Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2

April 28, 2021 updated by: NSABP Foundation Inc

A Randomized Trial Comparing the Safety and Efficacy of Adriamycin and Cyclophosphamide Followed by Taxol (AC-T) to That of Adriamycin and Cyclophosphamide Followed by Taxol Plus Herceptin (AC-T+H) in Node-Positive Breast Cancer Patients Who Have Tumors That Overexpress HER2

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy plus trastuzumab is more effective than combination chemotherapy alone for treating breast cancer.

PURPOSE: This randomized phase III trial is studying how well giving combination chemotherapy together with trastuzumab works compared to combination chemotherapy alone in treating women with node-positive stage II or stage IIIA breast cancer that overexpresses HER2.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

  • Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin®) in women with operable, node-positive breast cancer that overexpresses HER2.
  • Compare the effect of these regimens on disease-free and overall survival of these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive nodes (1-3 vs 4-9 vs 10 or more), administration of hormonal therapy (tamoxifen vs anastrozole vs neither), surgery/radiotherapy (lumpectomy plus breast irradiation vs lumpectomy plus breast irradiation plus regional irradiation vs mastectomy without radiotherapy vs mastectomy with radiotherapy), paclitaxel schedule (every 3 weeks vs weekly), and participating center. Patients are randomized to one of two treatment arms.

  • Arm 1: Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses. Approximately 3 weeks after the last course, patients receive paclitaxel IV over 3 hours every 21 days for 4 courses OR paclitaxel IV over 1 hour once weekly for 12 weeks (12 doses).
  • Arm 2: Patients receive chemotherapy as in arm I and trastuzumab (Herceptin®) IV over 90 minutes on day 1 of the first course of paclitaxel. Trastuzumab is then administered IV over 30 minutes weekly for 51 weeks, beginning on day 8.

All patients with estrogen or progesterone receptor-positive tumors receive hormonal therapy* for at least 5 years, beginning within 3-12 weeks after the last dose of chemotherapy. Patients who have received prior tamoxifen for prevention may be treated with additional tamoxifen for no more than 5 years at the discretion of the principal investigator (PI).

NOTE: *Other hormonal therapeutic agents are allowed in sequence with or as an alternative to tamoxifen therapy.

All patients previously treated with lumpectomy undergo breast irradiation beginning after completion of chemotherapy and concurrently with trastuzumab (in arm 2) administration. Patients previously treated with mastectomy may also receive radiotherapy. Radiotherapy is administered daily for 5-6 weeks.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,700 patients will be accrued for this study within 4.75 years.

Study Type

Interventional

Enrollment (Actual)

