with the addition of neoadjuvant docetaxel
(8.5%, p=0.02 vs. the AC alone arm of B-27) and a nearly significant reduction with
adjuvant docetaxel (9.5%, p=0.08 vs. the AC alone arm of B-27).18

In the combined dataset, the 10-year cumulative incidence of LRR was 11.1% for the
entire cohort of patients (8.4% local and 2.7% regional). LRR incidence was 12.6%
among 1947 patients treated with mastectomy (9.0% local and 3.6% regional) and 10.3%
among 1100 patients treated with lumpectomy plus breast XRT (8.1% local and 2.2%
regional). Thus, local recurrences accounted for 71% of 10-year LRR in patients treated
with mastectomy and for 79% of 10-year LRR in patients treated with lumpectomy plus
breast XRT.

2.4.2 Multivariate analyses of predictors of LRR in the B-18 and B-27 combined dataset

Of the 3088 eligible patients with follow-up in the combined dataset, information on
surgery type and all covariates was known in 2961 patients. In this cohort, age at
randomization, clinical tumor size before neoadjuvant chemotherapy, clinical nodal status
before neoadjuvant chemotherapy, and pathologic nodal status/pCR in the breast
following neoadjuvant chemotherapy and surgery were significant independent predictors
of LRR by multivariate analysis: age at randomization (≥ 50 yrs vs. < 50 yrs; HR=0.78
[0.63–0.98], p=0.03), clinical tumor size before neoadjuvant chemotherapy
(> 5 cm vs. ≤ 5 cm; HR=1.51 [1.19–1.91], p=0.0007), clinical nodal status before
neoadjuvant chemotherapy (positive vs. negative; HR=1.61 [1.28–2.02], p<0.0001), and
pathologic breast tumor response/pathologic nodal status (node-negative/no Breast
pCR vs. node-negative/Breast pCR; HR=1.55 [1.01–2.39] and node-positive vs.
node-negative/Breast pCR (HR=2.71 [1.79–4.09], p<0.0001).18

Independent predictors of LRR were also evaluated separately for patients treated with
mastectomy and for those treated with lumpectomy plus breast XRT. In the multivariate
Cox proportional hazards model for patients treated with mastectomy, age was not a
significant independent predictor of LRR, but clinical tumor size, clinical nodal status,

07/10/13 NSABP B-51/RTOG 1304 Page 18

 and pathologic breast tumor response/pathologic nodal status were significant predictors
(Table 1). In the multivariate Cox proportional hazards model for patients treated with
lumpectomy plus breast XRT, clinical tumor size was not a significant independent
predictor of LRR, but age, clinical nodal status, and pathologic breast tumor
response/pathologic nodal tumor response were significant independent predictors
(Table 1).18
TABLE 1. Multivariate analysis of independent predictors of 10-year locoregional recurrence (LRR)
according to type of surgery
Patients Treated with Mastectomy (1071 patients, 131 LRR Events)*
Variable Hazard Ratio (95% CI) P
Clinical tumor size: > 5 vs. ≤ 5 cm† 1.58 (1.12–2.23) 0.0095
Clinical nodal status: cNode(+) vs. cNode(-)† 1.53 (1.08–2.18) 0.017
Breast/nodal pathologic status:
2.21 (0.77–6.30)
ypNode(-)/No Breast pCR vs. ypNode(-)/Breast pCR†
0.0002
ypNode(+) vs. ypNode(-)/Breast pCR† 4.48 (1.64–12.21)
Patients Treated with Lumpectomy Plus Breast XRT (1890 patients, 189 LRR Events)*
Age: ≥ 50 vs. age < 50† 0.71 (0.53–0.96) 0.025
Clinical nodal status: cNode(+) vs. cNode(-)† 1.70 (1.26–2.31) 0.0005
Breast/nodal pathologic status:
1.44 (0.90–2.33)
ypNode(-)/No Breast pCR vs. ypNode(-)/Breast pCR†
0.0006
ypNode(+) vs. ypNode(-)/Breast pCR† 2.25 (1.41–3.59)
* Includes only patients for whom all covariates are known.
† Category used as baseline for comparison of risk.

2.4.3 Incidence of local and regional recurrence according to independent predictors

The incidence of local, regional, and LRR was examined separately in patients treated
with breast conserving surgery + breast XRT and in those treated with mastectomy,
according to the independent predictors of LRR (Figures 2, 3, 4, and 5)
• Patients treated with lumpectomy plus breast XRT
− Ipsilateral breast tumor recurrence: For patients treated with lumpectomy plus
breast XRT, the majority of LRR were ipsilateral breast tumor recurrences
(IBTR) with rates ranging from 5.2% to 8.7% in those ≥ 50 years of age and from
6.9% to 13.6% in those < 50 years (Figures 2 and 3). In patients ≥ 50 years of
age, IBTR rates did not appear to be influenced by pathologic breast tumor
response/pathologic nodal status or initial clinical nodal status (Figure 2).
However, in patients < 50 years of age, there was a trend of increasing IBTR
rates with decreasing pathologic breast tumor response and positive pathologic
nodal status (Figure 3). For clinically node-negative patients, IBTR rates were
6.9%, 8%, and 10.5% for those with negative nodes/Breast pCR, negative
nodes/no Breast pCR, and positive nodes, respectively.

07/10/13 NSABP B-51/RTOG 1304 Page 19

 For clinically node-positive patients, the respective IBTR rates were 7%, 10%,
and 13.6% (Figure 3).18
− Regional nodal recurrence: Rates of regional nodal recurrence in patients treated
with lumpectomy plus breast XRT were very low for patients with clinically
negative nodes (0.5%–2.3%) and for those with clinically positive nodes but
pathologically negative nodes at surgery (0–2.4%) (Figures 2 and 3). Pathologic
breast tumor response/pathologic nodal status did not seem to influence rates of
regional nodal recurrence in clinically node-negative patients, but in clinically
node-positive patients the rates of regional recurrence were higher in patients
who remained pathologically node-positive after neoadjuvant chemotherapy
(7.5%–8.7%) (Figures 2 and 3).
Figure 2. 10-year cumulative incidence of LRR in patients ≥ 50 years of age treated
with lumpectomy plus breast XRT

Clinically Node-negative Clinically Node-positive

Lumpectomy + Breast XRT n=122
> 50 years
n=58
n=348 n=31
n=212
n=90

Figure 3. 10-year cumulative incidence of LRR in patients < 50 years of age treated
with lumpectomy plus breast XRT

Clinically Node-negative Clinically Node-positive

Lumpectomy + Breast XRT n=154
< 50 years
n=223 n=84
n=57
n=135 n=376

07/10/13 NSABP B-51/RTOG 1304 Page 20

 • Patients treated with mastectomy
− Chestwall recurrence: Rates of chestwall recurrence generally increased with
decreasing pathologic breast tumor response and positive pathologic nodal status,
and this increase was more pronounced in patients with tumors > 5 cm compared
to those ≤ 5 cm and in patients with clinically positive nodes compared to those
with clinically negative nodes (Figures 4 and 5). Although the number of
patients is low, chestwall recurrences after mastectomy were very infrequent in
patients who achieved breast pCR with pathologic negative nodes irrespective of
tumor size and clinical nodal status (1 local recurrence in 94 patients)
(Figures 4 and 5).18
− Regional nodal recurrence: Regional nodal recurrence rates were generally low
in clinically node-negative patients irrespective of clinical tumor size
(2.3%–4.3% in patients with tumors ≤ 5 cm and 2.3%–6.2% in those with tumors
> 5 cm). Rates were higher for clinically node-positive patients, particularly if
they remained pathologically node-positive at surgery (Figures 4 and 5).
Figure 4. 10-year cumulative incidence of LRR in patients with ≤ 5 cm tumors treated
with mastectomy
25
10-Year Cum Incidence of LRR (%)

Clinically Node-negative Clinically Node-positive

20 n=143
Mastectomy < 5 cm
n=37
15 n=184
6.4
10 n=46 n=178 3.4
8.1
5 4.3 2.3 10.6
7.8 n=21
2.2 4 2.7
0 0
ypN(-)/ ypN(-) ypN(+) ypN(-)/ ypN(-) ypN(+)
Breast pCR No Breast Breast pCR No Breast
pCR pCR
Chest Wall Regional

Figure 5. 10-year cumulative incidence of LRR in patients with > 5 cm tumors treated with
mastectomy
30
10-Year Cum Incidence of LRR (%)

Clinically Node-negative Clinically Node-positive

25 n=128
Mastectomy > 5 cm
20 4.8
n=179
n=95 n=84
15
n=16 2.3
10 3.2 0
17.6
5 12.3
8.6 n=11 9.2
6.2
0 0 0
ypN(-)/ ypN(-) ypN(+) ypN(-)/ ypN(-) ypN(+)
Breast pCR No Breast Breast pCR No Breast
pCR pCR

Chest Wall Regional

07/10/13 NSABP B-51/RTOG 1304 Page 21

 2.4.4 Rates of LRR according to number of pathologically positive nodes at surgery

When rates of LRR for patients with pathologically positive nodes at surgery were
examined according to the number of positive nodes (1–3 vs. ≥ 4), the rates were
generally higher for those with ≥ 4 positive nodes vs. those with 1–3 positive nodes.
However, based on the independent predictors of LRR, the rates of LRR were
consistently above 10% for all subsets of patients with 1–3 positive nodes (with the
exception of clinically node-negative patients ≥ 50 years of age treated with breast
conserving surgery + XRT).18

The report of the B-18 and B-27 combined dataset describes the largest prospectively
collected cohort of patients with operable breast cancer treated with neoadjuvant
chemotherapy for which information of rates and patterns of LRR is available. Patients
met predefined eligibility criteria and were uniformly monitored as part of the B-18 and
B-27 neoadjuvant chemotherapy trials. The major strength of the data, however, is that
the use of XRT was legislated by protocol and was not left to the discretion of the
treating physician. Thus, patients undergoing mastectomy were not permitted to be
treated with chestwall or regional nodal XRT, and patients treated with lumpectomy were
required to receive breast XRT but were not permitted to receive additional regional
nodal XRT, irrespective of the number of residual positive nodes at surgery or the
original clinical nodal status or clinical tumor size before neoadjuvant chemotherapy. To
that extent, the two trials provide us with a large cohort of patients for whom the natural
history of LRR can be assessed without the confounding effects of non-uniform post-
mastectomy chestwall radiation or radiation to regional nodal basins. One significant
limitation of the study is the lack of information on ER, PgR, and HER2 neu status since
the majority of these patients were diagnosed by FNA. Thus, it is still not clear to what
extent pCR in the breast and sterilization of axillary nodes will influence the effect of
subtypes on rates of LRR.

2.5 Using neoadjuvant chemotherapy in order to tailor the use of loco-regional XRT

The results of the combined analysis of B-18 and B-27 clearly demonstrate that in addition to age
and clinical factors available before neoadjuvant chemotherapy (such as clinical tumor size and
clinical nodal status), pathologic response in the breast and pathologic axillary nodal status have a
major impact on the rates and patterns of LRR. The results further suggest that pCR in the breast
with pathologically negative axillary nodes minimizes the effect of age, clinical tumor size, and
clinical nodal status on the rates of LRR. Since clinical nodal status is a strong surrogate of
pathologic nodal status, these results indicate that in patients treated with neoadjuvant
chemotherapy, rates of LRR in patients who have positive nodes before neoadjuvant
chemotherapy can be modified downwards if the nodes become pathologically node-negative
after neoadjuvant chemotherapy (particularly if there is also pCR in the breast). Thus, patients
who have positive axillary nodes at presentation (who would be candidates for post-mastectomy
chestwall and regional nodal XRT or post-lumpectomy regional nodal XRT in addition to breast
XRT) can potentially avoid XRT if they become pathologically node-negative after neoadjuvant
chemotherapy. As there is active debate on the standard of care for such patients before either
strategy becomes the standard of care, randomized clinical trial data are needed to demonstrate
that the use of XRT (chestwall and regional nodal XRT for mastectomy patients and regional
nodal XRT for lumpectomy patients) would significantly improve patient outcomes. The results
of this proposed clinical trial have the potential to produce a major paradigm shift in the
loco-regional management of early-stage breast cancer assuming the data demonstrate that the
addition of XRT would not significantly improve outcomes in this originally high-risk group of

07/10/13 NSABP B-51/RTOG 1304 Page 22

 patients who significantly lower their risk of LRR by achieving pathologic down-staging of their
axillary nodes by neoadjuvant chemotherapy. For this reason (to determine if the addition of
XRT would significantly improve outcome and potentially lead to a paradigm shift), this study
has been designed as a superiority trial.

2.6 Issues with post-mastectomy breast reconstruction and the use of post-mastectomy
chestwall XRT

A major concern for patients who present with pathologically involved axillary nodes is that
decisions for immediate breast reconstruction can be complicated by the need for chestwall and
regional nodal XRT. Thus, for those patients the decision of whether to offer implant-based or
autologous tissue breast reconstruction is one that requires careful consideration. The approach
of a two-stage reconstruction with a tissue expander followed by a permanent breast implant after
post-mastectomy XRT, consistently reveals high rates of acute and chronic complications and
poor aesthetic outcomes (capsular contraction, pain, asymmetry, and need for implant
replacement ).19 Also, placement of an autologous tissue flap at the time of primary surgery has
the potential of flap contraction following the use of XRT. The approach of immediate-delayed
reconstruction where an expander is placed at the time of surgery followed by deflation of the
expander, chestwall XRT, and then, replacement of the expander with autologous flap
reconstruction offers an acceptable solution to the problem but requires a second major surgical
procedure. Thus, if one can avoid the need for XRT in a proportion of these node-positive
patients by down-staging their nodes with neoadjuvant chemotherapy, it could possibly lead to a
considerable improvement in the cosmetic outcome and quality of life of such patients.

The presence of a breast reconstruction has also been reported to compromise the planning of
post-mastectomy radiation. Investigators at MD Anderson Cancer Center analyzed the adequacy
of radiation dose delivery to women who had undergone immediate reconstruction versus those
without reconstruction present post-mastectomy. It was demonstrated that almost half of the
radiation plans were sub-optimal in the presence of an immediate reconstruction compared to
when there was not a reconstruction present in terms of dose delivery to the chestwall and internal
mammary nodes, and for minimization of dose to the lung and avoidance of the heart.20 To avoid
delivery of radiation that is potentially less effective and more toxic in reconstructed patients, it is
important to identify sub-optimal radiation treatment plans. This requires the development of
acceptance criteria for judging the adequacy of any given radiation treatment plan. Dose volume
analysis (DVA) with CT-based conformal radiation methods,
three-dimensional conformal radiation therapy (3DCRT), or intensity modulated radiation therapy
(IMRT) makes this feasible.

2.7 Standardization of IMRT and 3DCRT for regional nodal XRT and dose volume analysis

It is known that the addition of regional nodal XRT with chestwall post-mastectomy or regional
nodal XRT with breast XRT post-breast conserving surgery is associated with higher rates of
toxicity. The NCIC MA.20 study demonstrated that women who received comprehensive
regional nodal XRT + breast XRT compared to those who had breast XRT alone had higher rates
of acute and delayed toxicity including radiation dermatitis, pneumonitis, dyspnea and
lymphedema.17 The toxicities reported in this study and all prior post-mastectomy radiation
clinical trials evaluating regional nodal XRT reflect clinically directed or two-dimensional
radiation planning for dose delivery. CT-based conformal radiation methods such as 3DCRT or
IMRT allow DVA to be performed. Dose volume analyses quantitatively examine the dose
delivery/distribution to the intended target and unintended normal tissue volumes. This provides
a reliable means for comparing radiation treatments, and specifically, a method for quantifying

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 volume dose parameters for normal tissue and target volumes on radiation treatment plans that
could avoid toxicity or predict efficacy.

Dose volume analyses in association with known toxicity outcomes are crucial components to
more fully develop mathematical models that can predict normal tissue damage from radiation.
The normal tissue complication probability (NTCP) can be calculated from the non-uniform dose
distribution through an organ of interest in an integrative fashion.21 As an example, previous
studies have shown an increase in the number of nonfatal cardiac events associated with left-sided
irradiation for breast cancer patients.22–24 Ideally, at the time of the radiation plan evaluation,
knowledge of the critical DVA parameters predictive of cardiac events based on NTCP could
diminish its development. These models require DVA to quantify the partial organ irradiation.
Modeling radiation induced heart disease is relatively limited in the literature due in large part to
the lack of long-term results from 3D-based XRT in breast cancer.21 The banking of radiation
CT datasets and DVA in this trial will provide a means for developing NTCP for late radiation
toxicities for regional nodal XRT post-mastectomy and breast conserving surgery that can impact
all clinical practice.

One of the most important issues concerning IMRT and 3DCRT for breast cancer is the accurate
definition of target and normal tissue volumes. Conventional radiation techniques for breast
cancer used in all past clinical trials have been based predominantly on clinical palpation of
breast tissue and bony anatomy. In contrast to standard techniques, IMRT and 3DCRT require 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.25,26

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3.0 STUDY AIMS AND ENDPOINTS

3.1 Primary aim and endpoint

Aim: To evaluate whether the addition of chestwall + regional nodal XRT after mastectomy or
breast + regional nodal XRT after breast conserving surgery will significantly reduce the rate of
events for invasive breast cancer recurrence-free interval (IBC-RFI) in patients who present with
histologically positive axillary nodes but convert to histologically negative axillary nodes
following neoadjuvant chemotherapy.

Endpoint: IBC-RFI, defined as time from randomization until invasive local, regional, or distant
recurrence, or death from breast cancer.

3.2 Secondary aims and endpoints

3.2.1 Overall survival (OS)

Aim: To evaluate whether the addition of chestwall + regional nodal XRT after
mastectomy or breast + regional nodal XRT after breast conserving surgery will
significantly prolong OS in patients who present with histologically positive axillary
nodes but convert to histologically negative axillary nodes following neoadjuvant
chemotherapy.

Endpoint: OS, defined as time from randomization to death from any cause.

3.2.2 Loco-regional recurrence-free interval (LRRFI)

Aim: To evaluate whether the addition of chestwall + regional nodal XRT after
mastectomy or breast + regional nodal XRT after breast conserving surgery will
significantly reduce the rates of events for LRRFI in patients who present with
histologically positive axillary nodes but convert to histologically negative axillary nodes
following neoadjuvant chemotherapy.

Endpoint: LRRFI, defined as the time from randomization to the recurrence of the
primary breast cancer within the breast or in the lymph nodes in the ipsilateral axilla,
infraclavicular fossa, or ipsilateral internal mammary chain without evidence of distant
disease, or death due to breast cancer.

3.2.3 Distant recurrence-free interval (DRFI)

Aim: To evaluate whether the addition of chestwall + regional nodal XRT after
mastectomy or breast + regional nodal XRT after breast conserving surgery will
significantly reduce the rate of events for DRFI in patients who present with
histologically positive axillary nodes but convert to histologically negative axillary nodes
following neoadjuvant chemotherapy.

