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

Basic Trial Information

Objectives

I.  Determine whether larger but fewer doses of cyclophosphamide (CTX) improve 
disease-free and overall survival when administered to patients with axillary 
node-positive breast cancer randomized to postoperative adjuvant chemotherapy 
with standard dose/schedule AC (doxorubicin/cyclophosphamide) vs. a 
dose-intense schedule with the same cumulative dose of CTX.

II.  Determine whether disease-free and overall survival are improved when 
these patients are randomized to increased dose-intensity and cumulative-dose 
CTX vs. the same dose intensity of CTX administered over a shorter period 
(lower cumulative dose) in the AC regimen.

Entry Criteria

Disease Characteristics:

Histologically proven invasive carcinoma of the breast with at
least 1 histologically positive ipsilateral axillary node
definitively removed by either:
  Total mastectomy with axillary dissection
  Lumpectomy with axillary dissection
  (Radical mastectomy not allowed)

The interval between histologic diagnosis and definitive
surgery must not exceed 42 days

The interval between definitive surgery and initiation of
protocol therapy must not exceed 35 days

Histology established by excisional, incisional, or needle
biopsy and aspiration cytology

Tumor confined to breast and ipsilateral axilla on clinical
examination

Tumor must be movable relative to underlying pectoral muscle,
chest wall, and overlying skin

Palpable axillary nodes must be movable in relation to the
chest wall, neurovascular bundle, and each another, and must be
no greater than 2 cm in largest diameter

The following conditions are specifically excluded:
  Inflammatory carcinoma
  Ulceration
  Erythema
  Peau d'orange or any degree of skin edema
  Satellite nodules
  Parasternal nodules
  Edema of the arm
  Infiltration of the skin (tethering, skin dimpling, and
     nipple inversion are not to be interpreted as skin
     infiltration, and patients with these conditions are
     eligible)
  Bilateral breast cancer (any mass in the contralateral
     breast must be proved benign by biopsy)
  Distant metastases
     Patients with bone pain must have negative bone scan
     and/or x-ray

Patients with palpable contralateral axillary nodes or
palpable supraclavicular or infraclavicular nodes must have
biopsy proof of absence of tumor

ER and PR assays must be performed on the primary tumor
  Any ER and PR status allowed
  Recommended methods of determination include:
     Dextran-coated charcoal or sucrose density
     Enzyme immunoassay (EIA)
     Immunocytochemical assay (ER-ICA and PR-ICA)

Lumpectomy patients must additionally meet the following
requirements:
  Tumor clinically no greater than 5 cm in greatest diameter

  Diffuse tumors on xeroradiography or mammography unless
  amenable to lumpectomy

  Breast of a size to permit cosmetically acceptable resection

  Histologically negative resection margins
     1 additional surgical procedure allowed to achieve
     negative margins

     Second procedure must be within 28 days of histologic
     diagnosis

     If margins are positive following a second surgical
     procedure, total mastectomy is required for eligibility

  Any other dominant mass in the ipsilateral breast remnant
  must be biopsied and shown to be histologically benign

Prior/Concurrent Therapy:

Biologic therapy:
  No prior therapy for breast cancer

Chemotherapy:
  No prior therapy for breast cancer

Endocrine therapy:
  No prior therapy for breast cancer; oophorectomy for other
  reasons allowed, but radiation castration excludes

  Hormonal therapy other than that stipulated by protocol
  (e.g., birth control, replacement) must be discontinued on
  entry 

Radiotherapy:
  No prior therapy for breast cancer

  Radiotherapy prior to randomization not allowed in
  lumpectomy patients

Surgery:
  Total resection of tumor (total mastectomy/axillary
  dissection or lumpectomy/axillary dissection) required
  within 35 days of initiation of treatment

  Patients who have undergone radical mastectomy are ineligible
     Partial excision of the pectoralis major muscle does not
     constitute radical mastectomy

  Definitive surgery must have been performed within 28 days
  following histologic diagnosis

Patient Characteristics:

Age:
  18 to physiologic 75

Sex:
  Not specified

Menopausal status:
  Not specified

Performance status:
  Not specified

Life expectancy:
  At least 10 years excluding breast cancer

Hematopoietic:
  (obtained postoperatively)
  WBC at least 4,000
  Platelets at least 100,000

Hepatic:
  (obtained postoperatively)
  Bilirubin within normal limits
  SGOT or SGPT within normal limits

Renal:
  (obtained postoperatively)
  Creatinine within normal limits

Cardiovascular:
  No documented MI
  No angina pectoris requiring medication
  No history of CHF
  No arrhythmia associated with heart failure or cardiac
     dysfunction
  No valvular disease with documented cardiac dysfunction
  No cardiomegaly on chest x-ray
  No poorly controlled hypertension (diastolic greater than 100
     mm Hg)

Other:
  No known hypersensitivity to E. coli-derived drug
     preparations
  No nonmalignant systemic disease that would preclude
    protocol therapy or prevent prolonged follow-up
  No second malignancy except:
     Effectively treated nonmelanomatous skin cancer
     In situ cervical cancer treated by surgery only
  No pregnant women
  No psychiatric or addictive disorder that would preclude
     informed consent

Expected Enrollment

2,400 patients (800/arm) will be accrued over an estimated 3 years.

Outline

Randomized study.  Patients 50 years of age or older at time of definitive 
surgery, regardless of ER or PR status, are treated on Regimen A concomitantly 
with chemotherapy; those who underwent lumpectomy are treated on Regimen B 
following completion of chemotherapy.

Arm I:  2-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. 
 AC:  Doxorubicin, DOX, NSC-123127; Cyclophosphamide, CTX, NSC-26271; with 
Granulocyte Colony Stimulating Factor (Amgen), G-CSF, NSC-614629.  Standard 
dose/schedule.

Arm II:  2-Drug Combination Chemotherapy with Hematologic Toxicity 
Attenuation.  AC; with G-CSF.  Intensified CTX dose/short schedule.

Arm III:  2-Drug Combination Chemotherapy with Hematologic Toxicity 
Attenuation.  AC; with G-CSF.  Intensified CTX dose/standard schedule.

Regimen A:  Antiestrogen Therapy.  Tamoxifen, TMX, NSC-180973.

Regimen B:  Radiotherapy.  Breast irradiation using Co60 or x-rays with 
minimum energy of 4 MeV.

Fisher B, Anderson S, DeCillis A, et al.: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17 (11): 3374-88, 1999.[PUBMED Abstract]

DeCillis A, Anderson S, Wickerham DL, et al.: Acute myeloid leukemia (AML) in NSABP B-25. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-92, 98, 1995.

Wapnir IL, Anderson SJ, Mamounas EP, et al.: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 24 (13): 2028-37, 2006.[PUBMED Abstract]

Swain SM, Wilson JW, Mamounas EP, et al.: Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst 96 (7): 516-23, 2004.[PUBMED Abstract]

Taghian A, Jeong JH, Mamounas E, et al.: Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 22 (21): 4247-54, 2004.[PUBMED Abstract]

Wapnir I, Anderson S, Tan-Chiu E, et al.: Ipsilateral breast tumor recurrence (IBTR) and survival in NSABP node-positive breast cancer protocols. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A315, 2000.

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

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