2130

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Manitoba
      • Winnipeg, Manitoba, Canada, R3E 0V9
        • CancerCare Manitoba
    • Ontario
      • Mississauga, Ontario, Canada, L5M 2N1
        • Carlo Fidani Peel Regional Cancer Centre at Credit Valley Hospital
    • Quebec
      • Montreal, Quebec, Canada, H3G 1A4
        • Montreal General Hospital
      • Montreal, Quebec, Canada, H3A 1A1
        • Royal Victoria Hospital - Montreal
      • Montreal, Quebec, Canada, H2L 4M1
        • Centre Hospitalier de l'Universite de Montreal
      • Montreal, Quebec, Canada, H3T 1E2
        • Jewish General Hospital - Montreal
      • Montreal, Quebec, Canada, H3T 1M5
        • St. Mary's Hospital Center
      • Quebec City, Quebec, Canada, G1S 4L8
        • Hopital du Saint-Sacrement, Quebec
  • United States
    • Alabama
      • Huntsville, Alabama, United States, 35801
        • Comprehensive Cancer Institute
    • Alaska
      • Anchorage, Alaska, United States, 99519-6604
        • Providence Alaska Medical Center
    • Arizona
      • Phoenix, Arizona, United States, 85006-2726
        • CCOP - Western Regional, Arizona
    • California
      • Duarte, California, United States, 91010-3000
        • City of Hope Comprehensive Cancer Center
      • Greenbrae, California, United States, 94904
        • Sutter Health Western Division Cancer Research Group
      • La Jolla, California, United States, 92037
        • Scripps Cancer Center at Scripps Clinic
      • Loma Linda, California, United States, 92354
        • Loma Linda University Cancer Institute at Loma Linda University Medical Center
      • Long Beach, California, United States, 90813
        • Pacific Shores Medical Group Comprehensive Hematology-Oncology Services - Long Beach
      • Oakland, California, United States, 94609-3305
        • CCOP - Bay Area Tumor Institute
      • Orange, California, United States, 92868
        • Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center
      • Palm Springs, California, United States, 92262
        • Comprehensive Cancer Center at Desert Regional Medical Center
      • Sacramento, California, United States, 95816
        • Sutter Cancer Center
      • San Diego, California, United States, 92120
        • Kaiser Permanente Medical Center/Kaiser Foundation Hospital - San Diego
      • Santa Rosa, California, United States, 95403
        • CCOP - Santa Rosa Memorial Hospital
      • Vallejo, California, United States, 94589
        • Kaiser Permanente Medical Center - Vallejo
    • Colorado
      • Denver, Colorado, United States, 80209-5031
        • CCOP - Colorado Cancer Research Program, Incorporated
      • Denver, Colorado, United States, 80010
        • University of Colorado Cancer Center at University of Colorado Health Sciences Center
    • Connecticut
      • Farmington, Connecticut, United States, 06360-7106
        • Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
      • Hartford, Connecticut, United States, 06102-5037
        • Helen and Harry Gray Cancer Center at Hartford Hospital
    • Delaware
      • Wilmington, Delaware, United States, 19899
        • CCOP - Christiana Care Health Services
    • Florida
      • Clearwater, Florida, United States, 33756
        • Morton Plant Hospital
      • Daytona Beach, Florida, United States, 32114
        • Halifax Medical Center
      • Jacksonville, Florida, United States, 32207
        • Baptist Cancer Institute - Jacksonville
      • Miami, Florida, United States, 33136
        • University of Miami Sylvester Comprehensive Cancer Center
      • Miami Beach, Florida, United States, 33140
        • CCOP - Mount Sinai Medical Center
      • Orlando, Florida, United States, 32806
        • M.D. Anderson Cancer Center - Orlando
      • Plantation, Florida, United States, 33324
        • Cancer Research Network, Inc.
      • Sarasota, Florida, United States, 34236
        • Florida Cancer Specialists
    • Georgia
      • Albany, Georgia, United States, 31701
        • Phoebe Cancer Center at Phoebe Putney Memorial Hospital
      • Atlanta, Georgia, United States, 30322
        • Winship Cancer Institute of Emory University
      • Atlanta, Georgia, United States, 30342-1701
        • CCOP - Atlanta Regional
      • Augusta, Georgia, United States, 30912-4000
        • MBCCOP-Medical College of Georgia Cancer Center
      • Fort Gordon, Georgia, United States, 30905-5650
        • Dwight David Eisenhower Army Medical Center
    • Hawaii
      • Honolulu, Hawaii, United States, 96813
        • Cancer Research Center of Hawaii
    • Idaho
      • Coeur d'Alene, Idaho, United States, 83814
        • North Idaho Cancer Center
    • Illinois
      • Chicago, Illinois, United States, 60657
        • Creticos Cancer Center at Advocate Illinois Masonic Medical Center
      • Chicago, Illinois, United States, 60612
        • Rush Cancer Institute at Rush University Medical Center
      • Chicago, Illinois, United States, 60612-9985
        • John H. Stroger, Jr. Hospital of Cook County
      • Decatur, Illinois, United States, 62526
        • CCOP - Central Illinois
      • Evanston, Illinois, United States, 60201
        • CCOP - Evanston
      • Oak Park, Illinois, United States, 60302
        • West Suburban Hospital Medical Center
      • Peoria, Illinois, United States, 61602
