NSABP PROTOCOL B-39 RTOG PROTOCOL 0413 A …

1 NSABP PROTOCOL B-39. RTOG PROTOCOL 0413. A Randomized Phase III Study of Conventional Whole Breast Irradiation (WBI) Versus Partial Breast Irradiation (PBI) for Women with Stage 0, I, or II Breast Cancer NATIONAL SURGICAL ADJUVANT BREAST AND BOWEL PROJECT ( NSABP ). NSABP OPERATIONS CENTER NSABP BIOSTATISTICAL CENTER. East Commons Professional Building One Sterling Plaza Four Allegheny Center 5th Floor 201 North Craig Street, Suite 500. Pittsburgh, PA 15212-5234 Pittsburgh, PA 15213. TELEPHONE: 412-330-4600 TELEPHONE: 412-624-2666. FAX: 412-330-4660 FAX: 412-624-1082. RADIATION THERAPY ONCOLOGY GROUP (RTOG). 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 ).

2 Walter J. Curran, MD (RTOG). PROTOCOL Chairs: Frank Vicini, MD ( NSABP ) Lead PROTOCOL Chair Julia White, MD (RTOG). PROTOCOL Co-Chairs: Douglas Arthur, MD ( NSABP ). Robert Kuske, MD ( NSABP ). Rachel Rabinovitch, MD (RTOG). PROTOCOL Officers: Thomas Julian, MD ( NSABP ). David Parda, MD ( NSABP ). Behavioral and Health Outcomes Officer: Michael Scheier, PhD ( NSABP ). PROTOCOL Statisticians: Joseph Costantino, DrPH ( NSABP ) Lead PROTOCOL Statistician Kathryn Winter, MS (RTOG). Behavioral and Health Outcomes Statistician: Stephanie Land, PhD ( NSABP ). PROTOCOL Pathologist: Soonmyung Paik, MD ( NSABP ). ACOSOG Co-Chair: Henry Kuerer, MD, PhD, FACS. NCCTG Co-Chair Laura A. Vallow, MD. RTOG Co-Chairs: Julia White, MD and Rachel Rabinovitch, MD. SWOG Co-Chair: Lori J. Pierce, MD. All institutions that are not aligned with the NSABP will enroll patients via the NCI Cancer Trials Support Unit (CTSU). Version Date: March 7, 2011 (Replaces all other versions).

3 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 nor the RTOG assume any responsibility for unauthorized use of this PROTOCOL . [BLANK PAGE]. NSABP PROTOCOL B-39. RTOG PROTOCOL 0413. A Randomized Phase III Study of Conventional Whole Breast Irradiation (WBI) Versus Partial Breast Irradiation (PBI). for Women with Stage 0, I, or II Breast Cancer National Surgical Adjuvant Breast and Bowel Project ( NSABP ). Radiation Therapy Oncology Group (RTOG). Trial Activated: March 21, 2005. PROTOCOL Revision Record Original Version: December 8, 2004. Update Date: January 24, 2005. Amendment #1: March 30, 2006. Sections Changed: Cover Page, Table of Contents, Information Resources, Sections , Schema, , , , , (Tables 2 and 3), , , , , , (Figure 3), , , , , , , , , , , , , , , , , , (Tables 5A.)

4 And 5B), , Appendices A, C, D, E, F, G, H. Amendment #2: January 8, 2007. Sections Changed: Cover Page, Table of Contents, Information Resources, Sections , , , , (Table 2), , , , , , , , (Tables 5A and 5B), , , (Table 8), (Table 9), Appendices D, H. Amendment #3: March 13, 2007. Sections Changed: Cover Page, Sections (Table 2), (Table 5A). Amendment #4: November 2, 2009. Sections Changed: Cover Page, Table of Contents, Information Resources, Sections (Tables 2 and 3), , , (Table 5B), , , Appendices D, H. Amendment #5: March 7, 2011. Sections Changed: Cover Page, Table of Contents, Information Resources, Sections (Schema, Flow Diagram), , , , , , , , , , , , Appendices F, H. [BLANK PAGE]. TABLE OF CONTENTS 03/30/06, 01/08/07, 11/02/09, 03/07/11. INFORMATION RESOURCES ..iv SUMMARY OF THE 1. BACKGROUND .. 4. Clinical Background .. 4. Supporting data for PBI .. 7. Considerations regarding axillary staging.

5 13. Considerations regarding accelerated WBI 13. STUDY AIMS .. 15. Primary 15. Secondary aims .. 15. ENDPOINTS .. 16. Primary 16. Secondary endpoints .. 16. RADIATION ONCOLOGY FACILITY CREDENTIALING AND QUALITY ASSURANCE. 17. Radiation oncology facility credentialing .. 17. PBI quality assurance program .. 18. WBI quality assurance 19. PATIENT ELIGIBILITY AND INELIGIBILITY .. 20. Conditions for patient 20. Conditions for patient 21. PRE-RANDOMIZATION ASSESSMENTS .. 23. Pre-randomization breast CT for treatment planning .. 23. Pre-treatment digital images for patients in the QOL and cosmesis 23. REQUIRED ENTRY AND FOLLOW-UP 25. REQUIRED PATHOLOGY STUDIES .. 27. Summary of pathology and correlative science studies .. 27. Serum collection .. 29. BEHAVIORAL AND HEALTH OUTCOMES (BAHO) ASSESSMENTS .. 31. Cosmesis .. 31. Quality of 32. QOL and cosmesis instructions .. 33. Quality of life and cosmesis patient 34.