Endpoint: DRFI, defined as the time from randomization to the development of tumor in
all areas beyond local or regional limits, or death due to breast cancer.

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 3.2.4 Disease-free survival-ductal carcinoma in situ (DFS-DCIS)

Aim: To compare the rates of DFS-DCIS by treatment arm.

Endpoint: DFS-DCIS, defined as time from randomization to local recurrence following

mastectomy, local recurrence in the ipsilateral breast following lumpectomy (invasive or
DCIS), regional recurrence, distant recurrence, contralateral breast cancer (invasive or
DCIS), second primary cancer (other than squamous or basal cell carcinoma of the skin,
melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular
carcinoma in situ of the breast), or death from any cause prior to recurrence or second
primary cancer.

3.2.5 Second primary invasive cancer

Aim: To compare the rates of second primary invasive cancer by treatment arm.

Endpoint: Second primary invasive cancer, defined as the time from randomization to the
development of a second primary invasive cancer of any site excluding squamous and
basal cell carcinoma of the skin.

3.2.6 Quality of life

Aim: To compare the effect of adding XRT on the cosmetic outcomes in mastectomy
patients who have had reconstruction.
Aim: To compare the effect of adding XRT on quality of life including arm problems,
lymphedema, pain, and fatigue.
3.2.7 Toxicity
Aim: To evaluate the toxicity associated with each of the radiation therapy regimens.
Endpoint: Frequencies of adverse events categorized using the NCI Common
Terminology for Adverse Events Version 4.0 (CTCAE v4.0).
3.2.8 Treatment adequacy
Aim: To determine whether CT-based conformal methods (IMRT and 3DCRT) for
chestwall + regional nodal XRT post mastectomy and regional nodal XRT with breast
XRT following breast conserving surgery are feasible in a multi-institutional setting and
whether dose-volume analyses can be established to assess treatment adequacy and to
develop normal tissue complication probabilities (NTCP) for the likelihood of toxicity.
3.2.9 Effect of XRT
Aim: To compare the effect of XRT in patients receiving mastectomy and in patients
receiving lumpectomy.
3.2.10 Molecular predictors of recurrence
Aim: To examine the role of proliferation measures as a prognosticator for patients with
residual disease after neoadjuvant chemotherapy.

Aim: To develop predictors of the degree of reduction in LRR.

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4.0 RADIATION ONCOLOGY FACILITY CREDENTIALING AND QUALITY
ASSURANCE

4.1 Pre-registration requirements for 3DCRT/IMRT treatment approach

In order to utilize either 3DCRT 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 Radiological Physics Center (RPC) Web site.
Visit http://rpc.mdanderson.org/rpc and select "Credentialing".

This study will require each institution to complete a Benchmark case for each treatment
technique and for both Arms for credentialing Arm 1/Group 1A and Arm 2/Groups 2A and 2B.
These cases apply for both the 3CDRT and IMRT treatment modalities. Institutions that
previously credentialed for RTOG 1005 do not need to submit a Benchmark case for
Arm 1/Group 1A; however, if an institution was previously credentialed for RTOG 1005 but is
changing the treatment technique, then a new benchmark case must be submitted. The
Benchmark case is a treatment planning exercise. CT scans for each case will be made available
for downloading from the Advanced Technology Consortium (ATC) Web site
http://atc.wustl.edu, and the institution is expected to use this dataset to demonstrate their ability
to generate an acceptable dose distribution. For Arm 1/Group 1A, the CT datasets will include
contours of the breast tissue together with contours of the boost volume, and for Arm 2/Group 2A
or Group 2B the CT datasets will include contours of the breast or chestwall, respectively, and the
supraclavicular, axillary, and internal mammary nodes. The planning results will be submitted
electronically to the Image-therapy Guided Center (ITC) for review (http://atc.wustl.edu). The
results of this planning exercise will be examined and approved by the RPC before the first
patient can be enrolled from a particular institution. Upon successful completion and approval of
the Benchmark case, the NSABP Biostatistical Center will notify the institution that they have
completed this requirement.

4.2 Facility questionnaire and data submission

The institution or investigator must complete a Facility Questionnaire or modify their existing
questionnaire (on file at RTOG headquarters) and send it to the RPC for review prior to enrolling
any cases. Updating an existing electronic RPC Facility Questionnaire can be accomplished via
the link supplied to the institution's primary clinical trial physicist or by contacting the RPC
at 713-745-8989.

In order to submit the benchmark credentialing case and all digital data for registered patients, the
institution must set up an SFTP account for digital data submission. Information for establishing
this account can be found at the ATC Web site. Upon review and successful completion of all
requirements, the NSABP Biostatistical Center will notify the institution that they are eligible to
enroll patients on the B-51/1304 study.

The quality assurance (QA) program will cover the delivery of both 3DCRT and IMRT. Each
case will be submitted digitally to the ITC where it will be processed and made available for
review by study chairs or designees, the RPC, and the RTOG Headquarters Dosimetry Group.

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4.3 Quality assurance for standard whole breast irradiation with boost (Arm 1/Group 1A)

4.3.1 Rapid Review

The first case enrolled in Arm 1/Group 1A from each radiation oncology facility will
undergo rapid review. In this process, the finalized treatment plan must be electronically
submitted to ITC, reviewed, and approved prior to the start of treatment. No other
patients may be treated on this arm at the institution until approval from the rapid
review on the first case is received. If treatment is started prior to the Rapid Review
approval, this will be a major protocol deviation and another Rapid Review must be done.
Enrollment may continue during the rapid review process. 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 are received by the ITC. Cases that do not meet contouring and DVA
quality assurance criteria will not be approved. The institution will need to make
corrections and resubmit the case to obtain approval for treatment. When corrections or
additional documentation is requested, the subsequent submission of the case will be
given priority review.
4.3.2 Regular Reviews
All Arm 1/Group 1A cases enrolled on the trial will be reviewed. This includes all those
submitted after successful completion of the rapid review process. If a case does not
meet contouring and quality assurance criteria such that it is scored as "deviation
unacceptable," the radiation oncology facility will be required to repeat an additional
rapid review for the facility to continue to treat patients on this arm. The treatment plan
must be submitted to ITC within 30 days of treatment initiation. These cases will be
reviewed within the next 30 days with feedback given to the submitting radiation
oncology facility.
4.4 Quality assurance for regional nodal irradiation + breast XRT or chestwall XRT
(Arm 2/Groups 2A and 2B)
4.4.1 Rapid Review
The first case on Arm 2/Group 2A and the first case on Arm 2/Group 2B enrolled in the
trial from each radiation oncology facility will undergo rapid review. In this process, the
finalized treatment plan must be electronically submitted to ITC, reviewed, and approved
prior to the start of treatment. No other patients may be treated on the Group under
review at the institution until approval from the rapid review on the first case is
received. If treatment is started prior to Rapid Review approval, this will be a major
protocol deviation and another Rapid Review must be done. Enrollment may continue
during the rapid review process. 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 are received by
the ITC. Cases that do not meet contouring and DVA quality assurance criteria will not
be approved. The institution will need to make corrections to obtain approval for
treatment. When corrections or additional documentation is requested, the subsequent
submission of the case will be given priority review.
4.4.2 Regular Reviews
All Arm 2/Groups 2A and 2B cases enrolled on the trial will be reviewed. This includes
all those submitted after successful completion of the rapid review process. If a case does

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 not meet contouring and quality assurance criteria such that it is scored as "deviation
unacceptable," the radiation oncology facility will be contacted and required to repeat an
additional rapid review for the facility to continue to treat patients on the Arm/Group
under review. The treatment plan must be submitted to ITC within 30 days of treatment
initiation. These cases will be reviewed within the next 30 days with feedback given to
the submitting radiation oncology facility.

4.5 Radiation therapy Quality Assurance Review

The Radiation Oncology Chairs or designees will perform a radiation therapy 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 have been received at RTOG Headquarters, whichever occurs first.

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5.0 PATIENT ELIGIBILITY AND INELIGIBILITY

5.1 Patient selection guidelines

Although the guidelines in Section 5.1 are not inclusion/exclusion criteria, investigators should
consider each of these factors when selecting patients for the trial. Investigators should also
consider all other relevant factors (medical and non-medical), as well as the risks and benefits of
the study therapy, when deciding if a patient is an appropriate candidate for this trial.

• Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast
cancer. (Comorbid conditions should be taken into consideration, but not the diagnosis of
breast cancer.)
• Women of reproductive potential must agree to use an effective non-hormonal method of
contraception during radiation therapy.
• Submission of tumor samples is required for all patients (see Section 7.1). Therefore, the
local pathology department policy regarding release of tumor samples must be considered in
the screening process. Patients whose tumor samples are located in a pathology department
that by policy will not submit any samples for research purposes should not be approached
for participation in the B-51/1304 trial.

5.2 Conditions for patient eligibility

A patient cannot be considered eligible for this study unless all of the following conditions are
met.

5.2.1 The patient must have signed and dated an IRB-approved consent form that conforms to
federal and institutional guidelines.

5.2.2 The patient must be female.

5.2.3 The patient must be ≥ 18 years old.

5.2.4 The patient must have an ECOG performance status of 0 or 1 (see Appendix A).

5.2.5 Patient must have clinically T1-3, N1 breast cancer at the time of diagnosis (before
neoadjuvant therapy). Clinical axillary nodal involvement can be assessed by palpation,
ultrasound, CT scan, MRI, PET scan, or PET/CT scan.

5.2.6 Patient must have had pathologic confirmation of axillary nodal involvement at
presentation (before neoadjuvant therapy) based on either a positive FNA (demonstrating
malignant cells) or positive core needle biopsy (demonstrating invasive adenocarcinoma).
The FNA or core needle biopsy can be performed either by palpation or by image
guidance. Documentation of axillary nodal positivity by sentinel node biopsy (before
neoadjuvant therapy) is not permitted.

5.2.7 Patients must have had ER analysis performed on the primary breast tumor before
neoadjuvant therapy according to current ASCO/CAP Guideline Recommendations for
hormone receptor testing. If negative for ER, assessment of PgR must also be performed
according to current ASCO/CAP Guideline Recommendations for hormone receptor
testing (http://www.asco.org).

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 5.2.8 Patients must have had HER2 testing performed on the primary breast tumor before
neoadjuvant chemotherapy according to the current ASCO/CAP Guideline
Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast
Cancer (http://www.asco.org). Patients who have a primary tumor that is either
HER2-positive or HER2-negative are eligible.

5.2.9 Patient must have completed a minimum of 12 weeks of standard neoadjuvant

chemotherapy consisting of an anthracycline and/or taxane-based regimen.

5.2.10 For patients who receive adjuvant chemotherapy after surgery, a maximum of 12 weeks
of intended chemotherapy may be administered but must be completed before
randomization. (If treatment delays occur, chemotherapy must be completed within
14 weeks.) The dose and schedule of the adjuvant chemotherapy are at the investigator's
discretion. Note: It is preferred that all intended chemotherapy be administered in the
neoadjuvant setting.

5.2.11 Patients with HER2-positive tumors must have received neoadjuvant trastuzumab or
other anti-HER2 therapy (either with all or with a portion of the neoadjuvant
chemotherapy regimen), unless medically contraindicated.

5.2.12 At the time of definitive surgery, all removed axillary nodes must be histologically free
from cancer. Acceptable procedures for assessment of axillary nodal status at the time of
surgery include:
• axillary node dissection;
• sentinel node biopsy alone; or
• sentinel node biopsy followed by axillary node dissection.

Note: Patients are eligible whether there is residual invasive carcinoma in the surgical
breast specimen or whether there is evidence of pathologic complete response.

Patients who are found to be pathologically node-positive at the time of surgery, based
on sentinel node biopsy alone, are candidates for A011202, a study developed by the
Alliance in Oncology, an NCI Cooperative Group. If A011202 is open at the
investigator's institution, patients should be approached about participating in the
A011202 study.

5.2.13 Patients with pathologic staging of ypN0(i+) or ypN0(mol+) are eligible.

5.2.14 Patient who have undergone either a total mastectomy or a lumpectomy are eligible.
5.2.15 For patients who undergo lumpectomy, the margins of the resected specimen or re-
excision must be histologically free of invasive tumor and DCIS as determined by the
local pathologist. Additional operative procedures may be performed to obtain clear
margins. If tumor is still present at the resected margin after re-excision(s), the patient
must undergo total mastectomy to be eligible. (Patients with margins positive for LCIS
are eligible without additional resection.)
5.2.16 For patients who undergo mastectomy, the margins must be histologically free of residual
(microscopic or gross) tumor.
5.2.17 The interval between the last surgery for breast cancer (including re-excision of margins)
and randomization must be no more than 56 days. Also, if adjuvant chemotherapy was

07/10/13 NSABP B-51/RTOG 1304 Page 31

 administered, the interval between the last chemotherapy treatment and randomization
must be no more than 56 days.

5.2.18 The patient must have recovered from surgery with the incision completely healed and no
signs of infection.

5.2.19 If adjuvant chemotherapy was administered, chemotherapy-related toxicity that may

interfere with delivery of radiation therapy should have resolved.

5.3 Conditions for patient ineligibility

Patients with one or more of the following conditions are NOT eligible for this study.
5.3.1 Definitive clinical or radiologic evidence of metastatic disease.
5.3.2 T4 tumors including inflammatory breast cancer.
5.3.3 Documentation of axillary nodal positivity before neoadjuvant therapy by sentinel node
biopsy alone.
5.3.4 N2 or N3 disease detected clinically or by imaging.

5.3.5 Patients with histologically positive axillary nodes post neoadjuvant therapy.
5.3.6 Patients with microscopic positive margins after definitive surgery.
5.3.7 Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with
synchronous and/or previous contralateral LCIS are eligible.)
5.3.8 Any prior history, not including the index cancer, of ipsilateral invasive breast cancer or
ipsilateral DCIS treated with radiation therapy. (Patients with synchronous or previous
ipsilateral LCIS are eligible.)
5.3.9 History of non-breast malignancies (except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to
randomization.
5.3.10 Any radiation therapy for the currently diagnosed breast cancer prior to randomization.
5.3.11 Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone
replacement therapy. Patients are eligible if these medications are discontinued prior to
randomization (see Section 5.1).
5.3.12 Prior breast or thoracic RT for any condition.
5.3.13 Active collagen vascular disease, specifically dermatomyositis with a CPK level above
normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
5.3.14 Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be
performed within 2 weeks prior to randomization according to institutional standards
for women of childbearing potential.)
5.3.15 Other non-malignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up.
5.3.16 Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.

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6.0 REQUIREMENTS FOR ENTRY, TREATMENT, AND FOLLOW-UP

Tests, exams, and other assessments required prior to randomization are listed on Table 2.
Requirements following randomization are outlined on Table 3.

TABLE 2. Tests, exams, and other requirements prior to randomization

Required Assessments Prior to Randomization
Determination of local pathology department's policy
X
regarding submission of tumor samples (Section 5.1)
Consent form signed by the patient X
Determination of hormone receptor status (before
X
neoadjuvant therapy was given [Section 5.2.7])
HER2 analysis (before neoadjuvant therapy was given
X
[Section 5.2.8])
History & physical exam Xa
Assessment of performance status (Appendix A) X
Menopausal status Xb Within 4 weeks
Height & weight X
CBC/differential/platelet count Xc
Pregnancy test Xd Within 2 weeks
Bilateral breast imaging Xe Within 12 months
CT of chest/abdomen/pelvis and bone scan or PET/CT
Xf
scan
BAHO (QOL/PROs) questionnaire Xg Within 2 weeks
Tumor blocks (from primary breast tumor and from
definitive surgery) requested from local pathology Xh
department (See Section 7.1)
a Complete H&P by physician or other healthcare professional.
b Menopausal status at the time of breast cancer diagnosis.
c For patients who receive adjuvant chemotherapy, testing must be done at least 3 weeks from the
last dose of chemotherapy.
d For women of childbearing potential: Pregnancy testing should be performed according to
institutional standards.
e MRI is permitted as a substitute for mammogram before entry (ultrasound is not). Imaging may be
unilateral for patients who have had mastectomy with or without reconstruction.
f There must be no definitive radiologic evidence of metastatic disease on imaging performed
between time of breast cancer diagnosis until randomization.
g For patients who agree to participate in the QOL study, the BAHO questionnaire must be
administered after the informed consent is signed but before randomization (see Section 8.4). The
BAHO questionnaire must be submitted to the NSABP Biostatistical Center within 30 days
following randomization.
h Before study entry, the blocks must be requested and the pathology department must agree to
release the required tumor materials as outlined in Section 7.1. (Submit required tumor materials
within 90 days following randomization.)

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TABLE 3. Tests, exams, and other requirements during therapy and follow-up for Arm 1 and Arm 2
Years 3 through 10
6 months 12 months 18 and 24 months
After End of RT from
Required assessmentsa from from from
randomization (see footnote b) randomization
randomization randomization randomization
(every 12 months)
History & physical examc X X X X X
Breast assessment/exam X X X X X
Adverse event assessment Xd
X
Bilateral mammogram Xe (24 months only)
X

BAHO (QOL/PROs) X
X X X
questionnaire (24 months only)
Tumor block submission Xf
a H&P, scans, and other testing may be performed more frequently at the discretion of the investigator.
b Patients in Arm 1/Group 1B will have exams and assessments at 3 months after randomization.
c Updated H&P with exams (by physician or other healthcare professional) appropriate for therapy-related assessments and follow-up
evaluations.
d Final AE assessment 30 days after the last dose of radiation therapy for Group Arm 1/Group 1A and Arm 2/Groups 2A and 2B; assessment
may be based on office notes from other physician visits or telephone contact with the patient.
e Mammogram is required; unilateral for patients who have had mastectomy with or without reconstruction. First mammogram will be 1 year
from the most recent mammogram (or MRI) performed prior to randomization and then every 12 months. (Mammograms may be
performed more frequently at the discretion of the investigator.)
f Blocks from the diagnostic core biopsy and residual tumor (if gross residual disease > 0.5 cm) are required within 90 days (see Section 7.1).
NOTE: Tests, exams, and assessments, are not required following a documented invasive breast cancer recurrence, invasive contralateral
breast cancer, or second nonbreast primary cancer excluding squamous or basal cell skin cancers or new in situ carcinomas of any site.
Follow-up for subsequent cancer events and for survival continues to be required every 6 months through 24 months and then every
12 months from Year 3 through Year 10. (See Section 11.0 for adverse event reporting requirements.)

07/10/13 NSABP B-51/RTOG 1304 Page 34

7.0 PATHOLOGY AND CORRELATIVE SCIENCE STUDIES

7.1 Overview of requirements

Tumor sample submissions are a protocol requirement and, therefore, mandatory for participation
in the study (see Table 4 for specific requirements). By signing the B-51/1304 consent form, the
patient has agreed to tumor sample submissions.