        • CCOP - Illinois Oncology Research Association
      • Urbana, Illinois, United States, 61801
        • CCOP - Carle Cancer Center
    • Indiana
      • Indianapolis, Indiana, United States, 46206-1367
        • Methodist Cancer Center at Methodist Hospital
      • Munster, Indiana, United States, 46321
        • Community Hospital
      • South Bend, Indiana, United States, 46601
        • CCOP - Northern Indiana CR Consortium
    • Iowa
      • Davenport, Iowa, United States, 52803
        • Genesis Regional Cancer Center at Genesis Medical Center
      • Des Moines, Iowa, United States, 50309-1016
        • CCOP - Iowa Oncology Research Association
      • Iowa City, Iowa, United States, 52242-1009
        • Holden Comprehensive Cancer Center at University of Iowa
    • Kansas
      • Wichita, Kansas, United States, 67214-3882
        • CCOP - Wichita
    • Kentucky
      • Lexington, Kentucky, United States, 40536-0093
        • Markey Cancer Center at University of Kentucky Chandler Medical Center
      • Louisville, Kentucky, United States, 40207
        • Consultants in Blood Disorders and Cancer
      • Louisville, Kentucky, United States, 40202-5070
        • Norton Cancer Center at Norton Hospital
    • Louisiana
      • New Orleans, Louisiana, United States, 70121
        • CCOP - Ochsner
      • New Orleans, Louisiana, United States, 70112
        • Tulane Cancer Center at Tulane University Hospital and Clinic
      • New Orleans, Louisiana, United States, 70112
        • Stanley S. Scott Cancer Center at Louisiana State University Medical Center - New Orleans
    • Maine
      • Bangor, Maine, United States, 04401
        • CancerCare of Maine at Eastern Maine Medial Center
    • Maryland
      • Baltimore, Maryland, United States, 21237
        • Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center
      • Bethesda, Maryland, United States, 20889-5000
        • National Naval Medical Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02118
        • Cancer Research Center at Boston Medical Center
      • Pittsfield, Massachusetts, United States, 01201
        • Berkshire Medical Center
      • Springfield, Massachusetts, United States, 01199
        • Baystate Regional Cancer Program at D'Amour Center for Cancer Care
      • Worcester, Massachusetts, United States, 01655
        • UMASS Memorial Cancer Center - University Campus
    • Michigan
      • Ann Arbor, Michigan, United States, 48106
        • CCOP - Michigan Cancer Research Consortium
      • Detroit, Michigan, United States, 48202
        • Josephine Ford Cancer Center at Henry Ford Health System
      • East Lansing, Michigan, United States, 48824
        • Michigan State University
      • Grand Rapids, Michigan, United States, 49503
        • CCOP - Grand Rapids
      • Kalamazoo, Michigan, United States, 49007-3731
        • CCOP - Kalamazoo
      • Royal Oak, Michigan, United States, 48073
        • William Beaumont Hospital - Royal Oak
      • Southfield, Michigan, United States, 48075-9975
        • Providence Cancer Institute at Providence Hospital - Southfield Campus
    • Minnesota
      • Duluth, Minnesota, United States, 55805
        • CCOP - Duluth
      • Minneapolis, Minnesota, United States, 55415
        • Hennepin County Medical Center - Minneapolis
      • Saint Louis Park, Minnesota, United States, 55416
        • CCOP - Metro-Minnesota
    • Missouri
      • Columbia, Missouri, United States, 65203
        • Ellis Fischel Cancer Center at University of Missouri - Columbia
      • Kansas City, Missouri, United States, 64131
        • CCOP - Kansas City
      • Saint Louis, Missouri, United States, 63131
        • Missouri Baptist Cancer Center
      • Saint Louis, Missouri, United States, 63141
        • CCOP - St. Louis-Cape Girardeau
      • Saint Louis, Missouri, United States, 63110-0250
        • Saint Louis University Cancer Center
      • Springfield, Missouri, United States, 65807
        • CCOP - Cancer Research for the Ozarks
    • Montana
      • Billings, Montana, United States, 59101
        • CCOP - Montana Cancer Consortium
    • Nebraska
      • Omaha, Nebraska, United States, 68131
        • CCOP - Missouri Valley Cancer Consortium
      • Omaha, Nebraska, United States, 68114
        • Methodist Hospital Cancer Center at Nebraska Methodist Hospital - Omaha
    • Nevada
      • Las Vegas, Nevada, United States, 89106
        • CCOP - Southern Nevada Cancer Research Foundation
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • CCOP - Northern New Jersey
      • New Brunswick, New Jersey, United States, 08903
        • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
      • Newark, New Jersey, United States, 07112
        • Newark Beth Israel Medical Center
    • New Mexico
      • Albuquerque, New Mexico, United States, 87131
        • University of New Mexico Cancer Research and Treatment Center
    • New York
      • Albany, New York, United States, 12208
        • New York Oncology Hematology, P.C. at Albany Regional Cancer Care
      • Bronx, New York, United States, 10451
        • Lincoln Medical and Mental Health Center
      • Bronx, New York, United States, 10466
        • MBCCOP-Our Lady of Mercy Cancer Center
      • Glens Falls, New York, United States, 12801
        • Charles R. Wood Cancer Center at Glens Falls Hospital
