Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery

• ClinicalTrials.gov Identifier: NCT01349322
• Recruitment Status: Active, not recruiting
• First Posted: May 6, 2011
• Last Update Posted: August 28, 2018
• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); NRG Oncology
• Information provided by (Responsible Party): Radiation Therapy Oncology Group

Tracking Information

• First Submitted Date: May 5, 2011
• First Posted Date: May 6, 2011
• Last Update Posted Date: August 28, 2018
• Actual Study Start Date: May 2011
• Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 18, 2013): Local control [ Time Frame: From randomization to the date of first local failure or last follow-up. Analysis occurs after 245 local failures have been reported. ]
• Original Primary Outcome Measures (submitted: May 5, 2011): Local failure in patients treated with accelerated course of hypofractionated WBI versus standard WBI with a sequential boost

Current Secondary Outcome Measures (submitted: April 26, 2013)

• Overall survival [ Time Frame: From randomization to date of death due to any cause or last follow-up. ]
• Disease-free survival [ Time Frame: From randomization to date of local-regional disease recurrence, distant metastases, second primary, death due to any cause or last follow-up. ]
• Distant disease-free survival [ Time Frame: From randomization to date of distant metastases, second primary, death due to any cause or last follow-up. ]
• Changes in breast-related symptoms and side effects and cosmesis [ Time Frame: From randomization to three years. ]
• Correlation between dose-volume data and both adverse events and efficacy [ Time Frame: From randomization to end of follow-up. ]
• Treatment cost of accelerated course of hypofractionated WBI versus standard WBI with a sequential boost [ Time Frame: From randomization to end of treatment. ]

Original Secondary Outcome Measures (submitted: May 5, 2011)

• Overall survival
• Disease-free survival
• Distant disease-free survival
• Adverse events related to treatment
• Changes in breast-related symptoms and side effects and cosmesis
• Correlation between dose-volume data and both adverse events and efficacy
• Treatment cost of accelerated course of hypofractionated WBI versus standard WBI with a sequential boost

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery
• Official Title: 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

Brief Summary

RATIONALE: It is not yet know whether higher per daily radiation therapy is equally as effective as standard per daily radiation therapy in treating breast cancer.

PURPOSE: This randomized phase III trial studies how well an accelerated course of higher per daily radiation therapy with concomitant boost works compared to standard per daily radiation therapy with a sequential boost in treating patients with early-stage breast cancer that was removed by surgery.

Detailed Description

OBJECTIVES:

Primary

• To determine whether an accelerated course of hypofractionated whole-breast irradiation (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.

Secondary

• 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 radiation therapy (RT) based upon analysis of radiation dosimetry from CT-based treatment planning and NTCP calculations.
• To determine whether CT-based conformal methods intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) 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 WBI 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 WBI with sequential boost.

OUTLINE: This is a multicenter study. Patients are stratified according to age (< 50 vs. ≥ 50 years), prior chemotherapy (yes vs. no), estrogen-receptor status (+ vs. -), and histology grade (1-2 vs. 3). Patients are randomized to 1 of 2 treatment arms. Treatment begins within 9 weeks of last surgery or chemotherapy delivery.

• Arm I: Patients undergo standard whole-breast radiotherapy (WBI) comprising intensity-modulated radiation therapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) 5 days a week for 3-5 weeks followed by a sequential radiotherapy boost to the lumpectomy area 5 days a week for 1-1½ weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo accelerated hypofractionated WBI comprising IMRT or 3D-CRT with a concurrent boost to the lumpectomy area 5 days a week for 3 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients' tissue samples may be collected for future research studies.

After completion of study therapy, patients are followed at 1 month, at 6 months, and then yearly.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Radiation: Whole breast irradiation delivered by 3-dimensional conformal radiation therapy or intensity modulated radiation therapy
  Patients undergo whole breast radiotherapy by 3D-CRT or IMRT
• Radiation: Higher per daily radiation therapy
  Patients undergo higher per daily radiation therapy
• Radiation: Concurrent boost radiotherapy
  Patients undergo concurrent boost radiotherapy
• Radiation: Standard per daily radiation therapy
  Patients undergo standard per daily radiation therapy
• Radiation: Sequential boost radiotherapy
  Patients undergo sequential boost radiotherapy

Study Arms

• Active Comparator: Arm I
  Patients undergo standard whole-breast radiotherapy (WBI) comprising intensity-modulated radiation therapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) 5 days a week for 3-5 weeks followed by a sequential radiotherapy boost to the lumpectomy area 5 days a week for 1-1½ weeks in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Radiation: Whole breast irradiation delivered by 3-dimensional conformal radiation therapy or intensity modulated radiation therapy
  • Radiation: Standard per daily radiation therapy
  • Radiation: Sequential boost radiotherapy
• Experimental: Arm II
  Patients undergo accelerated hypofractionated WBI comprising IMRT or 3D-CRT with a concurrent boost to the lumpectomy area 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Radiation: Whole breast irradiation delivered by 3-dimensional conformal radiation therapy or intensity modulated radiation therapy
  • Radiation: Higher per daily radiation therapy
  • Radiation: Concurrent boost radiotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 18, 2017): 2354
• Original Estimated Enrollment (submitted: May 5, 2011): 2312
• Estimated Study Completion Date: August 2024
• Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Pathologically proven diagnosis of breast cancer resected by lumpectomy and whole-breast irradiation (WBI) with boost without regional nodal irradiation planned