TABLE 4. Summary of B-51/1304 tumor sample submission requirements

Specimen requirements After randomization

Paraffin block from the primary breast tumor Yes*

(A study requirement for all patients) (within 90 days)
Representative paraffin block of residual tumor
Yes*
> 0.5 cm
(within 90 days)
(A study requirement, if applicable)
Diagnostic H&E slides No
* If the pathology department refuses to provide a block for research purposes but will provide
alternative tissue specimens, refer to the B-51/1304 Pathology and Correlative Science Instructions
for alternative sample submission instructions.
NOTE: Refer to the Members' Area of the NSABP Web site for the B-51/1304 Pathology and
Correlative Science Instructions.

7.2 Use of specimens

The tumor samples collected in this study will be used for studies specified in the B-51/1304
protocol and for studies to be conducted in the future related to the purposes of the B-51/1304
study and not currently described in the protocol document.

Specific aims include testing the role of proliferation measures as a prognosticator for patients
with residual disease after neoadjuvant therapy and to develop predictors of the degree of
reduction in LRR. The procured specimens, including DNA samples derived from them, will
not be used for hereditary genetic studies involving genes conferring susceptibility to cancer or
other diseases unless additional consent is obtained from the patient or an anonymization
process is used. Results of the correlative science studies will not be reported to the patient or
her physician and will not have any bearing on her treatment.

7.3 Specimen submission and identification procedures

Refer to the B-51/1304 Pathology Instructions in the Members' Area of the NSABP Web site for
details regarding submission of specimens.

Submitted blocks are initially shipped to and logged into the database at the NSABP Biostatistical
Center. These samples are then stripped of patient identifiers except B-51/1304 Patient ID
numbers and forwarded to the NSABP Division of Pathology where they are assigned a code
number for further processing and study.

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7.4 Hypotheses

• To examine the role of proliferation measures as a prognosticator for patients with residual
disease after neoadjuvant chemotherapy.
• To develop predictors of the degree of reduction in LRR.

In B-27, ER expression by immunohistochemistry was as good a prognostic factor as the gene

expression profile discovered through microarray analysis. Patients with residual disease had
favorable prognosis if their pretreatment ER status was positive. However, with ER-positive
tumors, Ki67 could identify high-risk patients independent of nodal status (Figure 6). Therefore,
we can use pretreatment ER status by IHC, post-treatment Ki67 by IHC, and post-treatment nodal
status to identify very high-risk patients among those with residual tumors after neoadjuvant
chemotherapy. While we have not examined the B-27 data according to site of failure due to
small sample size, we could hypothesize based on our experience with Recurrence Score that
Ki67 may predict both loco-regional as well as distant recurrences.27

Figure 6. Survival of patients with residual disease after neoadjuvant chemotherapy according to
Ki67 status

In B-14 and B-20, Recurrence Score was a significant predictor of loco-regional recurrences
(Figure 7).28 About one half of these patients received lumpectomy and radiotherapy.

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 Figure 7. LRR of patients from NSABP trial B-20 based on Recurrence Score

Meta-analyses of gene expression data by Wirapati et al. demonstrated that the main driver of
Recurrence Score or other prognostic algorithms is the proliferation activity of tumor cells
(Figure 8).29 Therefore, it could be hypothesized that Ki67 will be strongly predictive of LRR
after neoadjuvant chemotherapy.

Figure 8. Gene expression algorithms and proliferation activity

In Figure 8, the Y-axis represents proliferation score, and the red color represents cases with high
risk classification by the algorithm. These data show that each algorithm identifies high-risk
tumors among ER-positive/HER2-negative subsets based on their high proliferation activity.

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 Therefore, this trial will provide a good basis to test the prognostic role of Ki67 or other gene
expression profiles assessed with residual tumor tissue. Furthermore, we will be able to test whether
Ki67 or proliferation (or other) genes will be predictive of the degree of reduction in LRR.

We have significant experience using the NanoString platform to interrogate gene expression
levels in formalin-fixed, paraffin-embedded samples.30 We will use a custom-designed gene set
of 800 genes that encompass all published prognostic genes, as well as genes associated with the
apoptosis pathway. We have also developed a robust next-generation-sequencing-based digital
gene expression method that can be readily applied to the residual tumor tissue collected from
this study for a discovery approach. A separate protocol (to include analytical and statistical
methodology) will be developed for use of the samples collected for the B-51/1304 study for
marker assays (including exploratory high-throughput assays such as Nanostring) and submitted
and approved in accordance with the National Clinical Trials Network.

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8.0 BEHAVIORAL AND HEALTH OUTCOMES CORRELATIVE SCIENCE STUDY

8.1 Overview

Women who receive neoadjuvant therapy for breast cancer usually have more advanced disease
and are hoping to obtain a clinical response that will permit breast conserving treatment. In
addition to the biological benefits of a tumor and nodal response, conversion of positive
pre-operative axillary nodal disease to a pathologically negative axilla may spare these women
the need for combined modality therapy (i.e., surgery and radiation). The latter, while ensuring
that any microscopic residual axillary disease is controlled, may lead to more extensive short and
long-term morbidity, including reduced arm function, lymphedema, pain, greater fatigue (from
addition of radiation if not necessary post-mastectomy), poorer cosmetic outcomes from breast
reconstruction, greater time off from work, increased health care costs, and greater personal
disruption from cancer treatment, which is extended over a longer period of time. Since the
benefits of post-neoadjuvant radiation therapy are unknown at this time, the opportunity to study
this question in a randomized trial provides an excellent opportunity for examining the impact of
radiation therapy on symptoms and domains of quality of life that are very important to women.
Integrating these health outcomes from the parent trial findings is essential. What are the human
costs of additional radiation treatments in all women, as we will not know who is truly at risk for
a local or regional recurrence? The goal of this correlative study is to answer this question. To
accomplish this, we will collect patient-reported outcomes (PROs) prior to randomization to
radiation or not, in both mastectomy and lumpectomy patients, and obtain follow-up data
collection at 3, 6, 12, and 24 months after randomization. We will pay special attention to the
impact of this treatment on women who have received immediate breast reconstruction as part of
their mastectomy, as the cosmetic results of the reconstructive surgery may be affected by the
addition of post-mastectomy chestwall irradiation (see Section 2.6). The 3-month/post-radiation
therapy assessment is assumed to be the time of maximum impact in terms of inconvenience (for
mastectomy patients who would not have received radiation) and the breast impact for those
women who received reconstruction, specifically related to cosmetic issues and discomfort.
Since a main focus of the BAHO study is the consequences of chestwall radiation on the
mastectomy population who have received reconstruction, the 3-month/post-treatment evaluation
comparing those with radiation to those who have no radiation, may be an essential data point and
could be predictive of future cosmetic outcome assessed later in the follow-up.

The NSABP has extensive experience with the inclusion of quality of life (QOL) studies within
its trials. Particularly relevant to this study concept is our past and ongoing work examining QOL
outcomes in the local regional treatment of breast cancer. Specifically, in the NSABP B-32 trial
that examined outcomes comparing sentinel node biopsy alone to sentinel node biopsy and
axillary dissection, we were able to track PROs related to arm function, breast/chestwall and arm
edema, pain, and QOL in over 700 women longitudinally for 36 months.31 Our questionnaires
were sensitive enough to detect significant differences between the two axillary treatment
strategies, especially in the first 6 months. In addition, longitudinally, patients in the axillary
dissection group were more likely to experience ipsilateral arm and breast symptoms, restricted
work and social activity, and impaired QOL (all Ps ≤ 0.002).31 Of note, our PRO data lined up
extremely well with actual measures of arm range of motion and edema.32 In addition, that
evaluation demonstrated that women who had radiation afterwards had substantially increased
odds of restricted shoulder motion (odds ratio 2.48) and lymphedema (odds ratio 3.47).32 Thus,
the addition of radiation therapy after axillary surgery will put women at substantially greater risk
of these morbidities.

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 A more recent active NSABP and RTOG collaborative trial is NSABP B-39/RTOG 0413, which
is examining breast cosmesis and function, comparing accelerated partial breast irradiation and
standard whole breast therapy. We have excellent measures of cosmesis, arm function symptoms
related to breast radiation, fatigue, pain, and disruption in everyday activities that have been
completed by over 1000 women enrolled in the QOL study, followed for 36 months. The major
validated scale being used in that trial is Stanton’s Breast Cancer Treatment Outcome Scale
(BCTOS), that was specifically designed to evaluate the cosmetic outcomes of breast conserving
treatment with radiation.33,34 Preliminary examination of the baseline results (pre-radiotherapy
in B-39/0413 demonstrates excellent psychometric properties for the BCTOS. Preliminary
examination of the baseline results (pre-radiotherapy in B-39/0413) demonstrates excellent
psychometric properties for the BCTOS. We expect that breast cosmetic concerns, as well as
body image overall, will be relevant to all trial participants, but will be of most interest in
answering the questions related to breast reconstruction in those women who have received
mastectomy. The BCTOS scale approach will require minimal adaptation to be used in all
patients, including mastectomy with or without reconstruction, for the B-51/1304 study.

In addition to using targeted PRO instruments for arm function, arm and breast edema, cosmesis,
pain, and fatigue, we will track disruption in everyday function (work, childcare, disability time)
related to the two strategies, along with overall QOL as measured by the MOS SF-36 and the
EuroQol-5D (EQ-5D).35–37 Fatigue will be measured with the Vitality scale from the
MOS SF-36.35

8.2 Aims and hypotheses

8.2.1 Primary aim

To determine the effect of radiation therapy on cosmesis at 12 and 24 months after

randomization among mastectomy patients who have had reconstructive surgery.

8.2.2 Secondary aims

• To compare the effect of adding XRT on the cosmetic outcomes in women who had a
lumpectomy.
• To examine and compare the effect of XRT on the pattern of arm function, arm
edema, pain, and breast/chestwall symptoms, as well as QOL, in women with
mastectomy who are also receiving breast reconstruction.
• To explore the predictors of post-treatment arm problems and arm edema at
12 months, examining medical and demographic characteristics, as well as PROs at
study entry.
• To explore the predictors of post-treatment fatigue at 12 months, examining medical
and demographic characteristics, as well as PROs at study entry.
• To compare the effect of adding XRT on cosmetic outcomes evaluated at 24 months
after randomization.
8.2.3 Primary hypothesis

Among mastectomy patients who have had reconstructive surgery, cosmetic results
evaluated at 12 and 24 months after randomization will be worse for women assigned to
radiation therapy compared to those assigned to the no radiation therapy group. (BCTOS
scale will be used.)

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 8.2.4 Secondary hypotheses

• All patients assigned to radiation therapy will have greater problems with arm
function, arm edema, breast/chestwall symptoms, pain, and restricted work and social
activity at 12 months after randomization compared to those women without
radiation. (NSABP B-32 scales will be used.)
• All patients assigned to radiation therapy will have greater post-treatment fatigue at
12 months after randomization compared to those women without radiation, as
measured by the SF-36 Vitality scale.
• There will be no difference in overall QOL as measured by the SF-36 PCS and MCS
scales (Physical and Mental Component Scales) at 12 and 24 months after
randomization comparing those with breast conserving surgery who received
radiation vs. those who did not.
• Mastectomy patients who do not receive radiation therapy will have a more rapid
recovery at 12 months in SF-36 physical functioning and SF-36 vitality compared to
those who receive radiation therapy.

8.3 Administration of B-51/1304 patient-completed questionnaires

8.3.1 Time points for administration

The B-51/1304 QOL questionnaire (Form QOL) will be administered at the following
time points:
• Prior to randomization (after surgery/adjuvant chemotherapy): After the B-51/1304
consent form has been signed.
• Following randomization at:
− 3 months for Arm 1/Group 1B or at the end of RT for Arm 1/Group 1A and
Arm 2/Groups 2A and 2B
− 6 months
− 12 months
− 24 months
8.3.2 Administration instructions
After the baseline, questionnaires are to be administered at follow-up visits, so that when
a follow-up visit is delayed, completion of Form QOL may also be delayed. Form QOL
should be administered during an office visit if at all possible, preferably while the
patient is waiting to be seen. Once the questionnaires are completed by the patient, the
staff member should review it to ensure that no items were unintentionally left blank.
When absolutely necessary, it may also be administered by mail or phone. Instructions
for administering questionnaires, including details such as how to administer over the
phone, can be found on the Members' Area of the NSABP Web site.
Patients who experience invasive breast cancer recurrence or invasive second primary
cancer will not be expected to continue completing Form QOL. Note: Patients in
Arm 1/Group 1A and Arm 2/Groups 2A and 2B who never initiate B-51/1304 study
therapy or discontinue the study therapy for other reasons will be expected to continue
completing Form QOL per protocol schedule.

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 If a patient declines to complete a scheduled Form QOL form or if the questionnaire is
not completed for any other reason (and cannot be completed by phone or mail), a
Missing Data Form for Quality of Life Questionnaire (Form QMD) should be submitted
online by the institution to the NSABP Biostatistical Center instead. Completed
questionnaires must be faxed to the NSABP Biostatistical Center (see Information
Resources).
8.4 BAHO patient population
PROs and QOL will be evaluated in 736 patients who read English, French, or Spanish, and who
have completed the baseline questionnaire. If a patient chooses to not complete the baseline
BAHO questionnaire or if completion of the baseline questionnaire is missed, the patient will not
be included in the BAHO patient sample but will still be eligible for B-51/1304.

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9.0 TREATMENT REGIMEN

• Radiation therapy must begin within 12 weeks of the last breast cancer surgery or the last
dose of adjuvant chemotherapy.
• It is preferred that all intended chemotherapy be administered in the neoadjuvant setting.
However, if adjuvant chemotherapy is administered, a maximum of 12 weeks of intended
chemotherapy may be given. (If treatment delays occur, chemotherapy must be completed
within 14 weeks.) Chemotherapy must be completed before randomization. The dose and
schedule of adjuvant chemotherapy are at the investigator's discretion.

9.1 Arm 1/Group 1A

Patients who had a lumpectomy and are randomized to Arm 1/Group 1A will receive standard
whole breast XRT as outlined in Section 10.0 and any additional systemic therapy as planned
(i.e., hormonal therapy for patients with hormone receptor-positive breast cancer and trastuzumab
or other anti-HER2 therapy for patients with breast cancer that is HER2-positive).

9.2 Arm 1/Group 1B

Patients who had a mastectomy and are randomized to Arm 1/Group 1B will not receive XRT but
will receive any additional systemic therapy as planned (i.e., hormonal therapy for patients with
hormone receptor-positive breast cancer and trastuzumab or other anti-HER2 therapy for patients
with breast cancer that is HER2-positive).

9.3 Arm 2/Group 2A

Patients who had a lumpectomy and are randomized to Arm 2/Group 2A will receive
comprehensive XRT, which is XRT to the breast plus regional nodal areas as outlined in
Section 10.0 and any additional systemic therapy as planned (i.e., hormonal therapy for patients
with hormone receptor-positive breast cancer and trastuzumab or other anti-HER2 therapy for
patients with breast cancer that is HER2-positive).

9.4 Arm 2/Group 2B

Patients who had a mastectomy and are randomized to Arm 2/Group 2B will receive
comprehensive XRT, which is XRT to the chestwall plus regional nodal areas as outlined in
Section 10.0, in addition to any additional systemic therapy as planned (i.e., hormonal therapy for
patients with hormone receptor-positive breast cancer and trastuzumab or other anti-HER2
therapy for patients with breast cancer that is HER2-positive).

9.5 Breast surgery

• Surgery should be performed within 42 days after completion of neoadjuvant chemotherapy.

• Breast reconstructive surgery is permitted.

9.6 Adjuvant endocrine therapy

• Patients with ER-positive and/or PgR-positive tumors should receive a minimum of 5 years
of endocrine therapy.

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 • Endocrine therapy may be initiated before, during, or after completion of XRT at the
discretion of the investigator.
• LHRH agonist/antagonists (e.g., Lupron and Zoladex) or ovarian ablation by surgery or
RT are permitted for premenopausal patients.
• Adjuvant endocrine therapy should be administered according to the current ASCO
guidelines (http://www.asco.org). However, selection of endocrine therapy will be at the
investigator's discretion. The dose and schedule of endocrine therapy should be consistent
with the drug package insert.
9.7 Anti-HER2 therapy

Anti-HER2 therapy (trastuzumab or other anti-HER2 therapy) is required for patients whose
tumors are HER2-positive. It can be given either with all or with a portion of the neoadjuvant
chemotherapy regimen with the remaining doses administered postoperatively at the
investigator's discretion. Use of anti-HER2 therapy during radiotherapy is permitted.

9.8 Non-protocol therapy

Partial breast irradiation techniques are prohibited.

9.9 Participation in other clinical trials

Contact the NSABP Clinical Coordinating Division (see Information Resources) to confirm that
participation in another clinical trial (including supportive therapy trials) by a B-51/1304 patient
is permitted.

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10.0 RADIATION THERAPY
Note: Radiation therapy must begin within 12 weeks of the last breast cancer surgery or the last
dose of adjuvant chemotherapy.

10.1 Radiation therapy for Arm 1/Group 1A

Post-lumpectomy patients who are to receive whole breast irradiation only will have treatment
delivered to the Breast Planning Target Volume (PTV) only with a boost to the Lumpectomy
Cavity PTV. (In Arm 1/Group 1A, modification of the breast fields to specifically include the
low axilla is not allowed.)

10.2 Radiation therapy for Arm 2

10.2.1 Post-lumpectomy (Arm 2/Group 2A)

Post-lumpectomy regional nodal irradiation and whole breast irradiation with boost are to
be delivered to the following planning target volumes: undissected axilla, supraclavicular
nodes, and internal mammary nodes in the first 3 intercostal spaces, and whole breast.

10.2.2 Post-mastectomy (Arm 2/Group 2B)

Post-mastectomy radiation is to be delivered to the following planning target volumes:

the chestwall, undissected axilla, supraclavicular nodes, and internal mammary nodes in
the first 3 intercostal spaces.