      • Staten Island, New York, United States, 10305
        • Nalitt Cancer Institute at Staten Island University Hospital
      • Syracuse, New York, United States, 13217
        • CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
    • North Carolina
      • Burlington, North Carolina, United States, 27216
        • Alamance Cancer Center
      • Chapel Hill, North Carolina, United States, 27599-7295
        • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
      • Greenville, North Carolina, United States, 27858-4354
        • Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital
      • Winston-Salem, North Carolina, United States, 27104-4241
        • CCOP - Southeast Cancer Control Consortium
      • Winston-Salem, North Carolina, United States, 27157-1082
        • Comprehensive Cancer Center at Wake Forest University
    • North Dakota
      • Fargo, North Dakota, United States, 58122
        • CCOP - Merit Care Hospital
    • Ohio
      • Akron, Ohio, United States, 44309
        • Akron City Hospital at Summa Health System
      • Canton, Ohio, United States, 44710
        • Aultman Hospital Cancer Center at Aultman Health Foundation
      • Cincinnati, Ohio, United States, 45267-0502
        • Charles M. Barrett Cancer Center at University Hospital
      • Cincinnati, Ohio, United States, 45236
        • Cancer Center at Jewish Hospital
      • Cleveland, Ohio, United States, 44106-5065
        • Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
      • Cleveland, Ohio, United States, 44122
        • South Pointe Hospital Cancer Care Center
      • Columbus, Ohio, United States, 43210-1240
        • Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University
      • Columbus, Ohio, United States, 43206
        • CCOP - Columbus
      • Kettering, Ohio, United States, 45429
        • CCOP - Dayton
      • Youngstown, Ohio, United States, 44501
        • Cancer Care Center at Northside Medical Center
    • Oklahoma
      • Tulsa, Oklahoma, United States, 74136
        • CCOP - Oklahoma
    • Oregon
      • Portland, Oregon, United States, 97213
        • CCOP - Columbia River Oncology Program
    • Pennsylvania
      • Allentown, Pennsylvania, United States, 18103
        • John and Dorothy Morgan Cancer Center at Lehigh Valley Hospital
      • Danville, Pennsylvania, United States, 17822-2001
        • Geisinger Medical Center
      • Philadelphia, Pennsylvania, United States, 19141
        • Albert Einstein Cancer Center
      • Philadelphia, Pennsylvania, United States, 19107-5541
        • Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
      • Pittsburgh, Pennsylvania, United States, 15212-4772
        • Allegheny General Hospital
      • Pittsburgh, Pennsylvania, United States, 15213-3489
        • Hillman Cancer Center at University of Pittsburgh Cancer Institute
      • Scranton, Pennsylvania, United States, 18501
        • Mercy Hospital Cancer Center - Scranton
      • York, Pennsylvania, United States, 17315
        • York Cancer Center at Wellspan Health
    • Rhode Island
      • Warwick, Rhode Island, United States, 02886
        • Kent County Memorial Hospital
    • South Carolina
      • Greenville, South Carolina, United States, 29615
        • CCOP - Greenville
      • Spartanburg, South Carolina, United States, 29303
        • CCOP - Upstate Carolina
    • South Dakota
      • Sioux Falls, South Dakota, United States, 57104
        • CCOP - Sioux Community Cancer Consortium
    • Texas
      • Dallas, Texas, United States, 75230
        • Medical City Dallas Hospital
      • Houston, Texas, United States, 77030
        • Baylor College of Medicine
      • Lubbock, Texas, United States, 79410-1894
        • Joe Arrington Cancer Research and Treatment Center
      • San Antonio, Texas, United States, 78284-7811
        • University of Texas Health Science Center at San Antonio
      • Temple, Texas, United States, 76508
        • CCOP - Scott and White Hospital
    • Utah
      • Provo, Utah, United States, 84604
        • Utah Valley Regional Medical Center - Provo
    • Vermont
      • Burlington, Vermont, United States, 05405-0075
        • Vermont Cancer Center at University of Vermont
    • Virginia
      • Norfolk, Virginia, United States, 23507
        • Sentara Cancer Institute at Sentara Norfolk General Hospital
      • Richmond, Virginia, United States, 23298-0037
        • MBCCOP - Massey Cancer Center
    • Washington
      • Seattle, Washington, United States, 98101
        • CCOP - Virginia Mason Research Center
      • Seattle, Washington, United States, 98109
        • Puget Sound Oncology Consortium
      • Tacoma, Washington, United States, 98405-0986
        • CCOP - Northwest
    • West Virginia
      • Charleston, West Virginia, United States, 25304-1297
        • David Lee Cancer Center at Charleston Area Medical Center
      • Parkersburg, West Virginia, United States, 26102
        • Camden-Clark Memorial Hospital
    • Wisconsin
      • Green Bay, Wisconsin, United States, 54307-3508
        • St. Vincent Hospital
      • Marshfield, Wisconsin, United States, 54449
        • CCOP - Marshfield Clinic Research Foundation
      • Milwaukee, Wisconsin, United States, 53226
        • Medical College of Wisconsin Cancer Center
      • Milwaukee, Wisconsin, United States, 53211-2906
        • Oncology Alliance, S.C. - Milwaukee

