Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	18 and over	NCI	NSABP-B-19 MAOP-1288, NCOG-NSABP-B-19

Objectives

I.  Compare survival and disease-free survival of patients who have undergone 
curative resection of ER-negative carcinoma of the breast with negative nodes 
randomly assigned to adjuvant postoperative chemotherapy with sequential 
methotrexate/5-fluorouracil followed by leucovorin vs. conventional CMF 
(cyclophosphamide/methotrexate/5-fluorouracil).
II.  Correlate tumor cell ploidy, kinetics, and pathological variables of 
tumor differentiation (e.g., nuclear grade) to clinical outcome.

Entry Criteria

Disease Characteristics:

See General Eligibility Criteria

Patient Characteristics:

See General Eligibility Criteria

General Eligibility Criteria:

Female patients aged 18 years and 
over who have undergone total mastectomy and axillary dissection or segmental 
mastectomy and axillary dissection to be followed (on protocol) by breast 
irradiation for potentially curable ER-negative breast cancer with negative 
nodes provided they have received no therapy other than mastectomy for the 
present breast cancer.  No more than 4 weeks may have intervened between 
establishment of histologic diagnosis (excisional, incisional, or needle 
biopsy and aspiration cytology) and definitive surgery, and protocol treatment 
must begin within 35 days of definitive surgery.  The tumor must be confined 
to the breast on clinical examination and must be movable in relation to the 
overlying skin and to the underlying muscle and chest wall.  There must be no 
ulceration, erythema, or peau d'orange of any magnitude and no satellite 
breast nodules, parasternal nodules, edema of the arm, or inflammatory 
carcinoma; suspected satellite foci of tumor involving the skin must be 
demonstrated histologically to be tumor-free.  The tumor must be invasive on 
histologic examination, and all axillary nodes must be histologically negative 
for tumor (patients may have had palpable ipsilateral axillary nodes 
preoperatively if these are histologically negative).  Patients with palpable 
contralateral axillary or palpable supraclavicular or infraclavicular nodes 
are ineligible unless these nodes are histologically demonstrated to be free 
of tumor.  Patients with bone pain may be entered only if a bone scan and/or 
radiographic examination reveals no evidence of metastatic disease.  Patients 
with bilateral breast cancer are not eligible, and those with a mass in the 
contralateral breast must have biopsy evidence that the mass is not malignant. 
 Quantitative analyses of ER and PgR content must have been carried out on 
tumor tissue by a laboratory that conforms to NSABP quality control 
requirements; patients with any PgR status are eligible, but the ER content 
must be less than 10 fmol/mg cytosol protein (patients with an ER content of 
10 fmol/mg cytosol protein or greater are eligible for NSABP-B-20).  Patients 
may have undergone a previous oophorectomy for reasons other than treatment of 
breast cancer, but patients who have had radiation castration are ineligible.  
Patients who are currently on hormonal therapy (e.g., birth control 
medication) must discontinue such therapy while on protocol until the first 
recurrence.  Exclusive of breast cancer, the life expectancy must be at least 
10 years.  Adequate postoperative hematopoietic, hepatic, and renal function 
must be documented by the following:  WBC at least 4,000 and platelets at 
least 100,000; serum bilirubin not greater than 1.5 mg/dl and SGOT not greater 
than 60 IU/ml; and serum creatinine not greater than 1.5 mg/dl and 24-hour 
creatinine clearance at least 60 ml/min.  A previous or concomitant second 
malignancy other than effectively treated squamous or basal cell skin cancer 
and in situ carcinoma of the cervix treated operatively only renders a patient 
ineligible.  There must be no nonmalignant systemic disease (e.g., 
cardiovascular, renal, hepatic) that would preclude protocol treatment or 
follow-up, and no psychiatric or addictive disorders that would preclude 
informed consent.  Pregnancy excludes.  In addition to fulfilling the 
foregoing entry criteria, patients who have undergone segmental resection must 
also satisfy the following requirements:  the tumor must have been 5 cm or 
less in greatest diameter on clinical examination; the breast must be of 
sufficient size to allow a cosmetically acceptable resection; xeroradiography 
or mammography must not reveal a diffuse tumor that would not be considered 
surgically appropriate for segmental mastectomy; a second dominant mass in the 
same breast must be biopsied and demonstrated to be histologically benign; and 
the resection specimen margins must be demonstrated to be histologically free 
of invasive and noninvasive tumor.  If the resection margins are positive for 
tumor histologically, one and only one additional surgical procedure is 
allowed in order to obtain clear margins, even if axillary dissection has been 
performed, but the same time constraints still pertain:  no more than 4 weeks 
may intervene between diagnosis and definitive surgery.  Patients with 
positive margins after a second surgical procedure must undergo total 
mastectomy.

Expected Enrollment

1,020 patients will be entered over about 3 years.

Outline

Randomized study.  Patients on either arm who have undergone segmental 
resection receive breast irradiation as described under Regimen A concurrently 
with chemotherapy.
Arm I:  2-Drug Sequential Combination Chemotherapy plus Leucovorin Rescue.  
Methotrexate, MTX, NSC-740; followed by 5-Fluorouracil, 5-FU, NSC-19893; plus 
Leucovorin calcium, Citrovorum Factor, CF, NSC-3590.
Arm II:  3-Drug Combination Chemotherapy.  CMF:  Cyclophosphamide, CTX, 
NSC-26271; MTX; 5-FU.
Regimen A:  Radiotherapy.  Irradiation of the remaining ipsilateral breast 
tissue with Co60 or linear accelerator equipment.

Fisher B, Jeong JH, Anderson S, et al.: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 96 (24): 1823-31, 2004.[PUBMED Abstract]

Taghian AG, Jeong JH, Mamounas EP, et al.: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol 24 (24): 3927-32, 2006.[PUBMED Abstract]

Fisher B, Jeong JH, Anderson S, et al.: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 96 (24): 1823-31, 2004.[PUBMED Abstract]

Fisher B, Dignam J, Tan-Chiu E, et al.: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93 (2): 112-20, 2001.[PUBMED Abstract]

Fisher B, Jeong JH, Dignam J, et al.: Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer. J Natl Cancer Inst Monogr (30): 62-6, 2001.[PUBMED Abstract]

McCaskill-Stevens W, Bryant J, Costantino J, et al.: Incidence of contralateral breast cancer (CBC), endometrial cancer (EC), and thromboembolic events (TE) in African American (AA) women receiving tamoxifen for treatment of primary breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A269, 2000.

Fisher B, Dignam J, Mamounas EP, et al.: Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 14 (7): 1982-92, 1996.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

National Surgical Adjuvant Breast and Bowel Project

Norman Wolmark, MD, Protocol chair		Ph: 412-359-3336; 866-680-0004

Clinical Research Program - Northern California Cancer Center

Robert Carlson, MD, Protocol chair		Ph: 650-725-6457; 800-756-9000

Mid-Atlantic Oncology Program

James Ahlgren, MD, Protocol chair		Ph: 202-741-2478 Email: w4rx@alum.mit.edu