10.3 Dose specifications

10.3.1 Post-lumpectomy whole breast irradiation + boost (Arm 1/Group 1A)

10.3.1.1 Breast: 50 Gy in 25 fractions of 2 Gy

10.3.1.2 Lumpectomy cavity: Boost dose will be 12 or 14 Gy in 6 or 7 fractions of 2 Gy

for cumulative total doses of 62–64 Gy

10.3.2 Post lumpectomy whole breast irradiation + regional nodal irradiation (Arm 2/Group 2A)

10.3.2.1 Breast: 50 Gy in 25 fractions of 2 Gy

10.3.2.2 Lumpectomy cavity: Boost dose will be 12 or 14 Gy in 6 or 7 fractions of 2 Gy

for cumulative total doses of 62–64 Gy

10.3.2.3 Undissected axilla, supraclavicular nodes, and internal mammary

nodes: 50 Gy in 25 fractions of 2 Gy

10.3.3 Post-mastectomy irradiation + regional nodal irradiation (Arm 2/Group 2B)

10.3.3.1 Chestwall: 50 Gy in 25 fractions of 2 Gy

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 10.3.3.2 Chestwall boost - Permissible ONLY in cases with close (≤ 2 mm) surgical
margins on the mastectomy specimen. Boost dose will be 12 or 14 Gy in
6-7 fractions of 2 Gy per investigator discretion for cumulative total doses
of 62–64 Gy

10.3.3.3 Undissected axilla, supraclavicular nodes, and internal mammary

nodes: 50 Gy in 25 fractions of 2 Gy

10.4 Technical factors

10.4.1 The guidelines for IMRT in this trial will conform to the policies set by the ATC and the
NCI http://atc.wustl.edu/home/NCI/NCI_IMRT_Guidelines.html.

10.4.2 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.

10.4.3 Megavoltage photon beams with energies ≥ 6 MV and megavoltage electron beams are
required. Proton beams are not allowed.

10.5 Localization, simulation, and immobilization

10.5.1 Simulation and treatment may be performed with the patient in the supine or prone
position post-lumpectomy for Arm 1/Group 1A and supine for Arm 2/Groups 2A and 2B.

10.5.2 Patients should be optimally positioned with alpha cradle casts, vac fix, breast boards,
wing boards and/or other methods of immobilization at the discretion of the treating
physician.

10.5.3 Methods to minimize the cardiac exposure to RT like heart block, gating, or breathhold
are allowed at the discretion of the treating physician.

10.5.4 For post-lumpectomy large-breasted patients, including those with a large inframammary
skin fold, devices to improve positioning of the breast and prone positioning are
permissible.

10.5.5 A treatment planning CT scan in the treatment position will be required to define the
clinical target volumes (CTV), planning target volumes (PTV), and Organs at Risk
(OAR).

10.5.6 The CT required for generation of a virtual plan with 3DCRT or IMRT must be post-final
surgery, either lumpectomy or mastectomy.

10.5.7 For post-lumpectomy (Arm1/Group 1A and Arm 2/Group 2A) - Radio-opaque markers
are to be placed on the patient skin in the treatment position as 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, and 3) the superior
border of the breast tissue at 12 o’clock based on palpation. Note that on
Arm 2/Group 2A this superior marker of the clinical extent of breast tissue can be at a
different location than the match line between the breast and regional nodal irradiation
fields.

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 10.5.8 For post-mastectomy (Arm 2/Group 2B) - Radio-opaque markers are to be placed on the
patient skin in the treatment position as external landmarks at the acquisition of the CT
scan to facilitate contouring segmentation of the CT data-set. These markers should
identify: 1) the mastectomy scar, and 2) the clinical outline at least from 2 o’clock to
10 o’clock representing the physician's clinical assessment of the "at risk" chestwall
which can include postoperative changes and where the ipsilateral breast previously was
located. (Note: The postion of the contralateral breast, if present, can be helpful.)

10.5.9 For patients that have an expander in place post-mastectomy for reconstruction, the
amount of expansion during radiation is per the investigator's discretion. The position of
the expander, ranging from collapsed to fully expanded, that is present at the time of
acquisition of the CT scan for treatment planning must remain stable until the completion
of radiotherapy.

10.5.10 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.

10.5.11 External skin localizing marks, which may include permanent tattoos, are recommended
for radiation daily localization and set-up accuracy.

10.6 Target volumes/treatment planning

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
International Commission on Radiation Units and Measurements (ICRU) Report #50:
Prescribing, Recording And Reporting Photon Beam Therapy.

See Appendix B for Contouring Guidelines for Arm 1/Group 1A and Arm 2/Groups 2A
and 2B.

10.6.1 Normal structures (Organs at Risk – OAR):

10.6.1.1 Ipsilateral lung: This may be contoured with auto-segmentation with manual
verification.
10.6.1.2 Contralateral lung: This may be contoured with auto-segmentation with
manual verification.
10.6.1.3 Heart: This is to be contoured on all cases-not just the left-sided. 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.

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 10.6.1.4 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.

10.6.1.5 Contralateral breast

The contralateral breast can be at risk for exposure to excess inadvertent

dosing, particularly in cases of very medially located lumpectomy sites in
Arm1/Group 1A and the inclusion of the IMN PTV for Arm 2/Groups 2A
and 2B. Therefore dose to the contralateral breast will be constrained in the
treatment planning.

Includes the apparent CT glandular breast tissue visualized by CT and

consensus definitions regarding "breast" 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: First or second rib medially
Caudal:border: Inframammary fold or inferior extent of the breast on CT
Anterior border: Skin minus 5 mm to minimize inaccuracy of dose calculation
at the skin surface
10.6.2 Breast target volumes post-lumpectomy (Arm 1/Group 1A and Arm 2/Group 2A)
Lumpectomy volumes:
10.6.2.1 Lumpectomy Gross Target Volume (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).
10.6.2.2 Lumpectomy Clinical Target Volume (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.
10.6.2.3 Lumpectomy Planning Target Volume (PTV): Lumpectomy CTV + 7 mm 3D
expansion (excludes heart).
10.6.2.4 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

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 most of the build-up region for the DVH analysis) and excluding the
Lumpectomy PTV expansion beyond the posterior extent of breast tissue
(chestwall, 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 should
not be used for beam aperture generation.
Breast volumes:
10.6.2.5 Breast CTV: Includes the palpable breast tissue demarcated with radio-opaque
markers at CT simulation (see Section 10.5), the apparent CT 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 (Section 10.6.2.2). 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.
RTOG anatomy consensus guidelines are available at:
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx.

10.6.2.6 Breast PTV: Breast CTV + 7 mm 3D expansion (excludes heart and does not
cross midline).
10.6.2.7 Breast PTV Eval: The Breast PTV Eval is intended to exclude the portion of
the Breast PTV that extends outside the patient or into the boney thorax and
lungs. The Breast PTV is copied to a Breast PTV Eval which is 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 to no deeper than the
anterior surface of the ribs (excludes boney thorax and lung). This Breast PTV
Eval is the structure used for DVH constraints and analysis.
10.6.3 Chestwall target volumes post-mastectomy (Arm 2/Group 2B)
10.6.3.1 Mastectomy Scar: Around the mastectomy scar is a common location for
chestwall recurrences post-mastectomy. To help reproducibility in the design
and evaluation of post-mastectomy radiotherapy treatment plans, an initial
clinical target volume for the mastectomy scar will be created. The
Mastectomy Scar will first be contoured by delineating the radiopaque wire
placed over the scar at CT simulation as a surrogate of the scar and including
any visible postoperative changes on CT in the subcutaneous tissue deep to the
wire per the investigator's discretion.
10.6.3.2 Mastectomy Scar CTV: Mastectomy Scar and associated surgical
change + 1 cm 3D expansion. Limit the CTV expansion posteriorly at anterior
surface of the ribs and anterolaterally at skin and should not cross midline.
(NOTE: Occasionally, the Mastectomy Scar location will lead to a CTV that
does cross midline. The investigator will have to assess clinically whether
adequate radiation can be delivered if the Mastectomy Scar CTV is truncated
at midline. If it is felt that the Mastectomy Scar CTV must cross midline – this
case may have significant challenges in meeting Compliance Criteria for this
protocol and might not be suitable for enrollment.)

07/10/13 NSABP B-51/RTOG 1304 Page 49

 10.6.3.3 Mastectomy Scar PTV: Mastectomy Scar CTV + 7 mm 3D expansion
(excludes heart).

10.6.3.4 Mastectomy Scar PTV Eval: Since a substantial part of the Mastectomy Scar
PTV often extends outside the patient – a Mastectomy Scar PTV Eval is
created. This Mastectomy Scar PTV Eval is limited to exclude the part that
extends outside the ipsilateral body/chestwall and the first 3 mm of tissue under
the skin (in order to remove some of the buildup region for the DVH analysis)
and posteriorly is limited to exclude lung and heart. The Mastectomy Scar
PTV Eval should not cross midline and should be contained within the borders
of the Chestwall PTV Eval. This is the structure used for DVH constraints,
analysis, and compliance.

(NOTE: Occasionally, the Mastectomy Scar location will lead to a CTV and
PTV Eval that does cross midline. The investigator will have to assess
clinically whether adequate radiation can be delivered if the Mastectomy Scar
CTV and PTV Eval is truncated at midline. If it is felt that the Mastectomy
Scar CTV and PTV Eval must cross midline – this case may have significant
challenges in meeting Compliance Criteria for this protocol and might not be
suitable for enrollment.)

10.6.3.5 Chestwall CTV: Includes the Mastectomy Scar CTV, and takes into account the
radiopaque markers placed at CT identifying clinical extent of chestwall,
surgical changes visualized by CT, and consensus definitions of anatomical
borders of chestwall from the RTOG Breast Cancer Atlas
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx.

The Chestwall CTV is limited by the skin anteriorly and should not extend
deeper than the ribs so that it excludes the lung and heart. Depending on the
location of the Mastectomy Scar CTV, it should exclude the sternum medially
and the axilla deep to anterior surface of the pectoralis major muscle laterally.
In general, the chestwall CTV should not cross midline.

Expanders, implants or autologous tissue present for reconstruction will be

included in the Chestwall CTV. The degree of expander expansion present is
per the treating physician’s discretion. The expander should remain at the
same expansion through the course of treatment that is present for the CT
simulation.

10.6.3.6 Chestwall PTV: Chestwall CTV + 7 mm 3D expansion (excludes heart and

does not cross midline).

10.6.3.7 Chestwall PTV Eval: As a part of the Chestwall PTV often extends outside the
patient, the Chestwall PTV is then copied to a Chestwall PTV Eval which is
edited. This Chestwall PTV Eval is limited anteriorly to exclude the part
outside the patient and the first 3 mm of tissue under the skin (in order to
remove some of the buildup region for the DVH analysis) and posteriorly is
limited to no deeper than the posterior rib surface and excludes lung and heart.
In general, the Chestwall CTV should not cross midline. This Chestwall PTV
Eval is the structure used for DVH constraints and analysis and not for beam
aperture generation.

07/10/13 NSABP B-51/RTOG 1304 Page 50

 (NOTE: Occasionally the Mastectomy Scar location will lead to a Chestwall
CTV and PTV Eval that does cross midline. The investigator will have to
assess clinically whether adequate radiation can be delivered if the Chestwall
CTV and PTV Eval is truncated at midline. If it is felt that the Chestwall CTV
and PTV Eval must cross midline – this case may have significant challenges
in meeting Compliance Criteria for this protocol and might not be suitable for
enrollment.)

10.6.4 Regional nodal target volumes (Arm 2/Groups 2A and 2B)

10.6.4.1 Supraclavicular CTV: Based on consensus definitions from RTOG Breast
Cancer Atlas. Superior extent typically is below the level of the cricoid;
medially excludes thyroid, trachea, and esophagus. The lateral border extends
to the lateral edge of the sternocleidomastoid muscle superiorly and the clavicle
at its more inferior extent, and the inferior border extends to the caudal aspect
of the clavicular head.
10.6.4.2 Supraclavicular PTV: Supraclavicular CTV + 5 mm margin in all directions.
The following structures should be excluded from the Supraclavicular PTV to
minimize excess dose to normal tissues: ipsilateral thyroid, trachea, esophagus,
and ipsilateral lung. This means that some or all of the medial border of the
Supraclavicular CTV and PTV will be similar. The Supraclavicular PTV
should exclude the vertebral body.
10.6.4.3 Axillary CTV: The extent of axilla to be targeted for regional nodal irradiation
will depend on the extent of axillary surgery performed. The axillary CTV
consists of the portion of the axilla that remains "undissected." When an
axillary node dissection has been done, the inferior border of the axillary CTV
will be the most cephalic extent of the dissection. Review of the operative
report, postoperative changes on the planning CT, and discussion with the
patient’s surgeon can be used for determining the most cephalic extent of the
dissection and inferior border of the Axillary CTV. Axillary dissection
typically removes level 1–2 axillary nodes, so that the Axillary CTV in these
cases is expected to include level 3 primarily and some of level 2 of the axilla.
When a sentinel node biopsy alone is done without completion axillary
dissection, the axillary CTV will then include all 3 levels of the axilla as all
three levels are "undissected." The consensus definitions for anatomical
borders of the axillary levels are from the RTOG Breast Cancer Atlas
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx.

10.6.4.4 Axillary PTV: Axillary CTV + 5 mm. The ipsilateral lung should be excluded
from the Axillary PTV. This means that some or all of the medial border of the
Axillary PTV can be similar to the Axillary CTV.

10.6.4.5 Internal mammary node (IMN) CTV: Includes the internal mammary/thoracic
vessels in the first three intercostal spaces.

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 10.6.4.6 Internal mammary node (IMN) PTV: The IMN CTV + 5 mm medially,
laterally, superiorly, and inferiorly. The IMN PTV is limited medially to not
extend into the sternum. In order to minimize excess normal tissue irradiation,
no additional expansion of the IMN CTV into the lung or heart should be done
for the IMN PTV. The deep edge for the IMN PTV will be similar to the IMN
CTV. No anterior expansion of the CTV into the chestwall or breast volumes
will be done.

10.6.5 Treatment planning

CT-based planning with tissue inhomogeneity correction is required.

10.6.5.1 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 to meet the target and critical structure dose-volume constraints.
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
Section 10.6.5.1 (1) should deliver > 50% of the total number of monitor
units for the beam orientation.
4. 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.
5. 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.
6. 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.
7. 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 3DCRT 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 3DCRT 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).

07/10/13 NSABP B-51/RTOG 1304 Page 52

 • 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

10.6.5.2 Whole breast plus boost radiation therapy (Arm 1/Group 1A and
Arm 2/Group 2A)

Whole breast plus boost irradiation alone is used in Arm 1/Group 1A and with
regional nodal irradiation in Arm 2/Group 2A. 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 3DCRT 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.

The lumpectomy boost may be given by either electron beam or photon beams
using either 3DCRT or IMRT. A composite dose distribution and DVHs that
include whole breast irradiation using either IMRT or 3DCRT and lumpectomy
cavity boost using electron beams, IMRT or 3DCRT must be completed and
provided for review. Simultaneous integrated boost using IMRT is not
allowed. Brachytherapy boost is not allowed.

Boost radiation must be planned from the initial CT for radiation planning.
Changes in patient positioning for the boost are not allowed. If electron boost
is used, there must be adequate dosimetric coverage of the Lumpectomy PTV
Eval.

10.6.5.3 Chestwall with or without reconstruction radiation therapy (Arm 2/Group 2B)

The goals of treatment planning are to encompass the Chestwall PTV (and
regional node targets) and minimize inclusion of the heart and lung. Field
arrangements for 3DCRT and IMRT are at the discretion of the treating
physician. Multiple beam arrangements that use photons alone of various or
mixed energies or in combination with electrons are to be designed during the
treatment planning process to produce an optimal plan that meets the
dose-volume constraints on the Chestwall PTV and normal tissues outlined
below.

In those cases where an expander is in place for purposes of breast

reconstruction, there can be a metal port that will need to be taken into account
in the radiation treatment planning. Every attempt should be made to acquire
the correct density of the expander port so correct modeling can be
accomplished. Beam arrangements are to be designed in these cases so that the
dose to the chestwall is considered "Per Protocol" or "Variation Acceptable" on
DVH analysis (see Section 10.10).

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 In general, there will be no boost for the chestwall post-mastectomy. For cases
with close surgical margins on the mastectomy specimen (e.g., ≤ 2 mm), the
treating physician can elect to deliver a chestwall boost (see Section 10.3.3.2).
Boost radiation must be planned from the initial CT for radiation planning. A
composite dose distribution and DVHs that include chestwall irradiation using
either IMRT or 3DCRT and chestwall boost using electron beams, IMRT or
3DCRT must be completed and provided for review. Simultaneous integrated
boost using IMRT is not allowed. Brachytherapy boost is not allowed.
Changes in patient positioning for the boost are not allowed. If electron boost
is used, the dose will be 12 or 14 Gy in 6 or 7 fractions of 2 Gy and, there must
be adequate dosimetric coverage of the Mastectomy Scar PTV Eval on the plan
composite dose volume analysis. The Compliance Criteria for Chestwall boost
are:
− Per Protocol: ≥ 95% of the Mastectomy Scar PTV Eval will receive
≥ 58.9–60.8 Gy which is 95% of the cumulative boost prescribed dose of
62–64 Gy
Variation Acceptable: ≥ 90% of the Mastectomy Scar PTV Eval will
receive 55.8– 57.6 Gy which is 90% of the cumulative boost prescribed
dose of 62-64 Gy
− Per Protocol: ≤ 5% of the Mastectomy Scar PTV Eval will receive
≥ 68.2–70.4 Gy which is 110% of the boost prescribed dose of 62–64 Gy
Variation Acceptable: ≤ 10% of the Mastectomy Scar PTV Eval will
receive ≥ 68.2-70.4 Gy which is 110% of the boost prescribed dose of 62-
64 Gy
− Per Protocol: Maximal point dose will be ≤ 71.3–73.6 Gy which is 115%
of the boost prescribed dose of 62–64 Gy
Variation Acceptable: Maximal dose point is ≤ 74.4–76.8 Gy which is
120% of the boost prescribed dose of 62–64 Gy

10.6.5.4 Regional nodal radiation therapy (Arm 1/Group 1A and Arm 2/Group 2B)
The goals of treatment planning are to encompass the supraclavicular, axillary
and internal mammary node targets alone with the Breast PTV in
Arm 1/Group 1A and the Chestwall PTV in Arm 2/Group 2B, respectively, and
minimize inclusion of the heart and lung. Field arrangements for 3D conformal
and IMRT 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
supraclavicular, axillary, and internal mammary node targets with the Breast
PTV in Arm 1/Group 1A and the Chestwall PTV in Arm 2/Group 2B,
respectively, and normal tissues outlined below. In particular, for inclusion of
the internal mammary nodes with either the chestwall or breast, there are
multiple known field arrangement methods, (e.g., partially wide tangents,
combined photon and electron fields, "Danish Technique," etc.) These or any
other treatment approach is permissible as long as the plan evaluation
demonstrates that the goals for dose coverage of the supraclavicular, axillary,
internal mammary node targets, Breast PTV in Arm 1/Group 1A and the
Chestwall PTV in Arm 2/Group 2B, respectively, and the normal tissue
constraints are met per protocol requirements (see Section 10.7).

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 10.6.5.5 Treatment plans must meet Dose Volume Constraints (Section 10.7) for the
contoured targets (10.6.2, 10.6.3, and 10.6.4) and normal structures
(Section 10.6.1). Various treatment approaches may be used to develop
treatment plans and a composite plan including boost plans must be generated.