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion criteria

  • The patient must have a life expectancy of at least 10 years, excluding her diagnosis of breast cancer. (Comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer.)
  • The interval between the last surgery for breast cancer treatment (lumpectomy, mastectomy, axillary dissection, or re-excision of lumpectomy margins) and randomization must be less than or equal to 84 days.

  • All of the following staging criteria must be met:

    • Primary tumor must be T1-3 by clinical and pathologic evaluation.
    • Ipsilateral nodes must be cN0-1 by clinical evaluation.
    • Ipsilateral nodes must be pN1, pN2a, or pN3a by pathologic evaluation.
    • M0
  • Patients must have undergone either a total mastectomy and an axillary dissection or a lumpectomy and an axillary dissection. Sentinel node biopsy is permitted, but must be followed by an axillary dissection.
  • The tumor must be invasive adenocarcinoma on histologic examination.
  • The tumor must be determined to be HER2-positive prior to randomization. Assays performed using fluorescent in situ hybridization (FISH) require gene amplification to be eligible. Assays using immunohistochemistry (IHC) must be performed at an NSABP-approved reference laboratory and require a strongly positive staining score.
  • Patients must have an analysis of both estrogen and progesterone receptors performed on the primary tumor prior to randomization. "Marginal," "borderline," etc., results (i.e., those not definitely negative) will also be considered positive regardless of the methodology used.
  • At the time of randomization, the patient must have had the following: history and physical exam, EKG, and PA and lateral chest x-ray within the past 3 months; and a bilateral mammogram (or unilateral if patient has had a mastectomy) and a pelvic exam (for women who have a uterus and who will be taking tamoxifen) within the past year.
  • Within 3 months prior to entry, the patient must have a baseline left ventricular ejection fraction (LVEF) measured by MUGA scan equal to or greater than the lower limit of normal for the radiology facility. (If LVEF is > 75%, the investigator should consider having the LVEF determination reviewed prior to randomization. Following randomization, the LVEF determination may be reviewed up until the time of the post-AC MUGA. Please note that if a more accurate value is obtained from the review of the baseline MUGA, the corrected value must be submitted to the NSABP Biostatistical Center before the post-AC MUGA is performed.)

