Radiation Therapy in Treating Women Who Have Undergone Surgery For Ductal Carcinoma In Situ or Stage I or Stage II Breast Cancer

• Survival at event occurrence OR every 6 months for 5 years, and annually thereafter [ Designated as safety issue: No ]
• Recurrence-free survival at event occurrence OR every 6 months for 5 years and annually thereafter [ Designated as safety issue: No ]
• Distant disease-free survival at event occurrence or every 6 months for 5 years and at recurrence or annually for 5 years [ Designated as safety issue: No ]
• Quality of life and patient-reported cosmesis by Breast Cancer Treatment Outcome Scale, MOS SF-36 Vitality, Convenience of Care scale, and symptoms at baseline, after completion of study tx, and 1 & 6 mo. and 1-3 years after completion of study tx [ Designated as safety issue: No ]
• Physician-reported cosmesis as assessed by physician cosmesis evaluation and digital photographs of treated and untreated breasts at baseline and 1 and 3 years after completion of study treatment [ Designated as safety issue: No ]
• Toxicity as assessed by adverse events during treatment, and at 4 weeks, 6 months, 12 months, and annually after completion of study treatment [ Designated as safety issue: Yes ]

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy in different ways may kill any tumor cells that remain after surgery. It is not yet known whether whole breast radiation therapy is more effective than partial breast radiation therapy in treating breast cancer.

PURPOSE: This randomized phase III trial is studying whole breast radiation therapy to see how well it works compared to partial breast radiation therapy in treating women who have undergone surgery for ductal carcinoma in situ or stage I or stage II breast cancer.

OBJECTIVES:

Primary

• Compare local tumor control in women with ductal carcinoma in situ or stage I or II breast cancer treated with adjuvant whole breast vs partial breast irradiation following lumpectomy.

Secondary

• Compare overall survival, recurrence-free survival, and distant disease-free survival in patients treated with these regimens.
• Compare the cosmetic result in patients treated with these regimens.
• Compare fatigue and treatment-related symptoms in patients treated with these regimens.
• Compare perceived convenience of care in patients treated with these regimens.
• Compare acute and late toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to disease stage (ductal carcinoma in situ [DCIS] only vs invasive and node negative vs invasive with 1-3 positive nodes), menopausal status (premenopausal vs postmenopausal), hormone receptor status (estrogen receptor [ER]-positive and/or progesterone receptor [PR]-positive vs ER-negative and PR-negative), intention to receive chemotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. (Patients who are 50 years of age and over with DCIS regardless of hormone receptor status AND patients with invasive breast cancer meeting all of the following criteria: ≥ 50 years of age, node-negative, and hormone-receptor positive status will not be enrolled in study after 12/30/2006.)

• Arm I: Patients undergo whole-breast irradiation (WBI) once daily, 5 days a week, for 5-7 weeks.
• Arm II: Patients undergo partial-breast irradiation (PBI) twice daily on 5 days over a period of 5-10 days. This may be delivered by intracavitary brachytherapy or 3-D conformal radiotherapy.

Patients in both arms may receive adjuvant chemotherapy at least 2 weeks prior to initiation of WBI OR at least 2 weeks after completion of PBI at the discretion of the treating physician. Patients with ER-positive or PR-positive tumors may also receive hormonal therapy, beginning 3-12 weeks after completion of adjuvant chemotherapy (or before, during, or after completion of WBI or PBI for patients not receiving adjuvant chemotherapy) and continuing for at least 5 years.

After completion of study treatment, patients are followed at 1 and 6 months, every 6 months for 4.5 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 4,300 patients (2,150 per treatment arm) will be accrued for this study within 4.6 years.

• Radiation: 3-dimensional conformal accelerated partial breast irradiation
  Patients undergo radiation therapy twice daily (days 1-5) for up to 7 weeks
• Radiation: brachytherapy
  Patients undergo brachtherapy as PBI
• Radiation: whole breast irradiation
  Patients undergo radiation therapy once daily (days 1-5) for up to 7 weeks

• Active Comparator: Arm I
  Patients undergo whole-breast irradiation (WBI) once daily, 5 days a week for 5-7 weeks.
  Intervention: Radiation: whole breast irradiation
• Experimental: Arm II
  Patients undergo partial-breast irradiation (PBI) twice daily on 5 days over a period of 5-10 days. This may be delivered by intracavitary brachytherapy or 3-D conformal radiotherapy.
  Interventions:

  • Radiation: 3-dimensional conformal accelerated partial breast irradiation
  • Radiation: brachytherapy

• Jain AK, Vallow LA, Gale AA, Buskirk SJ. Does Three-Dimensional External Beam Partial Breast Irradiation Spare Lung Tissue Compared with Standard Whole Breast Irradiation? Int J Radiat Oncol Biol Phys. 2009 Feb 19; [Epub ahead of print]
• Tendulkar RD, Chellman-Jeffers M, Rybicki LA, Rim A, Kotwal A, Macklis R, Obi BB. Preoperative breast magnetic resonance imaging in early breast cancer: implications for partial breast irradiation. Cancer. 2009 Feb 17; [Epub ahead of print]
• Patel RR, Christensen ME, Hodge CW, Adkison JB, Das RK. Clinical outcome analysis in "high-risk" versus "low-risk" patients eligible for national surgical adjuvant breast and bowel B-39/radiation therapy oncology group 0413 trial: five-year results. Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):970-3.
• Al-Hallaq H, Mell L, Advani S, et al.: Magnetic resonance imaging (MRI) identifies multifocal and multicentric disease in breast cancer patients eligible for the NSABP B-39/RTOG 0413 partial breast irradiation (PBI) trial. [Abstract] Int J Radiat Oncol Biol Phys 66 (3 Suppl 1): A-1086, S179-S180, 2006.
• Croshaw R, Kim Y, Lappinen E, Julian T, Trombetta M. Avoiding Mastectomy: Accelerated Partial Breast Irradiation for Breast Cancer Patients with Pacemakers or Defibrillators. Ann Surg Oncol. 2011 May 24; [Epub ahead of print]
• Hasan Y, Kim L, Wloch J, Chi Y, Liang J, Martinez A, Yan D, Vicini F. Comparison of Planned Versus Actual Dose Delivered for External Beam Accelerated Partial Breast Irradiation Using Cone-Beam CT and Deformable Registration. Int J Radiat Oncol Biol Phys. 2010 Jul 23; [Epub ahead of print]
• Hepel JT, Tokita M, Macausland SG, Evans SB, Hiatt JR, Price LL, Dipetrillo T, Wazer DE. Toxicity of Three-Dimensional Conformal Radiotherapy for Accelerated Partial Breast Irradiation. Int J Radiat Oncol Biol Phys. 2009 Apr 21; [Epub ahead of print]
• Kainz K, White J, Herman J, Li XA. Investigation of helical tomotherapy for partial-breast irradiation of prone-positioned patients. Int J Radiat Oncol Biol Phys. 2009 May 1;74(1):275-82.
• Langen KM, Buchholz DJ, Burch DR, Burkavage R, Limaye AU, Meeks SL, Kupelian PA, Ruchala KJ, Haimerl J, Henderson D, Olivera GH. Investigation of Accelerated Partial Breast Patient Alignment and Treatment with Helical Tomotherapy Unit. Int J Radiat Oncol Biol Phys. 2008 Jan 17; [Epub ahead of print]
• Wojcicka JB, Lasher DE, Malcom R, Fortier G. Clinical and dosimetric experience with MammoSite-based brachytherapy under the RTOG 0413 protocol. J Appl Clin Med Phys. 2007 Oct 24;8(4):2654.
• Akbari M, Russo SA, Jacobson JS, et al.: Association of women's local treatment decisions with local recurrence risk and life expectancy. [Abstract] Int J Radiat Oncol Biol Phys 66 (3 Suppl 1): A-2035, S228-9, 2006.
• Burch D, Langen KM, Buchholz D, et al.: Partial breast irradiation with helical tomotherapy using RTOG 0413 planning constraints. [Abstract] Int J Radiat Oncol Biol Phys 66 (3 Suppl 1): A-2047, S235-6, 2006.
• Hiatt JR, Evans SB, Price LL, Cardarelli GA, Dipetrillo TA, Wazer DE. Dose-modeling study to compare external beam techniques from protocol NSABP B-39/RTOG 0413 for patients with highly unfavorable cardiac anatomy. Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1368-74.
• Bovi JA, Li XA, White J, et al.: Comparison of three partial breast irradiation techniques: treatment effectiveness based upon biological models. [Abstract] Int J Radiat Oncol Biol Phys 63 (2 Suppl 1): A-1061, S181, 2005.
• Dickler A. The MammoSite((R)) breast brachytherapy device: targeted delivery of breast brachytherapy. Future Oncol. 2005 Dec;1(6):799-804.
• Sanghani M, Wazer DE. Patient selection for NSABP B-39/RTOG 0413: Have we posed the right questions in the right way? Brachytherapy. 2007 Apr-Jun;6(2):119-22. No abstract available.