10.7 Required dose-volume histogram (DVH) analysis

The composite treatment plan for the whole breast with boost in Arm1/Group 1A, whole breast
with boost and regional nodal irradiation in Arm 2/Group 2A, and chestwall and regional nodal
irradiation in Arm 2/Group 2B must be done prior to the start of irradiation. Every plan will
undergo a Quality Assurance Review as outlined in Section 4.3 and must meet the dose-volume
constraints listed in Section 10.10 under Compliance Criteria.
All maximum doses should be defined in one dose calculation voxel, e.g., 3x3x3 mm3 or 3 mm3.
The institution will be notified about plans whose DVH analysis does not meet the constraints
defined in Section 10.10 and are labeled "Deviation Unacceptable" on Quality Assurance review.
If a plan is labeled "Deviation Unacceptable" on a Rapid Review, the plan must be modified and
resubmitted prior to the initiation of irradiation. If a plan is labeled "Deviation Unacceptable" on
a Regular Review, the institution will have to complete another Rapid Review for that treatment
Group.
Chestwall or breast:
− ≥ 95% of the Chestwall or Breast PTV Eval will receive ≥ 95% (47.5 Gy) of the chestwall or
breast prescribed dose of 50 Gy
− ≤ 50% of the volume of Chestwall or Breast PTV Eval will receive ≥ 54 Gy when a boost is
included in the composite plan DVH
− Maximal point dose:
• Arm 1/Group 1A: ≤ 115% of the prescription chestwall or whole breast dose,
i.e., ≤ 57.5 Gy for a prescribed dose of 50 Gy
• Arm 2/Groups 2A and 2B when photons only are used for a composite plan that
includes the Chestwall or Breast PTV Eval and IMN PTV: ≤ 115% of the prescription
chestwall or whole breast dose, i.e., ≤ 57.5 Gy for a prescribed dose of 50 Gy
• Arm 2/Groups 2A and 2B when electon and photons are mixed for a composite plan
that includes the Chestwall or Breast PTV Eval and IMN PTV: ≤ 125% of the
prescription Chestwall or whole breast dose, i.e., ≤ 62.5 Gy for a prescribed dose
of 50 Gy
− Optional constraint: Conformity Index (CI) for Arm 1/Group 1A: defined as “the ratio of the
volume covered by the 95% prescription isodose over the volume of Breast PTV Eval”
(0.95 ≤ CI ≤ 2.0).
Lumpectomy PTV Eval:
− ≥ 95% of the Lumpectomy PTV Eval will receive ≥ 58.9–60.8 Gy which is 95% of the
cumulative boost prescribed dose of 62–64 Gy
− ≤ 5% of the Lumpectomy PTV Eval will receive ≥ 68.2–70.4 Gy which is 110% of the boost
prescribed dose of 62–64 Gy
− Maximal point dose will be ≤ 71.3–73.6 Gy which is 115% of the boost prescribed
dose of 62–64 Gy

07/10/13 NSABP B-51/RTOG 1304 Page 55

 Supraclavicular (SCL):
− ≥ 95% of the SCL PTV will receive ≥ 95% (47.5 Gy) of the prescribed dose of 50 Gy
− Maximal point dose will be ≤ 55 Gy which is 110% of the SCL prescribed dose of 50 Gy
Axillary volume:
− ≥ 95% of the Axillary PTV will receive ≥ 95% (47.5 Gy) of the prescribed dose of 50 Gy
− Maximal point dose will be ≤ 55 Gy which is 110% of the Axillary prescribed dose of 50 Gy
Internal mammary nodal (IMN) volumes:
− ≥ 90% of the IMN PTV will receive ≥ 90% (45 Gy) of the prescribed dose of 50 Gy
− Maximal point dose will be ≤ 55 Gy which is 110% of the IMN prescribed dose of 50 Gy
Contralateral breast:
− Arm 1/Group 1A: Maximum dose to contralateral breast is ≤ 310 cGy and < 5% receives
186 cGy
− Arm 2/Groups 2A and 2B: < 5% receives 300 cGy
Ipsilateral lung:
• Arm 1/Group 1A:
− ≤ 15% of the ipsilateral lung should receive ≥ 20 Gy
− ≤ 35% of the ipsilateral lung should receive ≥ 10 Gy
− ≤ 50% of the ipsilateral lung should receive ≥ 5 Gy
• Arm 2/Groups 2A and 2B:
− ≤ 30% of the ipsilateral lung should receive ≥ 20 Gy
− ≤ 50% of the ipsilateral lung should receive ≥ 10 Gy
− ≤ 65% of the ipsilateral lung should receive ≥ 5 Gy

Contralateral lung:
− ≤ 10% of the contralateral lung should receive ≥ 5 Gy
Heart:
• Arm 1/Group 1A
− ≤ 5% of the whole heart should receive ≥ 20 Gy for left-sided breast cancers, and 0% of
the heart should receive ≥ 20 Gy for right-sided breast cancers
− ≤ 30% of the whole heart should receive ≥ 10 Gy for left-sided breast cancers, and ≤ 10%
of the heart should receive ≥ 10 Gy for right-sided breast cancers
− Mean heart dose should be ≤ 400 cGy
• Arm 2/Groups 2A and 2B
− ≤ 5% of the whole heart should receive ≥ 25 Gy for left-sided breast cancers, and 0% of
the heart should receive ≥ 25 Gy for right-sided breast cancers
− ≤ 30% of the whole heart should receive ≥ 15 Gy for left-sided breast cancers, and ≤ 10%
of the heart should receive ≥ 15 Gy for right-sided breast cancers
− Mean heart dose should be ≤ 400 cGy

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10.8 Skin bolus

Skin bolus is not allowed on the intact breast in Arm 1/Group 1A or Arm 2/Group 2A. The use
of skin bolus for post-mastectomy irradiation in Arm 2/Group 2B is per the treating physician's
discretion. If using bolus, the skin dose should follow the same constraints as the Chestwall PTV
Eval.

10.9 Treatment verification

10.9.1 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.
10.9.2 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.
10.9.3 Documentation requirements
All films or images are to be maintained at the local facility. Do not submit to ITC unless
requested. (Please refer to Information Resources for data submission.)
10.10 Compliance criteria
All treatment plans will be submitted for Quality Assurance Review per Protocol Section 4.3.
DVHs for the target volumes and designated normal structures will be compared to determine
protocol compliance according to the following rules based on the parameters below:

10.10.1 Per Protocol: All specified DVH requirements identified as Per Protocol have been met.

10.10.2 Variation Acceptable: Specified DVH requirements within the Variation Acceptable have
been met.

10.10.3 Deviation Unacceptable: Specified DVH requirements for Variation Acceptable are not
met.

Note: Appendix C has all the compliance criteria for each arm presented in table format.

Chestwall or Breast PTV Eval:

Per Protocol: ≥ 95% of the Chestwall or Breast PTV Eval will receive ≥ 95% (≥ 47.5 Gy) of the
chestwall or breast prescribed dose of 50 Gy
Variation Acceptable: ≥ 90% of the Chestwall or Breast PTV Eval will receive ≥ 90% (≥ 45 Gy)
of the whole breast prescribed dose of 50 Gy

Per Protocol: ≤ 50% of the volume of Breast PTV Eval will receive 108% (≥ 54 Gy) of the
prescribed dose of 50 Gy when a boost is included in the composite plan DVH
Variation Acceptable: ≤ 50% of the volume of Breast PTV Eval will receive 112% (≥ 56 Gy) of
the prescribed dose of 50 Gy when a boost is included in the composite plan DVH

07/10/13 NSABP B-51/RTOG 1304 Page 57

 Per Protocol: ≤ 30% of the breast/chestwall PTV Eval will receive ≥ 100% of the boost
prescribed dose of 62–64 Gy
Variation Acceptable: ≤ 35% of the breast/chestwall PTV Eval will receive ≥ 100% of the boost
prescribed dose of 62–64 Gy

Maximum point dose:

• Arm 1/Group 1A
Per Protocol - maximum point dose: ≤ 115% of the prescription chestwall or whole breast
dose, i.e., ≤ 57.5 Gy for a prescribed dose of 50 Gy
Variation Acceptable: ≤ 120% (≤ 60 Gy for a prescription whole breast dose
of 50 Gy). The maximal dose may be evaluated without boost fields.

• Arm 2/Groups 2A and 2B

Per Protocol-maximum point dose when photons only are used for a composite plan that
includes the Chestwall or Breast PTV Eval and IMN PTV: ≤ 115% of the prescription
chestwall or whole breast dose, i.e., ≤ 57.5 Gy for a prescribed dose of 50 Gy
Variation Acceptable: ≤ 120% (≤ 60 Gy for a prescription whole breast or chestwall dose of
50 Gy). The maximal dose may be evaluated without boost fields.
Per Protocol - maximum point dose when electon and photons are mixed for a composite plan
that includes the Chestwall or Breast PTV Eval and IMN PTV: ≤ 125% of the prescription
chestwall or whole breast dose, i.e., ≤ 62.5 Gy for a prescribed dose of 50 Gy
Variation Acceptable: ≤ 130% (≤ 65 Gy for a prescription whole breast dose of 50 Gy) OR
≤ 10 cc of composite plan receives ≥ 125% of the prescription chestwall or whole breast dose,
i.e., ≥ 62.5 Gy for a prescribed dose of 50 Gy
Optional constraint: Conformity Index (CI) for Arm 1/Group 1A: defined as “the ratio of the
volume covered by the 95% prescription isodose over the volume of Breast PTV Eval."
Per Protocol: 0.95 ≤ CI ≤ 2.0. Variation Acceptable: 0.85 ≤ CI ≤ 2.5

Lumpectomy PTV Eval:

Arm 1/Group 1A and Arm 2/Group 2A
Per Protocol: ≥ 95% of the Lumpectomy PTV Eval will receive ≥ 58.9–60.8 Gy which is 95% of
the cumulative boost prescribed dose of 62–64 Gy
Variation Acceptable: ≥ 90% of the Lumpectomy PTV Eval will receive ≥ 55.8–57.6 Gy which is
90% of the cumulative boost prescribed dose of 62–64 Gy

Per Protocol: ≤ 5% of the Lumpectomy PTV Eval will receive ≥ 68.2–70.4 Gy which is 110% of
the boost prescribed dose of 62–64 Gy
Variation Acceptable: ≤ 10% of the Lumpectomy PTV Eval will receive ≥ 68.2–70.4 Gy which is
≥ 110% of the boost prescribed dose of 62–64 Gy

Per Protocol: Maximal point dose will be ≤ 71.3–73.6 Gy which is 115% of the boost prescribed
dose of 62–64 Gy
Variation Acceptable: Maximal dose point is ≤ 74.4–76.8 Gy which is 120% of the boost
prescribed dose of 62–64 Gy

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 Supraclavicular (SCL) PTV:
Per Protocol: ≥ 95% of the SCL PTV will receive ≥ 95% (≥ 47.5 Gy) of the prescribed dose of
50 Gy
Variation Acceptable: ≥ 90% of the SCL PTV will receive ≥ 90% (≥ 45 Gy) of the prescribed
dose of 50 Gy

Per Protocol: Maximal point dose will be ≤ 55 Gy which is 110% of the SCL prescribed dose of
50 Gy
Variation Acceptable: Maximal dose point is ≤ 57.5 Gy which is 115% of the SCL prescribed
dose of 50 Gy

Axillary PTV:
Per Protocol: ≥ 95% of the Axillary PTV will receive ≥ 95% (≥ 47.5 Gy) of the prescribed dose
of 50 Gy
Variation Acceptable: ≥ 90% of the Axillary PTV will receive ≥ 90% (≥ 45 Gy) of the prescribed
dose of 50 Gy
Per Protocol: Maximal point dose will be ≤ 55 Gy which is ≤ 110% of the Axillary prescribed
dose of 50 Gy
Variation Acceptable: Maximal dose point is ≤ 57.5 Gy which is ≤115% of the axillary
prescribed dose of 50 Gy
Internal mammary nodal (IMN) volumes:
Per Protocol: ≥ 90% of the IMN PTV will receive ≥ 90% (≥ 45 Gy) of the prescribed dose of
50 Gy
Variation Acceptable: ≥ 90% of the IMN PTV will receive ≥ 80% (≥ 40 Gy) of the prescribed
dose of 50 Gy

Per Protocol: Maximal point dose will be ≤ 55 Gy which is ≤ 110% of the IMN prescribed dose
of 50 Gy
Variation Acceptable: Maximal dose point is ≤ 57.5 Gy which is ≤ 115% of the IMN prescribed
dose of 50 Gy
Contralateral breast:
• Arm 1/Group 1A
Per Protocol: Maximum dose to contralateral breast is ≤ 310 cGy and < 5% receives 186 cGy
Variation Acceptable: Maximum dose is ≤ 496 cGy and < 5% receives 310 cGy

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 • Arm 2/Groups 2A and 2B

Per Protocol: < 5% receives 300 cGy

Variation Acceptable: < 5% receives 410 cGy
Ipsilateral lung:
• Arm 1/Group 1A

Per Protocol: ≤ 15% of the ipsilateral lung should receive ≥ 20 Gy

Variation Acceptable: ≤ 20% of the ipsilateral lung should receive ≥ 20 Gy
Per Protocol: ≤ 35% of the ipsilateral lung should receive ≥ 10 Gy
Variation Acceptable: ≤ 40% of the ipsilateral lung receives ≥ 10 Gy
Per Protocol: ≤ 50% of the ipsilateral lung should receive ≥ 5 Gy
Variation Acceptable: ≤ 55% of the ipsilateral lung receives ≥ 5 Gy

• Arm 2/Groups 2A and 2B

Per Protocol: ≤ 30% of the ipsilateral lung should receive ≥ 20 Gy

Variation Acceptable: ≤ 35 % of the ipsilateral lung should receive ≥ 20 Gy
Per Protocol: ≤ 50% of the ipsilateral lung should receive ≥ 10 Gy
Variation Acceptable: ≤ 60% of the ipsilateral lung receives ≥ 10 Gy
Per Protocol: ≤ 65% of the ipsilateral lung should receive ≥ 5 Gy
Variation Acceptable: ≤ 70% of the ipsilateral lung receives ≥ 5 Gy
Contralateral lung:
Per Protocol: ≤ 10% of the contralateral lung should receive ≥ 5 Gy
Variation Acceptable: ≤ 15% of the contralateral lung should receive ≥ 5 Gy
Heart:
• Arm 1/Group 1A

Per Protocol: ≤ 5% of the whole heart should receive ≥ 20 Gy for left-sided breast cancers,
and 0% of the heart should receive ≥ 20 Gy for right-sided breast cancers
Variation Acceptable: ≤ 5% of the whole heart should receive ≥ 25 Gy for left-sided breast
cancers, and 0% of the heart should receive ≥ 25 Gy for right-sided breast cancers
Per Protocol: ≤ 30% of the whole heart should receive ≥ 10 Gy for left sided breast cancers,
and ≤ 10% of the heart should receive ≥ 10 Gy for right-sided breast cancers
Variation Acceptable: ≤ 35% of the whole heart receives ≥ 10 Gy for left-sided breast
cancers, and ≤ 15% of the heart receives ≥ 10 Gy for right-sided breast cancers
Per Protocol: Mean heart dose should be ≤ 400 cGy
Variation Acceptable: ≤ 500 cGy. Every attempt should be made to make the cardiac
exposure to radiation as low as possible

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 • Arm 2/Groups 2A and 2B

Per Protocol: ≤ 5% of the whole heart should receive ≥ 25 Gy for left-sided breast cancers,
and 0% of the heart should receive ≥ 25 Gy for right-sided breast cancers
Variation Acceptable: ≤ 5% of the whole heart should receive ≥ 30 Gy for left-sided breast
cancers, and 0% of the heart should receive ≥ 30 Gy for right-sided breast cancers
Per Protocol: ≤ 30% of the whole heart should receive ≥ 15 Gy for left-sided breast cancers,
and ≤ 10% of the heart should receive ≥ 15 Gy for right-sided breast cancers
Variation Acceptable: ≤ 35% of the whole heart receives ≥ 15 Gy for left-sided breast
cancers, and ≤ 15% of the heart receives ≥ 15 Gy for right-sided breast cancers
Per Protocol: Mean heart dose should be ≤ 4 Gy
Variation Acceptable: ≤ 5 Gy. Every attempt should be made to make the cardiac exposure
to radiation as low as possible.

07/10/13 NSABP B-51/RTOG 1304 Page 61

11.0 ADVERSE EVENT REPORTING REQUIREMENTS

Please refer to Coordinator Online in the Members' Area of the NSABP Web site for general
information regarding AE reporting.

11.1 Adverse event characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found in the
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP Web
site (http://ctep.cancer.gov).

11.2 Adverse events and serious adverse events

11.2.1 Definition of an adverse event

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/intervention, whether or not considered related to the medicinal
(investigational) product/intervention (attribution of unrelated, unlikely, possible,
probable, or definite). (International Conference on Harmonisation [ICH] E2A, E6).

11.2.2 Definition of a serious adverse event

Any adverse event (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 drug experience
• Inpatient hospitalization or prolongation of existing hospitalization (for ≥ 24 hours)
• A persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions
• A congenital anomaly/birth defect
• Important Medical Events (IME) that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse experience 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 this definition (FDA, 21
CFR 312.32; ICH E2A and ICH E6).

11.3 Expedited reporting of adverse events

The NSABP follows procedures for centralized reporting of adverse events. Centralized
reporting requires that adverse events be reported to the NSABP Biostatistical Center. The
NSABP forwards reports to the appropriate regulatory agencies. Expedited reporting for
B-51/1304 utilizes the NCI's Adverse Event Expedited Reporting System (AdEERS).

07/10/13 NSABP B-51/RTOG 1304 Page 62

 AdEERS provides a radiation therapy-only pathway for events experienced that involve radiation
therapy only. Events involving radiation therapy-only must be reported via the AdEERS
radiation therapy-only pathway.

The NSABP Biostatistical Center is identified in AdEERS as the NSABP Lead Group for
AdEERS reporting. Expedited AE reporting for this study must be submitted to the NSABP Lead
Group using AdEERS, accessed via the CTEP home page
https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup. In the rare event when
Internet connectivity is disrupted, a 24-hour notification is to be made to the NSABP
Biostatistical Center by telephone at 412-624-2666. An electronic report must be submitted
immediately upon re-establishment of the Internet connection.

11.3.1 Expedited reporting methods

• AdEERS-24 Hour Notification requires that an AdEERS 24-hour notification is

electronically submitted to the NSABP Lead Group within 24 hours of learning of
the adverse event. Each AdEERS 24-hour notification must be followed by an
AdEERS 5 Calendar Day Report (see Table 5).
• AdEERS 5 Calendar Day Report requires that a complete report is electronically
submitted to the NSABP Lead Group within 5 calendar days of learning of the AE.
• Supporting documentation is required for all expedited (AdEERS) reports. Include
the protocol number, patient's ID number, and AdEERS ticket number on each page,
and fax supporting documentation to the NSABP Biostatistical Center
(412-622-2113).

