Phase III Comparison of Adjuvant Sequential Chemotherapy with MTX/5-FU vs No Adjuvant Therapy in Patients with Negative Axillary Nodes Following Mastectomy for ER-Negative Breast Cancer

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Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted18 to 70NCINSABP-B-13


I.  Compare disease-free interval and survival of patients with negative 
axillary nodes following mastectomy for ER-negative breast cancer who are 
randomly assigned to adjuvant sequential therapy with methotrexate followed by 
5-fluorouracil vs. no adjuvant therapy.
II.  In conjunction with the results of NSAPB-B-14, evaluate whether treatment 
failure and survival correlate with ER level in post-mastectomy, negative-node 
patients who receive no further treatment.
III.  Evaluate the influence of both hormone receptor status and the 
interaction of radiotherapy and sequential methotrexate/5-fluorouracil 
chemotherapy on the rate of local breast recurrence in patients who have 
undergone segmental mastectomy and axillary node dissection for their disease.

Entry Criteria

Disease Characteristics:

See General Eligibility Criteria

Patient Characteristics:

See General Eligibility Criteria

General Eligibility Criteria:

Female patients under the age of 71 
years who have undergone either total mastectomy and axillary dissection or 
segmental mastectomy and axillary dissection (to be followed by breast 
irradiation) for potentially curable carcinoma of the breast, provided all 
axillary nodes are proven histologically to be negative, the ER level of the 
tumor is less than 10 fmol/mg cytosol protein, and the PR level has been 
quantified.  The interval between mastectomy and proposed randomization and 
treatment must not exceed 35 days, and no more than 4 weeks may have 
intervened between diagnosis and mastectomy.  The tumor must be confined to 
the breast clinically, movable relative to the underlying muscle and chest 
wall, movable relative to the skin, and invasive on histological examination.  
There may be no ulceration, erythema, infiltration of the skin, peau d'orange, 
satellite breast nodules or parasternal nodules, or edema of the arm.  
Patients with inflammatory carcinoma and those with tumors other than 
carcinoma are excluded.  If there are palpable ipsilateral or contralateral 
axillary nodes preoperatively or palpable supraclavicular or infraclavicular 
nodes, these must be demonstrated to be free of tumor histologically.  
Patients with bilateral breast cancer are excluded, as are those with a mass 
in the contralateral breast unless there is biopsy proof of nonmalignancy.  
Patients with bone pain may be entered only if a bone scan and/or x-ray 
examination reveals no metastatic disease.  There may have been no prior 
therapy for breast cancer and no previous or concurrent second malignancy 
aside from effectively treated basal cell carcinoma of the skin and carcinoma 
in situ of the cervix that has been treated surgically only.  Patients may 
have had a previous surgical oophorectomy for a nonmalignant condition, but 
radiation castration renders a patient ineligible.  Adequate hematopoietic and 
hepatic function must be documented by the following:  WBC at least 4,000 and 
platelets at least 100,000; and bilirubin not over 1.5 mg/dl and SGOT not over 
60 IU/ml.  Renal function must be adequate, and a 24-hour creatinine clearance 
must be performed postoperatively and the results available prior to 
randomization.  There must be no nonmalignant systemic disease that would 
preclude any protocol treatment and no psychiatric or addictive disorder that 
would preclude obtaining informed consent.  Pregnancy excludes.  In addition 
to fulfilling the foregoing entry criteria, patients who undergo segmental 
resection must have a tumor that is no greater than 4 cm in greatest diameter 
on clinical examination and must have a breast of sufficient size to permit a 
cosmetically acceptable resection but not so large that satisfactory breast 
irradiation is not possible; the tumor must be so located that adequate 
resection can be accomplished without removal of the nipple.  Candidates for 
segmental mastectomy must not have diffuse tumor demonstrated on 
xeroradiography or mammography and must not have more than one tumor in the 
same breast unless all but one is histologically proven to be benign.  
Radiotherapy must not have been given following segmental resection prior to 

Expected Enrollment

1,350-1,440 patients will be accrued in 4-5 years.


Randomized study.  All patients are randomized on Arms I and II; segmental 
mastectomy patients are also treated on Regimen A.
Arm I:  2-Drug Sequential Combination Chemotherapy plus Leucovorin Rescue.  
Methotrexate, MTX, NSC-740; 5-Fluorouracil, 5-FU, NSC-19893; Citrovorum 
Factor, Leucovorin, CF, NSC-3590.
Arm II:  No further treatment.
Regimen A:  Radiotherapy.  Breast irradiation using Co60 or linear accelerator 

Published Results

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]

Fisher B, Costantino J, Wickerham L, et al.: Adjuvant therapy for node-negative breast cancer: an update of NSABP findings. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-79, 69, 1993.

Fisher B, Redmond C, Dimitrov NV, et al.: A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 320 (8): 473-8, 1989.[PUBMED Abstract]

Fisher B, Redmond C, Wickerham DL, et al.: Systemic therapy in patients with node-negative breast cancer. A commentary based on two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials. Ann Intern Med 111 (9): 703-12, 1989.[PUBMED Abstract]

Related Publications

Anderson SJ, Wapnir I, Dignam JJ, et al.: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five national surgical adjuvant breast and bowel project protocols of node-negative breast cancer. J Clin Oncol 27 (15): 2466-73, 2009.[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 ER, Kenny JP, Sass R, et al.: Medullary cancer of the breast revisited. Breast Cancer Res Treat 16 (3): 215-29, 1990.[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

Mid-Atlantic Oncology Program

Patrick Byrne, MD, Protocol chair (Contact information may not be current)
Ph: 703-560-3205

Clinical Research Program - Northern California Cancer Center

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

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.