DISEASE CHARACTERISTICS:

• Histologically confirmed ductal carcinoma in situ (DCIS*) or invasive* adenocarcinoma of the breast

  • Stage 0, I, or II disease

    • Stage II tumors must be ≤ 3 cm

  • Gross disease must be unifocal

    • Microscopic multifocality allowed provided total pathological tumor size is ≤ 3 cm
  • No proven multicentric carcinoma in more than 1 quadrant or separated by ≥ 4 cm
  • No non-epithelial breast malignancies (e.g., sarcoma or lymphoma) NOTE: *Patients who are 50 years of age and over with DCIS regardless of hormone receptor status AND patients with invasive breast cancer meeting all of the following criteria: ≥ 50 years of age, node-negative, and hormone-receptor positive status will not be enrolled in study after 12/30/2006

• Prior axillary staging required for patients with invasive breast cancer, including 1 of the following:

  • Sentinel node biopsy alone (if sentinel node is negative)
  • Sentinel node biopsy followed by axillary dissection or sampling with ≥ 6 axillary nodes (if sentinel node is positive)
  • Axillary dissection alone with ≥ 6 axillary nodes

• No more than 3 positive axillary nodes

  • No axillary nodes with definite evidence of microscopic or macroscopic extracapsular extension
  • No positive non-axillary sentinel nodes (intramammary nodes are staged as axillary nodes)
  • No palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes unless there is histologic confirmation that these nodes are negative for tumor

• Must have undergone lumpectomy

  • Resected margins histologically free of tumor
  • Re-excision of surgical margins allowed
  • Target lumpectomy cavity clearly delineated AND target lumpectomy/whole breast reference volume ≤ 30% based on postoperative pre-randomization CT scan
  • Final surgery (i.e., lumpectomy, re-excision of margins, or axillary staging procedure) within the past 42 days
• No suspicious microcalcifications, densities, or palpable abnormalities in the ipsilateral or contralateral breast unless biopsied and found to be benign
• No Paget's disease of the nipple

• No history of invasive breast cancer or DCIS

  • Prior lobular carcinoma in situ treated by surgery alone allowed
• No synchronous bilateral invasive or non-invasive breast cancer
• Partial breast irradiation deemed technically deliverable by radiation oncologist at a credentialed facility
• Must have undergone a history and physical exam within the past 4 months AND a bilateral mammogram within the past 6 months

• Hormone receptor status:

  • Estrogen receptor (ER) status known
  • Progesterone status known if ER analysis is negative
  • Marginal or borderline results are considered positive

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Premenopausal or postmenopausal

Performance status

• Not specified

Life expectancy

• At least 10 years, excluding diagnosis of breast cancer

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective non-hormonal contraception

• No other malignancy within the past 5 years except previously treated carcinoma in situ of the cervix or colon, melanoma in situ, or basal cell or squamous cell skin cancer

  • Deemed to be at low risk for recurrence
• No collagen vascular disease (e.g., systemic lupus erythematosus or scleroderma), specifically dermatomyositis with a CPK level above normal, or active skin rash
• No psychiatric or addictive disorder that would preclude study therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior biologic therapy for this malignancy

Chemotherapy

• No prior chemotherapy for this malignancy
• No concurrent chemotherapy during study radiotherapy

Endocrine therapy

• No prior hormonal therapy for this malignancy unless total duration of hormonal therapy was no more than 28 days before randomization
• Concurrent hormonal therapy allowed provided it is not administered during chemotherapy
• No concurrent raloxifene, tamoxifen, or other selective estrogen receptor modulating drugs
• No concurrent hormone replacement therapy
• No concurrent Femring^®

Radiotherapy

• No prior radiotherapy for this malignancy
• No prior breast or thoracic radiotherapy
• No concurrent brachytherapy boosts
• No concurrent intensity modulated radiotherapy
• No concurrent regional nodal irradiation

Surgery

• See Disease Characteristics

• No prior breast implants

  • Patients who have had implants removed are eligible

Other

• No other concurrent anticancer therapy

• National Cancer Institute (NCI)
• Radiation Therapy Oncology Group
• Southwest Oncology Group