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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

Description

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 normal tissue complication probability (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. After completion of study therapy, patients are followed at 1 month, at 6 months, and then yearly.

Phase

N/A

Inclusion and Exclusion Criteria

  • Pathologically proven diagnosis of breast cancer resected by lumpectomy and whole breast irradiation with boost without regional nodal irradiation planned
  • The patient must be female
  • The patient must meet at least one of the three following criteria: - A. Pathological stage I, II Breast Cancer AND at least one of the following: - Age < 50 years or - Positive axillary nodes or - Lymphovascular space invasion or - 2 or more close resection margins (> 0 mm to ≤ 2 mm) or - 1 close resection margin and extensive intraductal component (EIC) [Per College of American Pathologist (CAP) Recommendation] or - Focally positive resection margins or - Non-hormone sensitive breast cancer (estrogen receptor (ER)- and progesterone receptor(PR)-negative) or - Grade III histology or - Oncotype recurrence score > 25 or - B. Pathological stage 0 breast cancer with nuclear grade 3 ductal carcinoma in situ (DCIS) and patient age <50 years or - C. Post-neoadjuvant pathological 0, I, II breast cancer resected by lumpectomy after neoadjuvant systemic therapy
  • Study entry must be within 50 days from whichever comes later: last surgery (breast or axilla) or last chemotherapy. The day of surgery is Day "0".
  • 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: (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 (per College of American Pathologist (CAP) Recommendation) - 2 or more close resection margins. - A focally positive resection margin
  • For invasive breast cancer the axilla must be staged by one of the following: - Sentinel node biopsy alone, if sentinel node is negative, i.e. any of the following: - pN0: no regional lymph node metastasis identified histologically, - pN0(i-): pN0 and immunohistochemical (IHC) negative, or - pN0(i+): pN0 and IHc positive; - Sentinel node biopsy alone, OR followed by axillary node dissection per investigator discretion, for clinically node negative patients as described below: - microscopic sentinel node positive (pN1mic) - one or two sentinel nodes positive (pN1) without extracapsular extension - negative sentinel node biopsy after neoadjuvant chemotherapy - Axillary node dissection is required following sentinel node (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)
  • Age ≥ 18
  • CT-imaging of the ipsilateral breast within 28 days prior to study entry for the radiation treatment planning. Must be able to delineate on CT scan the extent of the target lumpectomy cavity for boost
  • 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 (inspection and palpation of the breasts) and documentation of weight and Zubrod Performance Status of 0-2 within 28 days prior to study entry; - Right and left mammography within 90 days of diagnostic biopsy establishing diagnosis
  • Patients must have had ER analysis performed on the primary breast tumor prior to study entry according to current American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) Guideline Recommendations for hormone receptor testing. If negative for ER, assessment of PR must also be performed according to current ASCO/CAP Guideline Recommendations for hormone receptor testing (http://www.asco.org)
  • Complete blood count (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.)
  • Women of childbearing potential must have a negative urine or serum pregnancy test within 14 days of study entry
  • Women of childbearing potential must be non-pregnant and non-lactating and willing to use medically acceptable form of contraception during radiation therapy
  • Patient must provide study specific informed consent prior to study entry
  • Breast implants allowed

  • American Joint Committee on Cancer (AJCC) pathologic T4, N2 or N3, M1 pathologic stages III or IV breast cancer
  • Treatment plan that includes regional node irradiation
  • 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
  • Prior invasive or in-situ carcinoma of the breast [-prior lobular carcinoma in situ (LCIS) is eligible]
  • Two or more breast cancers not resectable through a single lumpectomy incision
  • Bilateral breast cancer
  • DCIS only (without an invasive component) and age ≥ 50 years
  • DCIS nuclear grade 1 or 2 only (without an invasive component) and age < 50 years
  • 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 3.1.3.
  • 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)
  • Suspicious unresected microcalcification, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign
  • Non-epithelial breast malignancies such as sarcoma or lymphoma
  • Paget's disease of the nipple
  • Male breast cancer
  • Prior radiotherapy to the breast or prior radiation to the region of the ipsilateral breast that would result in overlap of radiation therapy fields
  • Intention to administer concurrent chemotherapy for current breast cancer.
  • Severe, 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 last 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 Centers for Disease Control and Prevention (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
  • Pregnancy or women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception
  • Active systemic lupus, erythematosus, or any history of scleroderma, dermatomyositis with active rash
  • Medical, psychiatric or other condition that would prevent the patient from receiving the protocol therapy or providing informed consent