11.3.2 Expedited reporting requirements – AdEERS-24 and AdEERS

Expedited reporting requirements begin with the administration of the first radiation
therapy dose. Expedited reporting requirements for all patients are provided in
Table 5.

11.3.3 Other recipients of adverse event reports

Adverse events determined to be reportable must also be reported by the investigator to

the Institutional Review Board responsible for oversight of the patient according to the
local IRB's policy and procedures.

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 TABLE 5. Expedited reporting requirements for adverse events that occur within 30 days of the last
dose of radiation therapy1
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 radiation therapy (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 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 AdEERS within the timeframes detailed in the table below.
Grade 1 Grade 2 Grade 3 Grade 4 & 5
Hospitalization Timeframes Timeframes Timeframes
Timeframes
Resulting in
Hospitalization Not required 5 Calendar Days
≥ 24 hrs 24-Hour,
Not resulting in 3 Calendar Days
Hospitalization Not required 5 Calendar Days
≥ 24 hrs
Expedited AE reporting timelines are defined as:
• "24-Hour, 3 Calendar Days" – The AE must initially be reported via AdEERS within 24 hours of
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial
24-hour report.
• "5 Calendar Days" – A complete expedited report on the AE must be submitted within 5 calendar
days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of protocol treatment
and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report with 3 calendar days for:
• All Grade 4 and Grade 5 AEs
Effective Date: May 5, 2011

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 11.3.4 Reporting a secondary malignancy

A secondary malignancy is a cancer caused by a treatment for previous malignancy

(e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A
secondary malignancy is not considered a metastasis of the initial neoplasm.
All secondary malignancies that occur on NCI-sponsored trials either during or following
treatment must be reported via AdEERS within 5 days of learning of the secondary
malignancy. 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
Supporting documentation, including pathology and cytogenetics reports which confirm
the secondary malignancy, must be faxed to the NSABP Biostatistical Center expedited
fax at 412-622-2113. Each page of supporting documentation must include the NCI
protocol number, the AdEERS ticket number, and the protocol-specific patient ID
number provided during trial registration.

11.3.5 Expedited reporting of pregnancy, fetal death, and death neonatal occurring during
radiation therapy
Any pregnancy or fetal death occurring while the patient is receiving radiation therapy must
be reported via AdEERS as a medically significant event. Definitions and reporting
instruction for these events are provided in the Cancer Therapy Evaluation Program's (CTEP)
revised NCI guidelines for Investigators: Adverse Event Reporting Requirements
(Section 5.6.6) located at the following CTEP website:
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf).

Upon learning of a pregnancy, fetal death, or death neonatal that occurs during radiation
therapy the investigator is required to:

• Immediately call the NSABP Clinical Coordinating Division (see Information

Resources). Patients must immediately discontinue receiving study therapy.
• Within 5 working days of learning of the event, and as required by the NCI
Guidelines for Investigators: Adverse Event Reporting Requirements (Section 5.6.6):
− Create and submit an AdEERS report;
− Complete the Pregnancy Information Form (located in the NSABP Members'
Area in Protocol B-51 "Forms and Supporting Documents"); and
− Fax the completed Pregnancy Information Form with all available supporting
documentation to the NSABP Biostatistical Center's expedited fax number at
412-622-2113.
• For questions concerning AE reporting, contact the AE Reporting Nurse
(see Information Resources).
• For clinical questions concerning study therapy, contact the NSABP Clinical
Coordinating Division (see Information Resources).

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11.4 Routine reporting of adverse events

11.4.1 Reporting routine adverse events through Medidata Rave

• Reporting of adverse events is done through Medidata Rave (see Section 14.3).
• All ≥ grade 2 adverse events not reported via AdEERS that occurred during study
therapy or during the 30 days following the last dose of XRT must be reported on one
of the B-51/1304 Adverse Event forms (the Listed Adverse Event form or the Other
Adverse Event form) through Medidata Rave, regardless of whether these adverse
events are expected or unexpected (even if no AEs were experienced by the
patient).
• Reporting of AEs is not required following a documented invasive breast cancer
recurrence or diagnosis of a second primary malignancy, if treated with systemic
anticancer therapy.
• Supporting documentation for each AE reported on either of the B-51/1304 Adverse
Event forms through Medidata Rave must be maintained in the patient's research
record. When submission of supporting documentation to the NSABP Biostatistical
Center is required, the online software will provide a transmittal form that must be
printed. Fax this transmittal form with the supporting documentation to 412-622-
2111. Remove patient names and identifiers such as social security number, address,
telephone number, etc., from reports and supporting documentation.

11.4.2 Schedule for reporting routine adverse events

Adverse event forms are to be submitted through Medidata Rave, even if no AEs were
experienced by the patient, according to the following schedule:
• Submit at the end of XRT for Arm 1/Group 1A and Arm 2/Groups 2A and 2B or at
3 months after randomization for Group 1B.
• Submit 30 days after the end of XRT (not required for Arm 1/Group 1B patients).
11.5 Reporting breast cancer recurrence and second primary cancer

Report breast cancer recurrence and second primary cancer (a malignancy which is unrelated to
the treatment of a prior malignancy and which is not a metastasis from the initial malignancy)
within the B-51/1304 Follow-up folder in Medidata Rave. Fax supporting documentation that
confirms the breast cancer recurrence or second primary cancer diagnosis with the transmittal
form (provided at the time of enrollment) to 412-622-2111.

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12.0 DOCUMENTATION OF BREAST CANCER RECURRENCE AND SECOND
MALIGNANCIES

12.1 General instructions

• Documentation of a breast cancer recurrence requires meeting at least one of the criteria
defined below. Suspicious findings do not provide adequate documentation of a breast
cancer recurrence, and should not be an indication to alter protocol therapy.
• Tumor marker evaluations alone do not document breast cancer recurrence.
• Treatment of a breast cancer recurrence or second primary cancer will be at the discretion of
the investigator.

12.2 Local recurrence

Note: If the first local recurrence is non-invasive breast cancer, the first invasive breast cancer
must also be reported.

Recurrent local tumor is defined as evidence of invasive breast cancer or DCIS in the ipsilateral
breast or invasive breast cancer in the skin of the ipsilateral breast. Patients who develop clinical
evidence of local recurrence in the ipsilateral breast must have a biopsy confirmation of
recurrence. However, if a patient also meets criteria for regional or distant metastatic disease,
results of clinical exams alone will be sufficient to document local recurrences.

12.2.1 Ipsilateral breast tumor recurrence (IBTR)

An IBTR event is defined as recurrent invasive breast cancer or DCIS in the ipsilateral
breast parenchyma or invasive breast cancer in the skin of the breast occurring after
lumpectomy.

Acceptable documentation includes core, incisional or excisional biopsy. Cytology alone

will not be adequate to establish IBTR.

12.2.2 Other local recurrence

Defined as recurrence in the skin of the chestwall (exclusive of the breast) or chestwall.

Acceptable documentation includes core, incisional or excisional biopsy, as well as

cytology.

12.3 Regional recurrence

Defined as the development of tumor in the ipsilateral internal mammary, ipsilateral

supraclavicular, ipsilateral infraclavicular and/or ipsilateral axillary nodes, as well as the soft
tissue of the ipsilateral axilla, following surgery. Recurrence must be confirmed by biopsy or
cytology. However, if a patient meets criteria for distant metastatic disease, results of clinical
exams alone will be sufficient to document regional recurrences.

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12.4 Distant recurrence

Defined as evidence of tumor in all areas, with the exception of those described in
Sections 12.2 and 12.3. Further treatment for distant metastasis, with or without evidence of
local-regional recurrence, will be at the discretion of the investigator.

12.4.1 Skin, subcutaneous tissue, and lymph nodes (other than local or regional)

Acceptable documentation includes positive cytology, aspirate or biopsy, or radiologic

evidence of metastatic disease.

12.4.2 Bone marrow

Acceptable documentation includes positive cytology, aspirate, biopsy, or MRI scan.

12.4.3 Lung

Acceptable documentation includes: (i) positive cytology, aspirate, or biopsy, or

(ii) radiologic evidence of multiple pulmonary nodules that are judged to be consistent
with pulmonary metastases.

Note: If a solitary lung lesion is found and no other lesions are present on lung
tomograms, CT scan, or MRI scan, further investigations, such as biopsy, needle
aspiration, PET-CT scan, or PET scan should be performed. Proof of neoplastic pleural
effusion must be established by cytology or pleural biopsy.

12.4.4 Skeletal

Acceptable documentation includes: (i) x-ray, CT, or MRI evidence of lytic or blastic
lesions consistent with bone metastasis, (ii) biopsy proof of bone metastases, or (iii) bone
scan, PET-CT scan, or PET scan clearly positive for bone metastases.

Note: If the diagnosis is equivocal by bone scan or radiologic evaluation, a biopsy is

strongly recommended. A bone scan with uptake limited to joints or in a recent area of
trauma (surgical or otherwise) cannot be used as a criterion for breast cancer recurrence.

12.4.5 Liver

Acceptable documentation includes: (i) abdominal CT scan, liver scan, ultrasound, MRI,
PET-CT scan, or PET scan consistent with liver metastases, or (ii) liver biopsy
confirmation of the metastatic disease.

Note: If the radiologic findings are not definitive (especially with solitary liver nodules),
a liver biopsy is recommended; however, if a biopsy is not performed, serial scans must
be obtained to document stability or progression.

12.4.6 Central nervous system

Acceptable documentation includes: (i) positive CT scan, PET-CT scan, PET scan, or
MRI scan, usually in a patient with neurological symptoms, or (ii) biopsy or cytology (for
a diagnosis of leptomeningeal involvement).

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12.5 Contralateral breast cancer

Contralateral breast cancer is defined as evidence of invasive breast cancer or DCIS in the
contralateral breast or chestwall. The diagnosis of a contralateral breast cancer must be
confirmed by core, incisional, or excisional biopsy. Cytology alone will not be adequate to
document a contralateral breast cancer.

12.6 Second primary cancer

Second primary cancer is defined as any invasive non-breast cancer other than squamous or basal
cell carcinoma of the skin. The diagnosis of a second primary cancer must be confirmed
histologically whenever possible.

12.7 Documentation requested following death

• Autopsy reports should be secured whenever possible and should be submitted to the NSABP
Biostatistical Center.
• A copy of the death certificate should be forwarded to the NSABP Biostatistical Center if it is
readily available or if it contains important cause-of-death information that is not documented
elsewhere.
• Please submit the last clinic/office note made before the death or the investigator’s note
summarizing events resulting in death.

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13.0 REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES

13.1 Investigator requirements

This study is supported by the NCI CTSU.

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 Member Web site (enter credentials at https://www.ctsu.org; then click on
the Register tab) or by calling the PMB at 301-496-5725 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 B-51/1304 site registration:

• CTSU IRB Certification

• CTSU IRB/Regulatory Approval Transmittal Sheet
• CTSU RT Facilities Inventory Form
NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy
component must participate in the Radiological Physics Center (RPC) monitoring program.
For non-lead group institutions, an RT Facilities Inventory Form 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.

13.2 Patient consent form

Before the patient is enrolled, the consent form, including any addenda, must be signed and dated
by the patient and the person who explains the study to that patient.

13.3 Required submission of tumor samples

As part of the B-51/1304 consent form, all patients have agreed to allow the submission of tumor
blocks (see Section 7.1).

13.4 Patient enrollment

Patient registration can occur only after pre-treatment evaluation 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.

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13.5 Oncology Patient Enrollment Network (OPEN)

All site staff (NSABP and CTSU Sites) will use OPEN to enroll patients to this study.

13.5.1 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 NSABP or CTSU Web site as a tool
to verify eligibility.
• All patients have signed an appropriate consent form and HIPAA authorization form
(if applicable).

13.5.2 Access requirements for OPEN

• Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU
Member Web site.
• 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 NSABP,
you must have an equivalent 'Registrar' role on the NSABP 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 Member 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, including the Patient ID number for the study, and treatment information.
Please print this confirmation for your records. Additionally, a transmittal form to be
used when faxing the signed consent form to the NSABP Biostatistical Center also will
be provided and must be printed. If it is necessary to reprint the randomization
confirmation or the transmittal form, they can be reprinted through Coordinator Online
via the View a Patient Entry Report under Patient Entry.

Further instructional information is provided on the OPEN tab of the CTSU Member side
of the CTSU Web site 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.

13.6 Investigator-initiated discontinuation of study therapy

In addition to the conditions outlined in the protocol, the investigator may require a patient to
discontinue study therapy if one of the following occurs:

• the patient develops a serious side effect that she cannot tolerate or that cannot be controlled
with other medications,
• the patient's health gets worse,

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 • the patient is unable to meet the study requirements, or
• new information about the study therapy or other treatments for breast cancer becomes
available.

If study therapy is stopped, study data and other materials should be submitted according to the
study schedule unless the patient withdraws from the study (see Section 13.8).

13.7 Patient-initiated discontinuation of study therapy

Even after a patient agrees to take part in this study, she may stop study therapy or withdraw from
the study at any time. If study therapy is stopped but she still allows the investigator to submit
information, study data and other materials should be submitted according to the study schedule.

13.8 Patient-initiated withdrawal from the study

If a patient chooses to have no further interaction regarding the study (i.e., allow no future
follow-up data to be submitted to the NSABP), the investigator must provide the NSABP
Biostatistical Center with written documentation of the patient’s decision to fully withdraw from
the study.

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14.0 REQUIRED DATA COLLECTION
14.1 Data collection
B-51/1304 data collection will include the following elements:
• Patient characteristics
• Characteristics of the breast cancer
• AJCC TNM stage
• Radiation therapy administered
• Other treatment including endocrine therapy and anti-HER2 therapy
• Adverse events as described in Section 11.0
• Breast cancer events (local, regional, and distant)
• Second primary cancer events
• Survival
• QOL/PROs for QOL patients as described in Section 8.0
14.2 Instructions for completion of B-51/1304 forms and materials
• Data form worksheets and specimen transmittal forms, as well as instructions for completion
and submission of data and materials, are available in the Members' Area of the NSABP Web
site, http://www.nsabp.pitt.edu or on the CTSU Member Web site, https://www.ctsu.org.
Contact the NSABP Webmaster at webmaster@nsabp.pitt.edu for an account to access the
NSABP Web site.
• Sites must use the current form versions and adhere to the instructions and submission
schedule outlined in the Table of Required Forms and Materials document available in the
Members' Area of the NSABP Web site or on the CTSU Member Web site.
14.3 Instructions for submission of B-51/1304 data, forms, and materials
• B-51/1304 will use Medidata Rave for remote data capture of all data. Query generation and
resolution for B-51/1304 are part of the Rave program. All queries will be issued and
responded to electronically within Rave. Access Medidata Rave using your active CTEP-
IAM user id and password at the following url: https://login.imedidata.com/selectlogin. Prior
to beginning data entry in Rave, study staff must be registered in Medidata and complete the
required training modules. Study staff will receive an invitation to join the study in Rave
after evidence of IRB approval is submitted to RSS.
• Exceptions to submission of data through Medidata Rave are the BAHO questionnaire and
required source documents which should be faxed to the NSABP Biostatistical Center
according to the instructions on the form worksheet. When submission of supporting
documentation to the NSABP Biostatistical Center is required, fax to 412-622-2111. Remove
patient names and identifiers such as social security number, address, telephone number, etc.
from reports and supporting documentation. Do not include a cover sheet for faxed data.
• The Expected/Delinquency Report can be found under the Institution Reports link in the
Study Management area of Coordinator Online in the Members' Area of the NSABP Web
site. The Expected/Delinquency Report is sorted by research network and site. It is a
reflection of the data in the NSABP database at the time the report is created. The report
contains each patient study ID for which a form is "due" or "late." Questions regarding the
online delinquency report can be directed to the NSABP Webmaster at
webmaster@nsabp.pitt.edu.

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14.4 Data reporting to CTEP

This study will be monitored by the Clinical Data Update System (CDUS) version 3.0 (CDUS
Abbreviated). Cumulative CDUS data will be submitted quarterly by the NSABP Biostatistical
Center to CTEP by electronic means.

14.5 Dosimetry digital data submission

14.5.1 Preliminary dosimetry information (DD)

• Digital Data Submission – The Treatment Plan is submitted to ITC via an SFTP
account exported from the treatment planning machine by the Physicist.

• Digital data submission includes the following:

− CT data, critical normal structures, all GTV, CTV, and PTV contours
− Digital beam geometry for initial and boost beam sets
− Doses 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

14.5.2 Digital Data Submission Information (DDSI) form

The DDSI form is submitted online. The form is located on the ATC Web site at
http://atc.wustl.edu/forms/DDSI/ddsi.html.

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15.0 STATISTICAL CONSIDERATIONS

15.1 Primary endpoint

The primary endpoint is invasive breast cancer recurrence-free interval (IBC-RFI).

15.2 Secondary endpoints

Secondary efficacy endpoints include overall survival (OS); loco-regional recurrence-free interval
(LRRFI) (separately analyzed for mastectomy patients and for lumpectomy patients); distant
recurrence-free interval (DRFI); disease-free survival-ductal carcinoma in situ (DFS-DCIS);
second primary invasive cancer; effect of XRT in mastectomy and lumpectomy patients; and the
frequency and severity of adverse events graded according to the CTCAE v4.0.

15.3 Stratification and randomization

Assignment of treatments to patients will be balanced with respect to type of breast surgery
(mastectomy, lumpectomy), hormone receptor status (ER-positive and/or PgR-positive, ER- and
PgR-negative), HER2 status (negative, positive), adjuvant chemotherapy (yes, no), and pCR in
breast (yes, no) using a biased-coin minimization algorithm.38

15.4 Sample size calculation

15.4.1 Estimates of annual hazard rates

When focusing on the subset of B-18 and B-27 patients with clinically positive nodes
who converted to pathologically node negative status following neoadjuvant therapy, the
average annual hazard rate of events for invasive breast cancer recurrence-free interval
was determined to be 0.0354. Reducing this value by 15% to account for the fact that
these legacy trials tend to over-estimate the rates in today’s population brings the
estimate of the expected annual hazard rate to 0.0301. This rate equates to a 5-year
cumulative rate of events for invasive breast cancer recurrence-free interval of about
14%. A 35% reduction in the average annual hazard rate to 0.0196 would reduce the
5-year cumulative rate to about 9.3% for an absolute risk reduction in the 5-year
cumulative rate of 4.6%.

15.4.2 Accrual rate and total sample size

Using the hazard rate of 0.0301 and assuming a two-tailed test at an alpha level of 0.05,
1636 patients accrued over a 5 year period (about 28 patients per month) with
2 additional years of follow-up would provide a statistical power of 80% to test the
hypothesis that treatment with XRT would reduce the annual hazard rate of events for
invasive breast cancer recurrence-free interval by 35%.

