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RTOG 1005   |   12-401
A Phase III Trial of Accelerated Whole Breast Irradiation with Hypofractionation Plus Concurrent Boost Versus Standard Whole Breast Irradiation Plus Sequential Boost For Early-Stage Breast Cancer

Main Campus
North Coast Cancer
Phase 3

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  1. Primary Objective
    • To determine whether an accelerated course of hypofractionated WBI including a concomitant boost to the tumor bed in 15 fractions following lumpectomy will prove to be non-inferior in local control to a regimen of standard WBI with a sequential boost following lumpectomy for early stage breast cancer patients.
  2. Secondary Objective
    • To determine whether breast-related symptoms and cosmesis from accelerated WBI that is hypofractionated (in only 3 weeks) with a concomitant boost is non-inferior to standard WBI with sequential boost
    • To determine whether the risk of late cardiac toxicity in patients with left-sided breast cancer treated with hypofractionation will be non-inferior to conventional fractionated RT based upon analysis of radiation dosimetry from CT-based treatment planning and NTCP calculations
    • To determine whether CT-based conformal methods IMRT and 3DCRT for WBI are feasible in a multi-institutional setting following lumpectomy in early-stage breast cancer patients and whether dose-volume analyses can be established to assess treatment adequacy and likelihood of toxicity;
    • To determine that cosmetic results and breast-related symptoms 3 years after hypofractionated breast radiation with concomitant boost will not be inferior to that obtained 3 years after whole breast irradiation with sequential boost;
    • To determine whether future correlative studies can identify individual gene expressions and biological host factors associated with toxicity and/or local recurrence from standard and hypofractionated WBI
    • If shown to be non-inferior, to then determine if accelerated course of hypofractionated WBI including a concomitant boost to the tumor bed in 15 fractions following lumpectomy will prove to be superior in local control to a regimen of standard WBI with a sequential boost following lumpectomy for early-stage breast cancer patients
    • To determine whether treatment costs for hypofractionated WBI with concomitant boost are not higher than that for WBI with sequential boost

Inclusion Criteria
  1. Pathologically proven diagnosis of breast cancer resected by lumpectomy and whole breast irradiation with boost without regional nodal irradiation planned
  2. The patient must be female
  3. pStage I, II Breast Cancer AND at least one of the following:
    • Age < 50 years
    • Positive axillary nodes
    • Lymphovascular space invasion
    • More than 2 close resection margins (> 0 mm to ≤ 2 mm)
    • 1 close resection margin and extensive in-situ component (EIC)
    • Focally positive resection margins
    • Non-hormone sensitive breast cancer (ER and PR-negative)
    • Grade III histology
    • Oncotype recurrence score > 25
  4. pStage 0 breast cancer with nuclear grade 3 DCIS and patient age <50 years
  5. ypStage 0, I, II breast cancer resected by lumpectomy after neoadjuvant systemic therapy
  6. Study entry must be within 50 days of whichever comes last: last surgery (breast or axilla) or last chemotherapy
  7. If multifocal breast cancer, then it must have been resected through a single lumpectomy incision with negative margins
  8. Breast-conserving surgery with margins defined as follows: (also see 3.1.3 for eligibility)
    • Negative margins defined as no tumor at the resected specimen edge.
    • Close resection margins > 0 mm to ≤ 2 mm. as follows:
      • One close resection margin and EIC
      • 2 or more close resection margins.
  9. A focally positive resection margin
  10. For invasive breast cancer the axilla must be staged by one of the following:
    • Sentinel node biopsy alone (if sentinel node is negative, pN0, pN0(IHC-,+));
    • Sentinel node biopsy alone, or followed by axillary node dissection per investigator discretion, for clinically node negative patients as described below: /li>
      • microscopic sentinel node positive (pN1mic)
      • one or two sentinel nodes positive (pN1) without extracapsular extension
      • negative sentinel node biopsy after neoadjuvant chemotherapy
  11. Axillary node dissection is required following sentinel node biopsy with a minimum total of 6 axillary nodes if any of the following exist
    • for > 2 positive SN
    • any positive SN biopsy after neoadjuvant chemotherapy
    • for clinically (by either imaging or examination) T3 disease
    • for extracapsular extension
  12. Axillary dissection alone (with a minimum of 6 axillary nodes)
  13. Age ≥ 18
  14. CT-imaging of the ipsilateral breast within 28 days of study entry for the radiation treatment planning. Must be able to delineate on CT scan the extent of the target lumpectomy cavity for boost (Placement of surgical clips to assist in treatment planning of the boost is strongly recommended, see Section for details)
  15. Appropriate stage for protocol entry, including no clinical evidence for distant metastases, based upon the following minimum diagnostic workup:
    • History/physical examination, including breast exam and documentation of weight and Zubrod Performance Status of 0-2 within 28 days prior to study entry; Bilateral or right and left mammography within 90 days prior to neoadjuvant chemotherapy or diagnostic biopsy establishing diagnosis, or last surgery (breast or axilla)
  16. Patients must have had ER analysis performed on the primary breast tumor prior to study entry according to current ASCO/CAP Guideline Recommendations for hormone receptor testing. If negative for ER, assessment of PgR must also be performed according to current ASCO/CAP Guideline Recommendations for hormone receptor testing (
  17. CBC/differential obtained within 14 days prior to study entry, with adequate bone marrow function defined as follows:
    • Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3
    • Platelets ≥ 75,000 cells/mm3
    • Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.)
  18. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry
  19. Women of childbearing potential must be non-pregnant and non-lactating and willing to use medically acceptable form of contraception during radiation therapy
  20. Patient must provide study specific informed consent prior to study entry
  21. Breast implants allowed

Exclusion Criteria
  1. AJCC pathologic T4, N2 or N3, M1 pathologic stages III or M1IV breast cancer
  2. Treatment plan that includes regional node irradiation
  3. Prior invasive non-breast malignancy (except non-melanomatous skin cancer, carcinoma in situ of the cervix) unless disease free for a minimum of 5 years prior to study entry
  4. Prior invasive or in-situ carcinoma of the breast (-prior LCIS is eligible)
  5. Two or more breast cancers not resectable through a single lumpectomy incision
  6. Bilateral breast cancer
  7. DCIS only (without an invasive component) and age ≥ 50 years
  8. DCIS nuclear grade 1 or 2 (without an invasive component) and age < 50 years
  9. Invasive breast cancer and low risk for 5-year in breast recurrence after lumpectomy with negative margins that does not meet one of the eligibility factors in
  10. Unable to delineate on CT scan the extent of the target lumpectomy cavity for boost (Placement of surgical clips to assist in treatment planning of the boost is strongly recommended, see Section 6.4.2. for details)
  11. Suspicious unresected microcalcification, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign
  12. Non-epithelial breast malignancies such as sarcoma or lymphoma
  13. Paget's disease of the nipple
  14. Male breast cancer
  15. Prior radiotherapy to the breast or prior radiation to the region of the ipsilateral breast that would result in overlap of radiation therapy fields
  16. Intention to administer concurrent chemotherapy for current breast cancer.
  17. Severe, active co-morbidity, defined as follows:
  18. Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  19. Transmural myocardial infarction within the last 6 months
  20. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
  21. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration;
  22. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
  23. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive
  24. Pregnancy or women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception
  25. Active systemic lupus, erythematosus, or any history of scleroderma, dermatomyositis with active rash
  26. Medical, psychiatric or other condition that would prevent the patient from receiving the protocol therapy or providing informed consent

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