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Phase III Randomized Comparison of Adjuvant Chemotherapy with AC (ADR/CTX) vs AC Plus Reinduction with Parenteral CMF (Intravenous CTX/MTX/5-FU) vs Conventional CMF in Patients with Totally Resected Breast Cancer with Positive Nodes

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

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted18 to 59NCINSABP-B-15
MAOP-1784, NCOG-NSABP-B-15

Objectives

I.  Compare the disease-free intervals and survival of patients under the age 
of 60 years with potentially curable carcinoma of the breast treated 
postoperatively with adjuvant chemotherapy:  AC (adriamycin/cyclophosphamide) 
vs. AC plus reinduction with parenteral CMF (intravenous 
cyclophosphamide/methotrexate/5-fluorouracil) vs. conventional CMF (oral 
cyclophosphamide/methotrexate/5-fluorouracil).
II.  Compare the morbidity associated with these therapeutic regimens.

Entry Criteria

Disease Characteristics:

See General Eligibility Criteria

Patient Characteristics:

See General Eligibility Criteria

General Eligibility Criteria:

Women under the age of 60 years who 
have undergone either total mastectomy plus axillary dissection or segmental 
mastectomy plus axillary dissection (the latter group will receive 
postoperative radiotherapy on protocol) for potentially curable carcinoma of 
the breast, provided they begin treatment 2-4 weeks postoperatively.  Patients 
aged 50-59 years must have a progesterone receptor level of less than 10 
fmol/mg cytosol protein, regardless of ER levels; specific receptor levels are 
not a condition for entry of patients aged 49 years and younger.  Prior to 
entry, receptor levels must be determined for all patients by a laboratory 
that complies with NSABP quality control requirements.  Patients who have 
undergone segmental mastectomy must not have had breast irradiation prior to 
entry.  The tumor must be confined to the breast or the breast and ipsilateral 
axilla on clinical examination, movable in relation to the underlying muscle 
and chest wall, and movable with respect to the overlying skin; it must be 
invasive histologically, and there must be histologic evidence of tumor in at 
least one axillary lymph node.  The axillary nodes must be movable in relation 
to the chest wall and neurovascular bundle and be no greater than 2 cm in 
size; there may be no edema of the arm.  The life expectancy exclusive of 
cancer must be at least 10 years, and there must be adequate hematopoietic, 
renal, and hepatic function.  Patients with skeletal pain are eligible only if 
the bone scan and/or x-ray examination reveals no evidence of metastatic 
disease.  Patients with previous surgical oophorectomy are eligible if the 
oophorectomy was not performed for malignancy; patients may not have had 
radiation castration.  Patients may not have breast malignancy other than 
carcinoma and may not have inflammatory carcinoma.  Any mass in the 
contralateral breast must be demonstrated by biopsy to be benign.  There may 
be no ulceration, erythema, skin infiltration, or peau d'orange of any 
magnitude, although patients with tethering or dimpling of the skin or nipple 
inversion are eligible.  Palpable nodes in the contralateral axilla or in the 
supraclavicular or infraclavicular areas must be confirmed by biopsy as 
benign.  Mastectomy must have taken place within 4 weeks of histologic 
diagnosis.  There may be no previous or concomitant second malignancy except 
for effectively treated squamous or basal cell skin carcinoma or surgically 
treated carcinoma in situ of the cervix.  There may have been no prior therapy 
for breast cancer other than mastectomy; hormonal therapy (e.g., birth control 
medication, replacement therapy, etc.) must be discontinued while on protocol. 
 There must be no nonmalignant systemic disease that would preclude any of the 
therapeutic options; specifically, there may be no active cardiac disease that 
would contraindicate the use of adriamycin, including any documented 
myocardial infarction, angina pectoris that requires medication, history of 
CHF, valvular disease with documented compromise of cardiac function, 
cardiomegaly on chest x-ray, ventricular hypertrophy by EKG, or poorly 
controlled hypertension.  Patients who have undergone segmental mastectomy 
must have had a tumor that was not greater than 4 cm in its largest dimension, 
must not have had removal of the nipple, must have had a breast small enough 
to permit satisfactory radiotherapy, and must have had a breast large enough 
to permit a cosmetically acceptable resection.

Expected Enrollment

800 patients will be entered over about 2 years.

Outline

Randomized study.  Patients are randomized to Arms I, II, and III.  All 
patients who had segmental mastectomy receive Radiotherapy.
Arm I:  2-Drug Combination Chemotherapy.  AC:  Adriamycin, ADR, NSC-123127; 
Cyclophosphamide, CTX, NSC-26271.
Arm II:  2-Drug Combination Chemotherapy followed by Reinduction with 3-Drug 
Combination Chemotherapy.  AC; followed by Parenteral CMF:  Intravenous CTX; 
Methotrexate, MTX, NSC-740; 5-Fluorouracil, 5-FU, NSC-19893.
Arm III:  3-Drug Combination Chemotherapy.  Conventional CMF.
Radiotherapy.  Irradiation of the involved breast using Co60 or linear 
accelerators.

Published Results

Paik S, Bryant J, Tan-Chiu E, et al.: HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92 (24): 1991-8, 2000.[PUBMED Abstract]

Cobleigh MA, Bines J, Harris D, et al.: Amenorrhea following adjuvant chemotherapy for breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-158, 115, 1995.

Fisher B, Brown AM, Dimitrov NV, et al.: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8 (9): 1483-96, 1990.[PUBMED Abstract]

Related Publications

Gennari A, Sormani MP, Puntoni M, et al.: A pooled analysis on the interaction between HER-2 expression and responsiveness of breast cancer to adjuvant chemotherapy. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-41, S19, 2006.

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]

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]

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.

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

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.

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