6 WHOLE BREAST IRRADIATION GROUP 1 .. 36. Treatment overview .. 36. CT-based WBI treatment plan .. 37. Fluoroscopy-based WBI treatment plan .. 38. PARTIAL BREAST IRRADIATION (PBI) BY MULTI-CATHETER BRACHYTHERAPY . GROUP 2 .. 40. PBI by multi-catheter brachytherapy .. 40. Quality assurance of dose distribution .. 42. PARTIAL BREAST IRRADIATION (PBI) BY MAMMOSITE OR SINGLE-ENTRY. MULTI-LUMEN INTRACAVITARY DEVICE GROUP 2 .. 43. PBI by MammoSite /multi-lumen (single-entry) intracavitary device .. 43. NSABP B-39/RTOG 0413 Page i Quality assurance of dose distribution .. 46. PARTIAL BREAST IRRADIATION (PBI) BY 3D CONFORMAL EXTERNAL BEAM. RADIOTHERAPY GROUP 2 .. 48. PBI by 3D conformal external beam radiotherapy (3D-CRT).. 48. Quality assurance of dose distribution .. 50. SYSTEMIC THERAPY .. 51. 51. Hormonal therapy .. 51. 51. DIAGNOSIS OF BREAST CANCER RECURRENCE AND OTHER CANCER 52. Ipsilateral in-breast 52. Local chest wall recurrence.

7 52. Regional recurrence .. 52. Distant recurrence .. 52. Second primary breast cancer .. 53. Second primary cancer (non-breast) .. 54. Documentation requested following death .. 54. ADVERSE EVENT REPORTING 55. B-39/0413 definitions for adverse event reporting .. 55. Adverse event 55. Expedited reporting of adverse events .. 55. Routine reporting of adverse events .. 57. Reporting on follow-up Form 59. NON- PROTOCOL THERAPY GUIDELINES .. 60. Radiation 60. Hormonal therapy for symptom management .. 60. PATIENT ENTRY AND WITHDRAWAL PROCEDURES .. 61. Closure of accrual to specific patient populations .. 61. Registration procedures .. 61. Patient consent form .. 61. Entry .. 61. Patient study number .. 62. Patient-initiated discontinuation of study therapy .. 62. Investigator-initiated discontinuation of study therapy .. 62. REQUIRED FORMS AND MATERIALS .. 63. STATISTICAL 66. Randomization and treatment 66.

8 Primary 66. Secondary endpoints .. 66. Estimates of event rates .. 66. Accrual rate and total sample size .. 67. Statistical Analysis - primary 68. Power considerations - primary analysis .. 70. Interpretation of relative risk .. 70. Statistical analysis - secondary 71. Power considerations - cosmesis and fatigue analyses .. 73. Monitoring of adverse 73. NSABP B-39/RTOG 0413 Page ii Analysis schedule .. 74. Issues related to racial and ethnic 74. PUBLICATION INFORMATION AND ADMINISTRATIVE AGREEMENTS .. 76. REFERENCES .. 77. SITE REGISTRATION AND PATIENT ENTRY FOR CTSU 90. SPECIAL MATERIALS AND 91. Submission of pathology 91. Serum 91. Quality of life and cosmesis 91. DATA SUBMISSION FOR CTSU 92. Routine 93. Expedited 93. Reporting breast cancer recurrence and second primary malignancies .. 93. Pregnancy occurring while the patient is on study 94. CT-BASED RADIATION .. 95. FLUOROSCOPIC SIMULATION .. 96.

9 NORMAL STRUCTURE AND TARGET CONTOURING .. 97. Thyroid .. 97. Heart .. 97. WHOLE BREAST REFERENCE VOLUME 97. Free-handed contouring .. 98. Automated 98. 3D-CRT BEAM 99. TARGET 99. 99. MammoSite /multi-lumen intracavitary 99. 110. DEFINITIONS FOR ADVERSE EVENT 110. Study therapy .. 110. Non- PROTOCOL therapy .. 110. Adverse event 110. PROTECTING PATIENT 111. Figure 1 NSABP B-39/RTOG 0413 schema .. 2. Figure 2 NSABP B-39/RTOG 0413 flow diagram .. 3. Figure 3 NSABP B-39/RTOG Behavioral and Health Outcomes (BAHO) 35. Table 1 Partial breast irradiation 8. Table 2 Studies required .. 25. Table 3 Required studies for QOL and cosmesis patient 26. Table 4 AdEERS expedited reporting requirements for adverse events that occur within 30 days of last treatment of study therapy .. 57. Table 5A Required forms and materials for all B-39/0413 patients .. 63. Table 5B Forms and materials only required for patients designated as participants NSABP B-39/RTOG 0413 Page iii in the QOL/cosmesis patient 65.

10 Table 6 Incidence of IBTR in selected populations of NSABP patients .. 67. Table 7 Operating characteristics of the primary analysis .. 70. Table 8 Number of events and p-values for interim and final 74. Table 9 Expected racial and ethnic composition of NSABP B-39/RTOG 0413 .. 75. Appendix A TNM nomenclature and staging for breast cancer .. 82. Appendix B Determination of menopausal 85. Appendix C Procedures for collecting, processing, and shipping serum specimens .. 86. Appendix D Cancer Trials Support Unit (CTSU) 90. Appendix E Whole breast 95. Appendix F Contouring 97. Appendix G Information basics for adverse event 110. Appendix H NSABP B-39/RTOG 0413 sample consent form .. 112. NSABP B-39/RTOG 0413 Page iv INFORMATION RESOURCES 03/30/06. NSABP Operations Center NSABP Biostatistical Center East Commons Professional Building One Sterling Plaza Four Allegheny Center 5th Floor 201 North Craig Street, Suite 500.