To account for delays in getting the trial approved by local IRBs and initiated at each
potential site of accrual, we assume linear ramp-up during the first year of accrual. A
steady monthly accrual of 28 patients was assumed thereafter.

As with all protocols, accrual to this trial will be closely monitored on a monthly basis. If
9 months after activation of the protocol it appears that we are not going to reach target
monthly accrual, the appropriate activities will be initiated to boost the accrual.

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 Unless the average monthly accrual in the sixth quarter or the accrual during the last
month of the sixth quarter is above 20% of our projected monthly accrual, the trial will be
stopped.

If the average monthly accrual in the eighth quarter is below 75% of our projected
numbers, the appropriate activities will be initiated to increase the accrual.

15.5 Statistical analysis

The primary analysis will be based on the primary endpoint of IBC-RFI. Events for this outcome
include any invasive local, regional, or distant recurrence, or death from breast cancer. Analysis
will be based on the intent-to-treat principle, with all patients analyzed as randomized, regardless
of eligibility or protocol compliance. The difference between treatment arms will be assessed by
the stratified log rank test, controlling for all stratification factors.

Analysis of the secondary endpoints of overall survival, local-regional recurrence-free interval,

distant recurrence-free interval, disease-free survival-ductal carcinoma in situ, second primary
cancer, and the comparison of the effect of XRT in mastectomy and lumpectomy patients will be
carried out in a fashion similar to that described above. All statistical tests for the secondary
endpoints will be two-sided and will be carried out at the 0.05 Type I error level. As part of a
secondary analysis of all time-to-event endpoints, Cox proportional hazards models will be used
to estimate and to control for the effects of potential prognostic variables. Likelihood ratio tests
will be used to assess the prognostic importance of each variable and treatment/covariate
interactions will be investigated.

15.6 Interim analyses

Three formal interim analyses of the primary endpoint will be carried out when 43, 86, and 129
events are observed in the study, respectively. The fourth and final analysis will be carried out
when 172 events are observed. Fleming-Harrington-O'Brien39 alpha levels are the basis for
superiority boundaries, however, the p-value for the definitive analysis is computed by alpha
spending40 to account for the presence of a futility boundary. The superiority and futility
boundaries for the four analyses to be used to make formal recommendations to the NSABP Data
Monitoring Committee are shown in Table 6. In addition, if ten years after initiation of the
protocol, the total number of events is still less than required to trigger the final analysis, the
considerations will be given to stop the trial and report the results.

TABLE 6. Proposed interim monitoring boundaries

Interim and Approximate number Lower Boundary Upper Boundary
final analysis of events significance level significance level
(k) in each comparison (for futility)a (for superiority)a
1 43 0.01 0.000835
2 86 0.20 0.000970
3 129 0.30 0.001165
Final analysis 172 N/A 0.024209
a One-sided p-values

07/10/13 NSABP B-51/RTOG 1304 Page 76

15.7 Statistical considerations for BAHO

15.7.1 BAHO sub-study analyses

The primary aim is determine the effect of radiation therapy on cosmesis at 12 and
24 months after randomization among mastectomy patients who have had reconstructive
surgery. For our primary hypothesis, the BCTOS cosmetic status for mastectomy
patients who have had reconstructive surgery measured at 12 months and 24 months after
randomization will be compared between the two treatment groups using analysis of
covariance (ANCOVA) with adjustment for the corresponding baseline measurement.
The comparison will be performed at the significance level of 0.05.

For the secondary analyses, the fatigue score, pain, arm-related morbidity, restricted work
and social activity, mental component summary (MCS) and physical component
summary (PCS) of the SF-36 measured at 12 months after randomization will be
compared between the two treatment groups using ANCOVA with adjustment for the
corresponding baseline measurement.

The variation of the MCS, PCS, fatigue score, arm-related morbidity scale score, BCTOS
cosmetic status score, and other symptoms over time will be evaluated using longitudinal
models with adjustment for the baseline evaluation. Presence of treatment-by-time
interaction will be tested for each of these endpoints. If the interaction effect is
significant, treatment differences will be tested at each time point using individual
ANCOVAs.

Outcomes from the broader symptom checklist (including subscales and some individual
items) evaluated at 12 months after randomization will be compared between the two
treatment groups by dichotomizing it as absent or present and using a logistic model
controlling for the presence of the item at baseline.

All secondary analyses will be performed at 0.05 alpha level.

15.7.2 Statistical power for BAHO study

A sample size of 196 mastectomy patients with reconstructive surgery would be

sufficient to provide a statistical power of 80% to detect a difference of 0.31 points on
BCTOS scale between treatment groups assuming a standard deviation of 0.7733 and
controlling the α-level at 0.05. Since we expect half of all randomized patients entering
the trial to receive mastectomy and 2/3 of the mastectomy patients to have received
reconstruction, a sample size of 588 patients is required to answer this endpoint question.
Adjusting upward to allow for 20% missing data at the 12 month time point we require
736 patients to be accrued into the quality of life sub-study to have sufficient numbers of
patients who have had mastectomy and reconstruction.

Among 736 patients, we expect that 294 lumpectomy patients will be available for the
assessment of the cosmetic outcome at the 12 month time point. This will be sufficient to
provide a statistical power of more than 90% to detect a difference of 0.31 points on the
BCTOS scale between two treatment groups under the assumptions specified above.

In addition, the total sample size of 736 will provide 86% power to detect a difference of
0.25 standard deviations at significance level of 0.05 for other endpoints.

07/10/13 NSABP B-51/RTOG 1304 Page 77

 15.7.3 Missing BAHO data

A certain amount of missing data is expected. The information from patients with
missing data will be reviewed in order to determine whether data analytic procedures are
likely to be biased. Patients with missing data will be reviewed for imbalances in factors
such as trial arm, treatment adherence, institution, and reason for non-adherence. When
QOL data are missing at a particular time point, data from prior time points will be
reviewed in order to investigate whether missing status was preceded by a significant
change in QOL scores. In addition, we will investigate whether missing item status is
related to other scores on the same questionnaire. If no missing data mechanism can be
detected following this review, the data will be analyzed assuming the data are missing at
random. If, on the other hand, a missing data mechanism appears to be present, we will
undertake to develop an appropriate analytic strategy to control for the potential bias and,
if possible, to impute the missing values. We will also present sensitivity analyses based
on varying assumptions about the missing-data mechanism.

15.8 Issues relating to racial and ethnic differences

Possible racial and ethnic variation in response to the treatment under consideration is of great
concern to African-Americans. Researchers have noted poorer survival rates for
African-American breast cancer patients as compared to Caucasians.41,42 This difference has
been attributed to many factors, including more advanced disease at the time of diagnosis,43
social and economic factors,44 or specific tumor characteristics such as ER positivity.45,46
Although outcomes tend to be less favorable for African-Americans, significant
race-by-treatment interactions have not been previously reported suggesting that, where treatment
efficacy exists, both groups appear to benefit. Previous NSABP investigations of the relationship
between race and prognosis support these conclusions.47,48

Potential for the enrollment of minority patients in this protocol is enhanced by the NSABP's
recognition of the importance of increasing minority accrual. To this end, we provide educational
opportunities for NSABP investigators and coordinators to increase their awareness and skills
related to recruitment of racial and ethnic minority populations. The distributions of ethnicity and
race for B-51/1304 are projected from the NSABP B-28 study. The ethnicity distribution of the
NSABP B-28 population consisted of 3% Hispanic and 97% non-Hispanic. The racial
distribution in the B-28 study was 86% white; 8% black, not of Hispanic origin; 4% Asian or
Pacific Islander descent; and 2% American Indian or Alaskan Native. The prognostic effect of
race/ethnicity will be evaluated using statistical models. Unfortunately, because of power
limitations, we will not be able to compare effects separately for the different cultural or racial
groups.

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 TABLE 7. Expected racial and ethnic composition of NSABP B-51/RTOG 1304
Ethnic Category Total
Hispanic or Latino 49
Not Hispanic or Latino 1587
Ethnic Category: Total of all subjects 1,636
Racial Category
American Indian or Alaskan Native 33
Asian 49
Black or African American 131
Native Hawaiian or other Pacific Islander 16
White 1407
Racial Category: Total of all subjects 1,636
Ethnic Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or
Categories: Central American, or other Spanish culture or origin, regardless of race.
Not Hispanic or Latino
Racial American Indian or Alaskan Native – a person having origins in any of the
Categories: original peoples of North, Central or South America, and who maintains tribal
affiliations or community attachment.
Asian – a person having origins in any of the original peoples of the Far East,
Southeast Asia, or the Indian subcontinent including, for example, Cambodia,
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands,
Thailand, and Vietnam.
Black or African American – a person having origins in any of the black
racial groups of Africa.
Native Hawaiian or other Pacific Islander – a person having origins in any
of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands.
White – a person having origins in any of the original peoples of Europe, the
Middle East, or North Africa.

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16.0 PUBLICATIONS INFORMATION

The publication or citation of study results will be made in accordance with the publication policy
of the NSABP that is in effect at the time the information is to be made publicly available.

07/10/13 NSABP B-51/RTOG 1304 Page 80

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48. Costantino JP, Redmond CK, Wicherham D, et al. A comparison of survival between white and
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 APPENDIX A

ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY LIVING

1.0 PERFORMANCE STATUS

ECOG or Zubrod Scale Karnofsky Score

Fully active; able to carry on all
0 pre-disease performance without 90-100%
restriction
Restricted in physically strenuous
1 70-80%
activity but ambulatory
Ambulatory and capable of
2 self-care; but unable to carry out 50-60%
any work activities
Capable of only limited self-care;
3 confined to bed or chair more than 30-40%
50% of waking hours
4 Completely disabled 10-20%

2.0 ACTIVITIES OF DAILY LIVING

The following definitions for activities of daily living (ADL) should be used when the
CTCAE v4.0 grading criteria are based on ADL:
• Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
• Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden.

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 APPENDIX B

CONTOURING GUIDELINES

1.0 CONTOURING TARGETS AND ORGANS AT RISK (OAR)

Contouring accurately and consistently is essential for case evaluation and data comparison. The
structures to be contoured vary by ARM to which the patient is randomized and her surgical
treatment. Patients undergoing lumpectomy for breast conservation will be “Group A” within
each treatment ARM and those undergoing mastectomy will be in “Group B.”
1.1 Targets:
For Arm 1/Group 1A the targets to be contoured on every case are:
1. Lumpectomy,
2. Lumpectomy clinical target volume (CTV),
3. Lumpectomy planning target volume (PTV),
4. Lumpectomy planning target volume for evaluation (PTV-eval),
5. Breast CTV,
6. Breast PTV, and
7. Breast PTV-eval.
For Arm 2/Group 2A the targets to be contoured on every case are:
1. Lumpectomy (GTV),
2. Lumpectomy clinical target volume (CTV),
3. Lumpectomy planning target volume (PTV),
4. Lumpectomy planning target volume for evaluation (PTV-eval),
5. Breast CTV,
6. Breast PTV,
7. Breast PTV-eval,
8. Supraclavicular CTV,
9. Supraclavicular PTV,
10. Axillary CTV,
11. Axillary PTV,
12. IMC CTV, and
13. IMC PTV.
For Arm 2/Group 2B the targets to be contoured on every case are:
1. Mastectomy scar,
2. Mastectomy scar CTV,
3. Mastectomy scar PTV,
4. Mastectomy scare PTV-eval,
5. Chestwall CTV,
6. Chestwall PTV,
7. Chestwall PTVeval,
8. Supraclavicular CTV,
9. Supraclavicular PTV,
10. Axillary CTV,
11. Axillary PTV,
12. IMC CTV, and
13. IMC PTV.

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 APPENDIX B (continued)

1.2 Organs at Risk (OAR)

The OAR to be contoured on all cases:
1. Ipsilateral lung
2. Contralateral lung
3. Heart
4. Contralateral breast
5. Thyroid

2.0 CONTOURING LUMPECTOMY AND WHOLE BREAST TARGETS

The targets to be contoured for each arm and group are listed in the protocol under Section 10.6.2.
The lumpectomy and whole breast targets will be contoured for patients randomized to
Arm 1/Group1A that are to receive whole breast irradiation with boost, and Arm 2/Group 2A that
receives whole breast irradiation with boost plus regional nodal irradiation.

2.1 Lumpectomy Target Volumes

2.1.1 Lumpectomy GTV: See Figure 1. For this protocol, the term “lumpectomy” will
represent the surgical cavity from the breast conserving surgery. 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).

2.1.2 Lumpectomy Clinical Target Volume (CTV): See 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): See 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): See 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 chestwall or thorax. 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 build-up region for the DVH analysis) and excluding
the Lumpectomy PTV expansion beyond the posterior extent of breast tissue (chestwall,
pectoralis muscles, and lung) when pertinent. This Lumpectomy PTV-eval is the
structure used for DVH constraints and analysis.

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 APPENDIX B (continued)

Figure 1. Lumpectomy and Lumpectomy Clinical Target Volume (CTV)

Figure 2. Lumpectomy Planning Target Volume (PTV)

07/10/13 NSABP B-51/RTOG 1304 Page 88

 APPENDIX B (continued)

Figure 3. Lumpectomy Planning Target Volume for Evaluation (PTV-eval)

2.2 Breast Target Volumes

2.2.1 Breast Clinical Target Volume (CTV): See 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/pdf_document/BreastCancerAtlas.pdf.

2.2.2 Breast Planning Target Volume (PTV): See 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): See Figure 5. The Breast
PTV-eval is intended to exclude the portion of the Breast PTV that extends 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.

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 APPENDIX B (continued)

Figure 4. Breast Clinical Target Volumes (CTV) and Breast Planning Target Volumes (PTV)

Figure 5. Breast Planning Target Volume for evaluation (PTV-eval)

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 APPENDIX B (continued)

3.0 CONTOURING MASTECTOMY SCAR AND CHESTWALL TARGETS

(Arm 2/Group 2B–Post-mastectomy chestwall and regional nodal irradiation)
3.1 CT simulation
Contouring the post-mastectomy chestwall targets on CT is aided by the physician placing
radiopaque marker at the time of CT simulation for identification of: 1) the mastectomy scar; and
2) the area of the chestwall, in the physician’s clinical judgment, at risk for recurrence and ideally
to be included in the prescription dose. The medial, lateral, superior, inferior extent of this should
be marked with radiopaque markers. This area should clinically include the mastectomy scar
(see Figure 6).
Figure 6. Example of radiopaque wire placement at CT simulation for post-mastectomy radiotherapy on
ARM 2/Group 2B

3.2 Mastectomy scar targets

3.2.1 Mastectomy Scar: The mastectomy scar and the surrounding immediate vicinity are a
common location for chestwall recurrences post-mastectomy. To ensure this area of the
chestwall is adequately covered by post-mastectomy radiotherapy, an initial clinical
target volume for the mastectomy scar will be created. The Mastectomy Scar will first be
contoured by delineating the radiopaque wire placed over the scar at CT simulation as a
surrogate of the scar and including any additional visible postoperative changes on CT in
the subcutaneous tissue deep to the wire per the investigator’s discretion.

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 APPENDIX B (continued)

3.2.2 Mastectomy Scar CTV: See Figure 7. Mastectomy scar and associated surgical change
+ 1 cm 3D expansion. Limit the CTV expansion posteriorly at anterior surface of the ribs
and anterolateral at skin and should not cross midline. The Mastectomy Scar CTV
should be contained within the Chestwall CTV.
Figure 7. Axial CT slice illustrating Mastectomy Scar CTV

3.2.3 Mastectomy Scar PTV: See Figure 8. Mastectomy scar CTV + 7 mm 3D expansion
(excludes heart).
3.2.4 Mastectomy Scar PTV-eval: See Figure 9. Since a substantial part of the Mastectomy
Scar PTV often extends outside the patient – a Mastectomy Scar PTV-eval is created.
This Mastectomy Scar PTV-eval is limited to exclude the part that extends outside the
ipsilateral body/chestwall and the first 3 mm of tissue under the skin (in order to remove
some of the buildup region for the DVH analy`sis) and posteriorly is limited to exclude
lung and heart). The Mastectomy Scar PTV-eval should not cross midline and should be
contained within the borders of the Chestwall PTV-eval. This is the structure used for
DVH constraints, analysis, and compliance.

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 APPENDIX B (continued)
Figure 8. Same axial CT slice illustrating Mastectomy Scar PTV

Figure 9. Same axial CT slice illustrating Mastectomy Scar PTV-eval

07/10/13 NSABP B-51/RTOG 1304 Page 93

 APPENDIX B (continued)

3.3 Chestwall Targets (See Figure 10, Figure 11, Figure 12, Figure 13, Figure 14, Figure 15)
3.3.1 Chestwall CTV: Includes the Mastectomy Scar CTV and takes into account the
radiopaque markers placed at CT identifying clinical extent of chestwall, surgical
changes visualized by CT, and consensus definitions of anatomical borders of chestwall
from the RTOG Breast Cancer Atlas
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx.
The Chestwall CTV is limited by the skin anteriorly and should not extend deeper than
the ribs so that it excludes the lung and heart. Depending on the location of the
Mastectomy Scar CTV, it should exclude the sternum and the axilla deep to anterior
surface of the pectoralis major muscle laterally. In general, the Chestwall CTV should
not cross midline.
Expanders, implants or autologous tissue present for reconstruction will be included in
the Chestwall CTV. The degree of expander expansion present is per the treating
physician’s discretion. The expander should remain at the same expansion through the
course of treatment that is present for the CT simulation
3.3.2 Chestwall PTV: Chestwall CTV + 7 mm 3D expansion (excludes heart and does not
cross midline).
3.3.3 Chestwall PTV-eval: As a part of the Chestwall PTV often extends outside the patient,
the Chestwall PTV is then copied to a Chestwall PTV-eval which is edited. This
Chestwall PTV-eval is limited anteriorly to exclude the part that extends outside the
body/patient and the first 3 mm of tissue under the skin (in order to remove some of the
buildup region for the DVH analysis), medially excludes the sternum, and posteriorly is
limited to no deeper than the ribs to exclude all intra thoracic structures; e.g., vessels,
lung, and heart. This Chestwall PTV-eval is the structure used for DVH constraints and
analysis and not for beam aperture generation.