Sites

  • California

    • 21st Century Oncology - El Segundo, El Segundo, California, 90245
    • University of California at Los Angeles (UCLA ), Los Angeles, California, 90095
    • UC San Diego Moores Cancer Center, LA Jolla, California, 92093
    • Santa Clara Valley Medical Center, San Jose, California, 95128
    • Kaiser Permanente Radiation Oncology Cancer Treatment Center, Santa Clara, California, 95051
    • Epic Care-Dublin, Dublin, California, 94568
    • Kaiser Permanente Oakland-Broadway, Oakland, California, 94611
    • South Sacramento Cancer Center, Sacramento, California, 95823
    • Kaiser Permanente-Rancho Cordova Cancer Center, Rancho Cardova, California, 95670
    • The Permanente Medical Group-Roseville Radiation Oncology, Roseville, California, 95678
    • Enloe Medical Center, Chico, California, 95926

  • Nevada

    • Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, 89148
    • Radiation Oncology Centers of Nevada Central, Las Vegas, Nevada, 89106
    • Renown Regional Medical Center, Reno, Nevada, 89502
    • Saint Mary's Regional Medical Center, Reno, Nevada, 89503

  • Arizona

    • 21st Century Oncology-Scottsdale, Scottsdale, Arizona, 85251
    • Arizona Oncology Associates-West Orange Grove, Tucson, Arizona, 85704

  • Utah

    • McKay-Dee Hospital Center, Ogden, Utah, 84403

  • Oregon

    • Providence Medford Medical Center, Medford, Oregon, 97504
    • Three Rivers Community Hospital, Grants Pass, Oregon, 97527
    • Willamette Valley Cancer Center, Eugene, Oregon, 97401

  • New Mexico

    • Memorial Medical Center - Las Cruces, Las Cruces, New Mexico, 88011

  • Colorado

    • The Shaw Regional Cancer Center, Edwards, Colorado, 81632

  • Washington

    • Tri-Cities Cancer Center, Kennewick, Washington, 99336
    • Cancer Care Northwest-North Spokane, Spokane, Washington, 99218
    • Olympic Medical Cancer Care Center, Sequim, Washington, 98384
    • Harrison Medical Center, Bremerton, Washington, 98310

  • Texas

    • West Texas Cancer Center, Odessa, Texas, 79761
    • Texas Oncology-Wichita Falls Texoma Cancer Center, Wichita Falls, Texas, 76310
    • Texas Oncology-Seton Williamson, Round Rock, Texas, 78665
    • Brooke Army Medical Center, Fort Sam Houston, Texas, 78234
    • Cancer Care Centers of South Texas- Northeast, San Antonio, Texas, 78217
    • Texas Oncology-Denton South, Denton, Texas, 76210
    • Texas Oncology - Round Rock Cancer Center, Round Rock, Texas, 78681
    • Texas Oncology-Arlington South, Arlington, Texas, 76014
    • Texas Oncology - Lewisville, Lewisville, Texas, 75067
    • Texas Oncology - South Austin Cancer Center, Austin, Texas, 78745
    • Texas Oncology-Austin Midtown, Austin, Texas, 78705
    • Baylor Medical Center at Irving, Irving, Texas, 75061
    • Texas Oncology-Plano West, Plano, Texas, 75093

  • South Dakota

    • Avera Cancer Institute, Sioux Falls, South Dakota, 57105

  • Missouri

    • Liberty Hospital, Liberty, Missouri, 64068
    • Saint Luke's Hospital, Chesterfield, Missouri, 63017
    • Cape Radiation Oncology, Cape Girardeau, Missouri, 63703