  • At the time of randomization:

    • The postoperative absolute neutrophil count (ANC) must be ≥ 1500/mm3 (or <1500/mm3 if, in the opinion of the investigator, this represents an ethnic or racial variation of normal).
    • Postoperative platelet count must be ≥ 100,000/mm3. Significant underlying hematologic disorders must be excluded when the platelet count is above the upper limit of normal for the lab.
  • There must be postoperative evidence of adequate hepatic function, i.e., total bilirubin must be ≤ ULN for the lab unless the patient has a chronic grade 1 bilirubin elevation (>ULN to ≤1.5 x ULN) due to Gilbert's disease or similar syndrome; and alkaline phosphatase must be <2.5 times the ULN for the lab; and the serum glutamic-oxaloacetic transaminase (SGOT [AST]) must be <1.5 times the ULN for the lab.
  • There must be postoperative evidence of adequate renal function (serum creatinine within or less than the institution's normal range).
  • Patients must have no clinical or radiologic evidence of metastatic disease. Suspicious findings must be confirmed as benign by radiologic evaluation or biopsy. A patient with skeletal pain is eligible for inclusion in the study if bone scan and/or roentgenological examination fails to disclose metastatic disease.
  • Patients with a history of non-breast malignancies are eligible if they have been disease-free for 5 or more years prior to randomization and are deemed by their physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
  • Prior to randomization, the investigator must designate whether the patients who had a lumpectomy will receive local or locoregional radiation therapy. For patients who had a mastectomy, the investigator must designate whether or not the patient will receive radiation therapy. (Pre-randomization discussion and/or consultation with a radiation oncologist is encouraged.) Note: Irradiation of any internal mammary nodes is prohibited in this trial.
  • Special conditions for eligibility of lumpectomy patients: irradiation and surgery
  • Patients treated by lumpectomy and axillary node dissection to be followed by breast radiation therapy must meet all the eligibility criteria in addition to the following: Generally, lumpectomy should be reserved for tumors <5 cm. However, at the investigator's discretion, patients treated with lumpectomy for tumors ≥ 5 cm are eligible. The margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. In patients in whom pathologic examination demonstrates tumor present at the line of resection, additional operative procedures may be performed to obtain clear margins. This is permissible even if axillary dissection has been performed. Patients in whom tumor is still present at the resected margin after re-excision(s) must undergo total mastectomy to be eligible. Whole breast irradiation is required. Irradiation of regional lymph nodes is optional, but partial breast irradiation and irradiation of any internal mammary nodes are prohibited in this trial. Intent to irradiate the axilla or other regional node groups must be declared by the investigator prior to randomization for stratification purposes.
  • Special conditions for eligibility of mastectomy patients: irradiation. The decision to use locoregional irradiation in patients who have undergone total mastectomy and axillary node dissection must be declared by the investigator prior to randomization for stratification purposes. Failure to adhere to the radiation therapy plan will be a protocol violation.

Exclusion criteria

  • Bilateral malignancy or a mass or mammographic abnormality in the opposite breast suspicious for malignancy unless there is biopsy proof that the mass is not malignant.
  • Primary tumor staged as T4 for any reason.
  • Nodes staged as clinical N2 or N3 for any reason and nodes staged as pathologic pN2b, pN3b, or pN3c.
  • Prior history of breast cancer, including DCIS (patients with a history of lobular carcinoma in situ [LCIS] are eligible).
  • Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy administered for the currently diagnosed breast cancer prior to randomization. The only exception is hormonal therapy, which may have been given for up to a total of 28 days anytime after diagnosis and before randomization. In such a case, hormonal therapy must stop at or before randomization and be re-started if indicated following chemotherapy.
  • Prior anthracycline or taxane therapy for any malignancy.
  • Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible only if this therapy is discontinued prior to randomization.)
  • Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention. (Patients are eligible only if these medications are discontinued prior to randomization. These medications are not permitted while on the study except for the use of tamoxifen as described in the protocol)
  • Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude a patient from being subjected to any of the treatment options or would prevent prolonged follow-up.
  • Cardiac disease that would preclude the use of Adriamycin, Taxol or Herceptin. This includes:

  • Active cardiac disease:

    • angina pectoris that requires the use of antianginal medication;
    • cardiac arrhythmia requiring medication;
    • severe conduction abnormality;
    • clinically significant valvular disease;
    • cardiomegaly on chest x-ray;
    • ventricular hypertrophy on EKG; or
    • patients with poorly controlled hypertension, i.e., diastolic greater than 100 mm/Hg. (Patients with hypertension who are well controlled on medication are eligible for entry.)