• Must meet one of the following three criteria:

  • pStage I or II breast cancer AND at least one of the following:

    • Age < 50 years or
    • Positive axillary nodes or
    • Lymphovascular space invasion (LVI) or
    • At least 2 close resection margins (> 0 mm to ≤ 2 mm) or
    • One close resection margin and extensive in-situ component (EIC) or
    • Focally positive resection margins or
    • Non-hormone-sensitive breast cancer (estrogen and progesterone receptor negative (ER- and PR-) or
    • Grade III histology or
    • Oncotype recurrence score > 25 or
  • pStage 0 breast cancer with nuclear grade 3 ductal carcinoma in situ (DCIS) and patient age < 50 years or
• If multifocal breast cancer, then it must have been resected through a single lumpectomy incision with negative margins

• Breast-conserving surgery with margins defined as follows:

  • Negative margins defined as no tumor at the resected specimen edge

  • Close resection margins > 0 mm to ≤ 2 mm as follows:

    • One close resection margin and EIC
    • Two or more close resection margins
  • A focally positive resection margin

• Allowable options for mandatory axillary staging include:

  • Sentinel node biopsy alone (if sentinel node is negative, pN0, pN0[IHC-,+])

  • Sentinel node biopsy alone, OR followed by axillary node dissection, for clinically node-negative patients as described below:

    • Microscopic sentinel node (SN) positive (pN1mic)
    • One or two SNs positive (pN1) without extracapsular extension
    • Negative SN biopsy after neoadjuvant chemotherapy

  • Axillary node dissection is required following SN 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
  • Axillary dissection alone (with a minimum of 6 axillary nodes)

• 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)

• No clinical evidence for distant metastases, based upon the following minimum diagnostic workup:

  • History/physical examination, including breast exam (inspection and palpation of the breasts) and documentation of weight and Zubrod Performance Status of 0-2 within 28 days prior to study entry
  • A mammogram of both right and left breast within only 1 time point of 90 days of the diagnostic biopsy establishing the diagnosis
• No prior invasive or in-situ carcinoma of the breast (prior LCIS is eligible)
• No American Joint Committee on Cancer (AJCC) pathologic T4, N2 or N3, or M1 breast cancer
• Must not have two or more breast cancers that are not resectable through a single lumpectomy incision
• Must not be DCIS and ≥ 50 years old
• Must not be DCIS only (without an invasive component), nuclear grade 1 or 2 and < 50 years old
• No suspicious unresected microcalcification, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign
• No non-epithelial breast malignancies such as sarcoma or lymphoma
• No Paget disease of the nipple
• No male breast cancer
• Breast implants allowed

PATIENT CHARACTERISTICS:

• ANC ≥ 1,800/mm³
• Platelet count ≥ 75,000/mm³
• Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable)
• Negative urine or serum pregnancy test within 14 days of study entry
• Women of childbearing potential must not be pregnant or nursing and willing to use medically acceptable form of contraception during radiotherapy
• No prior invasive non-breast malignancy (except non-melanomatous skin cancer or carcinoma in situ of the cervix) unless disease free for a minimum of 5 years prior to study entry

• No severely active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the past 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol

  • Acquired Immune-Deficiency Syndrome (AIDS) based upon current CDC definition

    • HIV testing is not required for entry into this protocol
• No active systemic lupus, erythematosus, or any history of scleroderma or dermatomyositis with active rash
• Medical, psychiatric, or other condition that would prevent the patient from receiving the protocol therapy or providing informed consent

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Study entry must be within 50 days of last breast/axillary surgery and/or last chemotherapy
• No treatment plan that includes regional-node radiotherapy
• No prior radiotherapy to the breast or prior radiation to the region of the ipsilateral breast that would result in overlap of radiation therapy fields
• No intention to administer concurrent chemotherapy for current breast cancer

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Hong Kong, Israel, Japan, Korea, Republic of, Singapore, Switzerland, United States

Administrative Information

• NCT Number: NCT01349322
• Other Study ID Numbers: RTOG 1005; NCI-2011-02669 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000700069
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Radiation Therapy Oncology Group
• Study Sponsor: Radiation Therapy Oncology Group

Collaborators

• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Frank A. Vicini, MD, FACR; St. Joseph Mercy Oakland
• Study Chair: Gary M. Freedman, MD; University of Pennsylvania
• Study Chair: Julia R. White, MD; Ohio State University
• Study Chair: Douglas W. Arthur, MD; Virginia Commonwealth University

• PRS Account: Radiation Therapy Oncology Group
• Verification Date: August 2018