  • Iowa

    • Mercy Cancer Center-West Lakes, Clive, Iowa, 50325
    • Mercy Medical Center - Des Moines, Des Moines, Iowa, 50314
    • Iowa Methodist Medical Center, Des Moines, Iowa, 50309
    • Finley Hospital, Dubuque, Iowa, 52001

  • Arkansas

    • Mercy Cancer Center-Hot Springs, Hot Springs, Arkansas, 71913

  • North Dakota

    • Altru Cancer Center, Grand Forks, North Dakota, 58201

  • Minnesota

    • Mayo Clinic Health Systems-Mankato, Mankato, Minnesota, 56001
    • Mayo Clinic Health System in Albert Lea, Albert Lea, Minnesota, 56007
    • Miller-Dwan Hospital, Duluth, Minnesota, 55805

  • Wisconsin

    • Mayo Clinic Health System-Franciscan Healthcare, La Crosse, Wisconsin, 54601
    • Mayo Clinic Health System Eau Claire Hospital - Luther Campus, Eau Claire, Wisconsin, 54703
    • University of Wisconsin Hospital and Clinics, Madison, Wisconsin, 53792
    • Beloit Memorial Hospital, Beloit, Wisconsin, 53511
    • Aspirus Regional Cancer Center, Wausau, Wisconsin, 54401
    • UW Cancer Center Johnson Creek, Johnson Creek, Wisconsin, 53038
    • Langlade Hospital and Cancer Center, Antigo, Wisconsin, 54409
    • Agnesian Cancer Center, Fond Du Lac, Wisconsin, 54935
    • Community Memorial Hospital, Menomonee Falls, Wisconsin, 53051
    • Aurora West Allis Medical Center, West Allis, Wisconsin, 53227
    • Aurora Saint Luke's Medical Center, Milwaukee, Wisconsin, 53215
    • Bellin Memorial Hospital, Green Bay, Wisconsin, 54301
    • Vince Lombardi Cancer Clinic-Sheboygan, Sheboygan, Wisconsin, 53081
    • Vince Lombardi Cancer Clinic, Two Rivers, Wisconsin, 54241

  • Illinois

    • Saint John's Hospital, Springfield, Illinois, 62702
    • FHN Leonard C. Ferguson Cancer Center, Freeport, Illinois, 61032
    • Community Cancer Center Foundation, Normal, Illinois, 61761
    • Rush - Copley Medical Center, Aurora, Illinois, 60504
    • Advocate Lutheran General Hospital., Park Ridge, Illinois, 60068
    • Advocate Illinois Masonic Medical Center, Chicago, Illinois, 60657

  • Louisiana

    • Tulane University Health Sciences Center, New Orleans, Louisiana, 70112

  • Mississippi

    • Singing River Hospital, Pascagoula, Mississippi, 39581

  • Kentucky

    • Owensboro Health Mitchell Memorial Cancer Center, Owensboro, Kentucky, 42303

  • Indiana

    • IU Health West Hospital, Avon, Indiana, 46123
    • IU Health Methodist Hospital, Indianapolis, Indiana, 46202
    • Indiana University Medical Center, Indianapolis, Indiana, 46202
    • Community Regional Cancer Care-East Radiation Oncology, Indianapolis, Indiana, 46219
    • Community Regional Cancer Care-North, Indianapolis, Indiana, 46256
    • IU Health Goshen Center for Cancer Care, Goshen, Indiana, 46526
    • Saint Vincent Anderson Regional Hospital/Cancer Center, Anderson, Indiana, 46016
    • IU Health Ball Memorial Hospital, Muncie, Indiana, 47303

  • Florida

    • 21st Century Oncology - Fort Walton Beach, Fort Walton Beach, Florida, 32547

  • Ohio

    • The Christ Hospital, Cincinnati, Ohio, 45219

  • Georgia

    • Northside Hospital, Atlanta, Georgia, 30342

  • Israel

    • Chaim Sheba Medical Center, Tel Hashomer, 52621
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