  • History of cardiac disease:

    • myocardial infarction documented as a clinical diagnosis or by EKG or any other tests;
    • documented congestive heart failure; or
    • documented cardiomyopathy.
  • Psychiatric or addictive disorders that would preclude obtaining informed consent.
  • Pregnancy or lactation at the time of proposed randomization. This protocol excludes pregnant or lactating women based on the fetal toxicity of both tamoxifen and Taxol which are listed as Pregnancy Category D agents. Pregnant women who received tamoxifen have experienced fetal deaths, birth defects, spontaneous abortions, and vaginal bleeding. Women of reproductive potential must agree to use an effective barrier method of contraception. Hormonal birth control methods are not permitted.
  • Sensory/motor neuropathy ≥ grade 2, as defined by the NCI's Common Toxicity Criteria version 2.0.
  • Contraindications to corticosteroid use which, in the opinion of the investigator, would preclude participation in this study.
  • Concurrent treatment with other investigational agents.
  • Sensitivity to benzyl alcohol.

  • Special conditions for ineligibility of lumpectomy patients: irradiation and surgery. For patients treated by lumpectomy with axillary dissection, breast irradiation is required. Please see guidelines for radiation therapy in Appendix A. In addition, the following patients will also be ineligible:

    • Patients with diffuse tumors (as demonstrated on mammography) that would not be considered surgically amenable to lumpectomy.
    • Patients treated with lumpectomy in whom there is another clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast remnant. Such a mass must be biopsied and demonstrated to be histologically benign prior to randomization or, if malignant, must be surgically removed with clear margins.
    • Patients in whom the margins of the resected specimen are involved with invasive tumor or ductal carcinoma in situ (DCIS). Additional surgical resections to obtain free margins are allowed. Patients in whom tumor is still present after the additional resection(s) must undergo mastectomy to be eligible.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm 1: adriamycin + cyclophosphamide then taxol
Drug: adriamycin
60 mg/m2 IV push every 21 days for 4 cycles.
Other Names:
  • doxorubicin
Drug: cyclophosphamide
600 mg/m2 IV every 21 days for 4 cycles
Drug: taxol
175 mg/m2 IV every 21 days for 4 cycles
Other Names:
  • paclitaxel
Experimental: Arm 2: adriamycin + cyclophosphamide then taxol + herceptin
Drug: adriamycin
60 mg/m2 IV push every 21 days for 4 cycles.
Other Names:
  • doxorubicin
Drug: cyclophosphamide
600 mg/m2 IV every 21 days for 4 cycles
Drug: taxol
175 mg/m2 IV every 21 days for 4 cycles
Other Names:
  • paclitaxel
Biological: herceptin
4 mg/kg loading dose then 2 mg/kg weekly for 1 year.
Other Names:
  • trastuzumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease Free Survival (DFS)
Time Frame: Time from randomization through 5 years
Breast cancer recurrence, second primary cancer, death from any cause as first event
Time from randomization through 5 years
Cardiotoxicity
Time Frame: time from randomization through 4 months
time from randomization through 4 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival
Time Frame: time from randomization through 5 years
Death from any cause.
time from randomization through 5 years
Long term effect of trastuzumab on cardiac function
Time Frame: At 5 and 10 years after randomization
Ejection fraction will be measured by multigated acquisition scan (MUGA).
At 5 and 10 years after randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NSABP Foundation Inc

Collaborators

National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2000

Primary Completion (Actual)

March 1, 2005

Study Completion (Actual)

November 1, 2019

Study Registration Dates

First Submitted

December 10, 1999

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Actual)

April 29, 2021

Last Update Submitted That Met QC Criteria

April 28, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NSABP B-31
  • CDR0000067269

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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