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 APPENDIX B (continued)
Figure 10. Axial CT Slice illustrating Chestwall CTV and Chestwall PTV; and the relation to the
Mastectomy Scar CTV and Mastectomy Scar PTV-eval

Figure 11. Same axial CT slice illustrating Chestwall PTV-eval

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 APPENDIX B (continued)
Figure 12. Different and more caudal axial CT slice illustrating Chestwall CTV (blue), Chestwall PTV
(white), and Chestwall PTV-eval (white)

Figure 13. Sagittal CT slice illustrating Mastectomy scar and Chestwall targets

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 APPENDIX B (continued)

Figure 14. Coronal CT slice illustrating Mastectomy scar targets – Mastectomy scar CTV (yellow) and
Mastectomy Scar PTV-eval ( cyan), and Chestwall targets- Chestwall CTV (blue), Chestwall
PTV (white), and Chestwall PTV-eval (red)

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 APPENDIX B (continued)

Figure 15. Axial CT slice illustrating Mastectomy scar targets and Chestwall targets in the
presence of an implant reconstruction

4.0 CONTOURING REGIONAL NODAL TARGET VOLUMES: ARM 2/GROUPS 2A

AND 2B

4.1 Regional node target volumes will be contoured for patients randomized to
ARM 2/Group 2A or Group 2B

4.1.1 Supraclavicular CTV: See Figure 16A and Figure 16B. Consensus definitions based on
the RTOG Breast Cancer Atlas. Superior extent typically is below the level of the
cricoid; medially excludes thyroid, trachea, and esophagus; extends laterally to the edge
of the sternocleidomastoid muscle superiorly and the clavicle at its more inferior extent,
and the inferior border extends to the caudal aspect of the clavicle head.

4.1.2 Supraclavicular PTV: See Figure 16A and Figure 16B. Supraclavicular CTV + 5 mm
margin in all directions. The following structures should be excluded from the
Supraclavicular PTV to minimize excess dose to normal tissues: ipsilateral thyroid,
trachea, esophagus, and ipsilateral lung. This means that some or the entire medial
border of the Supraclavicular CTV and PTV will be similar. The Supraclavicular PTV
should exclude the vertebral body.

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 APPENDIX B (continued)

Figure 16A and Figure 16B. Supraclavicular (SCL) CTV and SCL PTV
16A. Non-contiguous Axial CT slices illustrating the Supraclavicular (SCL) CTV and SCL PTV.
The SCL PTV is a 5 mm expansion on the SCL CTV. Note that the SCL PTV excludes thyroid,
trachea, etc., medially and therefore some or all of it can have a similar medial extent as the
SCL CTV.

16B. Coronal CT slice illustrating the SCL CTV and SCL PTV in relation to the Axillary CTV and
Axillary PTV

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 APPENDIX B (continued)

4.1.3 Axillary CTV: The extent of axilla to be targeted for regional nodal irradiation will
depend on the extent of axillary surgery performed. The axillary CTV consists of the
portion of the axilla that remains "undissected. " When an axillary node dissection has
been done, the inferior border of the axillary CTV will be the most cephalic extent of the
dissection. Review of the operative report, postoperative changes on the planning CT,
and discussion with the patient’s surgeon can be used for determining the most cephalic
extent of the dissection and inferior border of the axillary CTV. Axillary dissection
typically removes level 1–2 axillary nodes, so that the axillary CTV in these cases is
expected to include level 3 primarily and some of level 2 of the axilla. When a sentinel
node biopsy alone is done without completion axillary dissection, the axillary CTV will
then include all 3 levels of the axilla as all three levels are "undissected." The consensus
definitions from the RTOG breast cancer for anatomical borders of the axillary levels are
from the RTOG Breast Cancer Atlas
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx.

4.1.4 Axillary PTV: See Figure 17A and Figure 17B and Figure 18A and Figure 18B.
Axillary CTV + 5 mm. The ipsilateral lung should be excluded from the Axillary PTV.
This means that some or all of the medial border of the Axillary PTV can be similar to
the Axillary CTV.

Figure 17A and Figure 17B. Axillary CTV and Axillary PTV after AXILLARY DISSECTION
17A. Non-contiguous Axial CT slices illustrating Axillary CTV and Axillary PTV.
Axillary PTV is a 5 mm expansion on the Axillary CTV. Axillary PTV excludes the lung.

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 APPENDIX B (continued)

17B. Coronal CT slice illustrating Axillary CTV and Axillary PTV in setting of AXILLARY
DISSECTION

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 APPENDIX B (continued)
Figure 18A and Figure 18B. Axillary CTV and Axillary PTV after AXILLARY DISSECTION
18A. Non-contiguous Axial CT slices illustrating Axillary CTV and Axillary PTV. Axillary PTV is a
5 mm expansion on the Axillary CTV. Axillary PTV excludes the lung.

18B. Coronal CT slice illustrating Axillary CTV and Axillary PTV in setting of SENTINTEL NODE
BIOSY ONLY WITHOUT AXILLARY DISSECTION

4.1.5 Internal mammary node (IMN) CTV: See Figure 19A and Figure 19B. Includes the
internal mammary/thoracic vessels in the first three intercostal spaces.
4.1.6 Internal mammary node (IMN) PTV: The IMN CTV + 5 mm expansion medially,
laterally, superiorly, and inferiorly. The IMN PTV is limited medially to not extend into
the sternum. In order to minimize excess normal tissue irradiation, no additional
expansion into the lung should be done for the IMN PTV. The deep edge of the IMN
PTV will be similar to the IMN CTV. No anterior expansion into the chestwall or breast
volumes will be done.

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 APPENDIX B (continued)
Figure 19A and Figure 19B. IMN CTV and IMN PTV
19A. Non-contiguous Axial CT slices illustrating IMN CTV and IMN PTV. IMN PTV is a 5 mm
medial and lateral expansion of the IMN CTV. IMN PTV excludes the lung, heart, sternum,
chestwall and/or breast

19B. Sagittal CT slice illustrating IMN CTV and IMN PTV are limited to the first 3 intercostal spaces

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 APPENDIX B (continued)

5.0 ORGANS AT RISK (OAR)

The OAR to be contoured on all cases are the ipsilateral and contralateral lung, heart, thyroid, and
contralateral breast.
5.1 Ipsilateral and contralateral lung: This may be contoured with auto-segmentation with manual
verification.
5.2 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, and 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.
5.3 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 of the thyroid are somewhat triangular in shape and often do not converge anteriorly at mid-
line. All “bright” thyroid tissue should be contoured.
5.4 Contralateral Breast: Includes contralateral breast as defined by clinical markers and apparent CT
glandular breast tissue visualized by CT and consensus definitions of anatomical borders from the
RTOG Breast Cancer Atlas. In general the borders are:
Posterior border: At the anterior surface of the pectoralis, serratus 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.

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 APPENDIX C

COMPLIANCE CRITERIA TABLE

Chestwall or Breast PTV Eval

ARM 1/ ARM 2/ ARM 2/
Group 1A Group 2A Group 2B

Breast: Breast: Chestwall:

50 Gy in 25 f. 50 Gy in 25 f. 50 Gy in 25 f.
sequential sequential
Compliance Criteria
12-14 Gy 12-14 Gy boost No Boost
boost total total 62-64 Gy
62-64 Gy RNI Scl, Ax, RNI Scl, Ax,
No RNI IMN: IMN:
Criteria Volume Dose 50 Gy in 25 f. 50 Gy in 25 f.
Breast or Per Protocol ≥ 95% of ≥ 95% of ≥ 47.5 Gy ≥ 47.5 Gy ≥ 47.5 Gy
chestwall the PTV 50 Gy
PTV Eval Eval
receiving receives
whole-breast Variation ≥ 90% of ≥ 90% of ≥ 45 Gy ≥ 45 Gy ≥ 45 Gy
/chestwall Acceptable the PTV 50 Gy
dose Eval
receives
Breast/ Per Protocol ≤ 30% of ≥ 100% of ≥ 62-64 Gy ≥ 62-64 Gy −
Chestwall the breast/ boost dose (see footnote a)
PTV Eval chestwall
receiving PTV Eval
boost dose receives
Variation ≤ 35% of ≥ 100% of ≥ 62-64 Gy ≥ 62-64 Gy −
Acceptable the breast/ boost dose (see footnote a)
chestwall
PTV Eval
receives
Breast PTV Per Protocol ≤ 50% of ≥ 108% of ≥ 54 Gy ≥ 54 Gy −
Eval the volume 50 Gy (see footnote a)
receiving of breast/
above the chestwall
whole breast PTV Eval
dose receives
Variation ≤ 50% of ≥ 112% of ≥ 56 Gy ≥ 56 Gy −
Acceptable the volume 50 Gy (see footnote a)
of breast/
chestwall
PTV Eval
receives

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 APPENDIX C (continued)

Chestwall or Breast PTV Eval continued

ARM 1/ ARM 2/ ARM 2/
Group 1A Group 2A Group 2B

Breast: Breast: Chestwall:

50 Gy in 25 f. 50 Gy in 25 f. 50 Gy in 25 f.
sequential sequential
Compliance Criteria
12-14 Gy 12-14 Gy boost No Boosta
boost total total 62-64 Gy
62-64 Gy RNI Scl, Ax, RNI Scl, Ax,
No RNI IMN: IMN:
Criteria Volume Dose 50 Gy in 25 f. 50 Gy in 25 f.
Per Protocol Point doseb ≤ 115% of ≤ 57.5 Gy All Photons: All Photons:
50 Gy ≤ 57.5 Gy ≤ 57.5 Gy
Breast/
Chestwall
PTV Eval Variation ≤ 120% of ≤ 60 Gy
Point doseb All Photons: All Photons:
maximum Acceptable 50 Gy ≤ 60.0 Gy ≤ 60.0 Gy
doseb

Per Protocol Point doseb Photon ≤ 62.5 Gy ≤ 62.5 Gy

electron −
mix: ≤
125%
Breast/
Variation Point doseb Photon ≤ 65.0 Gy ≤ 65.0 Gy
Chestwall
Acceptable electron OR OR
PTV Eval
mix: ≤ ≤ 10 cc ≥ 62.5Gy ≤ 10 cc ≥ 62.5Gy
maximum
130%
dose
OR
(Photon
≤ 10 cc of −
electron
composite
mix)
plan
receives
≥ 125% of
50 Gy
Conformity Per Protocol 0.95 ≤ CI
Index ≤ 2.0 − −
(Ratio of Variation 0.85 ≤ CI
irradiated Acceptable ≤ 2.5
volume
covered by
47.5 Gy/ − −
volume of
Breast PTV
Eval)

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 APPENDIX C (continued)

Lumpectomy PTV Eval

ARM 1/ ARM 2/ ARM 2/
Group 1A Group 2A Group 2B

Breast: Breast: Chestwall:

50 Gy in 25 f. 50 Gy in 25 f. 50 Gy in 25 f.
sequential sequential
Compliance Criteria
12-14 Gy 12-14 Gy boost No Boosta
boost total total 62-64 Gy
62-64 Gy RNI Scl, Ax, RNI Scl, Ax,
No RNI IMN: IMN:
Criteria Volume Dose 50 Gy in 25 f. 50 Gy in 25 f.
Target
Lumpectomy Per ≥ 95% of the ≥ 95% of ≥ 58.9-60.8 ≥ 58.9-60.8 Gy
PTV Eval Protocol lumpectomy cumulative Gy
−
receiving PTV Eval boost dose
boost dose receives 62-64 Gy
Variation ≥ 90% of the ≥ 90% of ≥ 55.8-57.6 ≥ 55.8-57.6 Gy
Acceptable lumpectomy boost dose Gy
−
PTV Eval
receives
Lumpectomy Per ≤ 5% of the ≥ 110% of ≥ 68.2-70.4 ≥ 68.2-70.4 Gy
PTV Eval Protocol lumpectomy boost dose Gy
−
receiving PTV Eval
above boost receives
dose Variation ≤ 10% of the ≥ 110% of ≥ 68.2-70.4 ≥ 68.2-70.4 Gy
Acceptable lumpectomy boost dose Gy
−
PTV Eval
receives
Lumpectomy Per ≤ 115% of ≤ 71.3-73.6 ≤ 71.3-73.6 Gy
PTV Eval Protocol boost dose Gy −
maximum Variation ≤ 120% of ≤ 74.4-76.8 ≤ 74.4-76.8 Gy
−
doseb Acceptable boost dose Gy
Conformity Per 0.95 ≤ CI
−
Index (Ratio Protocol ≤ 2.5
of volume Variation 0.9 ≤ CI
covered by Acceptable ≤3
95%
prescription
isodose / −
volume of
Lumpectomy
PTV Eval)

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 APPENDIX C (continued)

Regional nodes
ARM 1/ ARM 2/ ARM 2/
Group 1A Group 2A Group 2B

Breast: Breast: Chestwall:

50 Gy in 25 f. 50 Gy in 25 f. 50 Gy in 25 f.
sequential sequential
Compliance Criteria
12-14 Gy 12-14 Gy boost No Boost
boost total total 62-64 Gy
62-64 Gy RNI Scl, Ax, RNI Scl, Ax,
No RNI IMN: IMN:
Criteria Volume Dose 50 Gy in 25 f. 50 Gy in 25 f.
Target
Supraclavicu- Per Protocol ≥ 95% of ≥ 95% of ≥ 47.5 Gy ≥ 47.5 Gy
lar (SCL) the SCL 50 Gy
−
PTV PTV
receiving receives
Nodal dose Variation ≥ 90% of ≥ 90% of ≥ 45 Gy ≥ 45 Gy
Acceptable the SCL 50 Gy −
PTV
Supraclavicu- Per Protocol Point doseb ≤ 110% of ≤ 55 Gy ≤ 55 Gy
−
lar (SCL) 50 Gy
PTV Variation Point doseb ≤ 115% of ≤ 57.5 Gy ≤ 57.5 Gy
Maximal Acceptable 50 Gy −
Point Doseb
Axillary (Ax) Per Protocol ≥ 95% of ≥ 95% of ≥ 47.5 Gy ≥ 47.5 Gy
PTV the Ax 50 Gy
−
receiving PTV
Nodal Dose receives
Variation ≥ 90% of ≥ 90% of ≥ 45 Gy ≥ 45 Gy
Acceptable the Ax 50 Gy −
PTV
Axillary (Ax) Per Protocol Point doseb ≤ 110% of ≤ 55 Gy ≤ 55 Gy
−
PTV 50 Gy
Maximal Variation Point doseb ≤ 115% of ≤ 57.5 Gy ≤ 57.5 Gy
−
Point Doseb Acceptable 50 Gy
IMN PTV Per Protocol ≥ 90% of ≥ 90% of ≥ 45 Gy ≥ 45 Gy
receiving the IMN- 50 Gy
−
Nodal Dose PTV
receives
Variation ≥ 90% of ≥ 80% of ≥ 40 Gy ≥ 40 Gy
Acceptable the IMN 50 Gy −
PTV
IMN PTV Per Protocol Point doseb ≤ 110% of ≤ 55 Gy ≤ 55 Gy
−
Maximal 50 Gy
Point Doseb Variation Point doseb ≤ 115% of ≤ 57.5 Gy ≤ 57.5 Gy
−
Acceptable 50 Gy

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 APPENDIX C (continued)

Normal Tissue Constraints

ARM 1/ ARM 2/ ARM 2/
Group 1A Group 2A Group 2B

Breast: Breast: Chestwall:

50 Gy in 25 f. 50 Gy in 25 f. 50 Gy in 25 f.
sequential sequential
OAR Compliance Criteria
12-14 Gy 12-14 Gy boost No Boosta
boost total total 62-64 Gy
62-64 Gy RNI Scl, Ax, RNI Scl, Ax,
No RNI IMN: IMN:
Description Criteria Volume 50 Gy in 25 f. 50 Gy in 25 f.
Heart dose Per Protocol ≤ 5% of the heart for
constraint 1 left-sided cancer
0% of the heart for ≤ 20 Gy ≤ 25 Gy ≤ 25 Gy
right-sided receives
Variation ≤ 5% of the heart for
Acceptable left-sided cancer
≤ 25 Gy ≤ 30 Gy ≤ 30 Gy
0% of the heart for
right-sided receives
Heart dose Per Protocol ≤ 30% of the heart
constraint 2 for left-sided cancer
≤ 10% of the heart ≤ 10 Gy ≤ 15 Gy ≤ 15 Gy
for right-sided
receives
Variation ≤ 35% of the heart
Acceptable for left-sided cancer
≤ 15% of the heart ≤ 10 Gy ≤ 15 Gy ≤ 15 Gy
for right-sided
receives
Heart dose Per Protocol Mean dose is ≤ 4 Gy ≤ 4 Gy ≤ 4 Gy
constraint 3 Variation Mean dose is
≤ 5 Gy ≤ 5 Gy ≤ 5 Gy
Acceptable
Ipsilateral lung Per Protocol % of the ipsilateral
dose lung that can receive ≤ 15% ≤ 30% ≤ 30%
≥ 20 Gy
Variation % of the ipsilateral
Acceptable lung that can receives ≤ 20% ≤ 35% ≤ 35%
≥ 20 Gy
Ipsilateral lung Per Protocol % of the ipsilateral
dose constraint 1 lung that can receive ≤ 35% ≤ 50% ≤ 50%
≥10 Gy
Variation % of the ipsilateral
Acceptable lung that can receive ≤ 40% ≤ 60% ≤ 60%
≥ 10 Gy
Ipsilateral lung Per Protocol % of the ipsilateral
dose constraint 2 lung that can receive ≤ 50% ≤ 65% ≤ 65%
≥ 5 Gy
Variation % of the ipsilateral
Acceptable lung that can receive ≤ 55% ≤ 70% ≤ 70%
≥ 5 Gy

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 APPENDIX C (continued)

Normal Tissue Constraints continued

ARM 1/ ARM 2/ ARM 2/
Group 1A Group 2A Group 2B

Breast: Breast: Chestwall:

50 Gy in 25 f. 50 Gy in 25 f. 50 Gy in 25 f.
sequential sequential
OAR Compliance Criteria
12-14 Gy 12-14 Gy boost No Boosta
boost total total 62-64 Gy
62-64 Gy RNI Scl, Ax, RNI Scl, Ax,
No RNI IMN: IMN:
Description Criteria Volume 50 Gy in 25 f. 50 Gy in 25 f.
Contralateral Per Protocol ≤ 10% receives
≤ 5 Gy ≤ 5 Gy ≤ 5 Gy
Lung
Variation ≤ 15% receives
≤ 5 Gy ≤ 5 Gy ≤ 5 Gy
Acceptable
Contralateral Per Protocol Dmax / < 5% ≤ 3.1 Gy max/
≤ 3 Gy < 5% ≤ 3 Gy < 5%
Breast receives 1.86 Gy < 5%
Variation < 5% Dmax / < 5% ≤ 4.96 Gy
Acceptable receives max/ ≤ 4.1 Gy < 5% ≤ 4.1 Gy < 5%
3.1 Gy < 5%

Footnotes:
a. Arm 2/Group 2B: No boost to be delivered post-mastectomy except in the case of close invasive cancer
margins post-mastectomy. If boost is delivered – it should comply with the constraints outlined in
Section 10.6.5.3.

b. Point dose: All maximum doses should be defined in one dose calculation voxel; e.g., 3 x 3 x 3 mm or 3 mm3.

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