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NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Comparison of Preoperative vs Postoperative Short-Term Intensive Combination Chemotherapy with AC (DOX/CTX) in Women with Resectable Carcinoma of the Breast

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

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted18-75, pre/postmenopausalNCINSABP-B-18
MAOP-1188, NCOG-NSABP-B-18

Objectives

I.  Compare disease-free survival and overall survival among patients with 
operable carcinoma of the breast randomly assigned to four courses of 
preoperative vs. postoperative combination chemotherapy with AC 
(doxorubicin/cyclophosphamide).

II.  Evaluate the response of the primary tumor to preoperative chemotherapy, 
and correlate the response with disease-free survival and survival.

III.  Determine whether reduction in the size of the primary tumor by 
preoperative chemotherapy will permit more conservative surgery and decrease 
the incidence of recurrence in the ipsilateral breast.

Entry Criteria

Disease Characteristics:


Breast cancer with tumor palpable on clinical examination
(T1-3) and confined to the breast or breast and ipsilateral
axilla

Diagnosis made on tissue obtained by fine needle
aspiration cytology (preferred) or by core biopsy but not
by incisional or excisional biopsy

Tumor must be movable in relation to overlying skin and
underlying muscle and chest wall on clinical examination

Palpable axillary nodes must be movable in relation to each
other and to chest wall and neurovascular bundle

Nodes may be of any size but must not be associated with
edema of the arm

No ulceration, erythema, complete fixation to the skin, peau
d'orange of any degree, satellite breast nodules, or
parasternal nodules

Tethering or dimpling of skin or nipple inversion allowed

No cancer in the contralateral breast

Patients with a mass in the opposite breast and those with
palpable nodes in the contralateral axilla or in the
supraclavicular or infraclavicular areas must have biopsy
proof that there is no malignancy in these areas

No bone pain unless bone scan and/or x-ray rules out
metastatic disease

Interval between initial diagnosis and randomization may not
exceed 56 days

Hormone receptor status:
  Not required prior to randomization


Prior/Concurrent Therapy:


Biologic therapy:
  No prior immunotherapy for breast cancer

Chemotherapy:
  No prior chemotherapy for breast cancer

Endocrine therapy:
  No prior hormonal therapy for breast cancer
  Sex hormone therapy other than that stipulated on protocol
   (e.g., birth control pills, ovarian replacement hormonal
   therapy) must be discontinued for duration of protocol
   treatment

Radiotherapy:
  No prior radiotherapy for breast cancer
  No prior radiation castration

Surgery:
  No prior surgery
  Prior surgical oophorectomy for reasons other than
   malignancy allowed


Patient Characteristics:


Age:
   18 to 75

Sex:
  Women only

Menopausal status:
  Pre- or postmenopausal

Performance status:
  Not specified

Life expectancy:
  At least 10 years exclusive of breast cancer

Hematopoietic:
  WBC at least 4,000
  Platelets at least 100,000

Hepatic:
  Bilirubin no greater than 1.5 mg/dl
  SGOT no greater than 60 IU/ml
  No hepatic disease that would preclude protocol therapy

Renal:
  Creatinine no greater than 1.5 mg/dl
  No renal disease that would preclude protocol therapy

Cardiovascular:
  No contraindication to the use of doxorubicin, i.e.:
    No documented MI
    No angina pectoris requiring medication
    No history of CHF
    No cardiac arrhythmia associated with cardiac dysfunction
    No valvular disease with documented compromise in
      cardiac function
    No cardiomegaly on x-ray
    No poorly controlled hypertension (diastolic pressure
      greater than 100 mm Hg)

Other:
  No other nonmalignant systemic disease that would preclude
    protocol therapy
  No pregnancy at randomization
  No previous or concomitant malignancy except:
    Effectively treated nonmelanomatous skin cancer
    Surgically treated in situ cervical or uterine carcinoma
  No psychiatric or addictive disorder that precludes informed
    consent

Expected Enrollment

A total of 1,510 patients will be entered.

Outline

Randomized study.  All patients are randomized on Arms I and II.  All patients 
aged 50 years and older at the time of randomization receive antiestrogen 
therapy with tamoxifen (Regimen A) following chemotherapy on either arm.  
Patients on either arm whose surgical procedure is a segmental mastectomy 
receive postoperative radiotherapy on Regimen B.

Arm I:  Surgery followed by 2-Drug Combination Chemotherapy.  Radical or 
segmental mastectomy and axillary dissection; followed by AC:  Doxorubicin, 
DOX, NSC-123127; Cyclophosphamide, CTX, NSC-26271.

Arm II:  2-Drug Combination Chemotherapy followed by Surgery.  AC; followed by 
radical or segmental mastectomy and axillary dissection.

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

Regimen B:  Radiotherapy.  Irradiation of the remaining breast tissue 
(equipment not specified).

Published Results

Mamounas EP, Wang J, Bryant J, et al.: Patterns of loco-regional failure (LRF) in patients receiving neoadjuvant chemotherapy (NC): results from NSABP B-18. [Abstract] Breast Cancer Res Treat 82 (Suppl 1): A-35, S17, 2003.

Fisher ER, Wang J, Bryant J, et al.: Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95 (4): 681-95, 2002.[PUBMED Abstract]

Wolmark N, Wang J, Mamounas E, et al.: Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr (30): 96-102, 2001.[PUBMED Abstract]

Fisher B, Bryant J, Wolmark N, et al.: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16 (8): 2672-85, 1998.[PUBMED Abstract]

Fisher B, Brown A, Mamounas E, et al.: Effect of preoperative therapy for primary breast (BC) on local-regional disease, disease-free survival (DFS) and survival (S) : results from NSABP B-18. [Abstract] Proceedings of the American Society of Clinical Oncology 16: A-449, 1997.

Fisher B, Brown A, Mamounas E, et al.: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15 (7): 2483-93, 1997.[PUBMED Abstract]

Fisher B, Rockette H, Robidoux A, et al.: Effect of preoperative therapy for breast cancer (BC) on local-regional disease: first report of NSABP B-18. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-57, 64, 1994.

Related Publications

Mamounas EP, Anderson SJ, Dignam JJ, et al.: Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol 30 (32): 3960-6, 2012.[PUBMED Abstract]

Rastogi P, Anderson SJ, Bear HD, et al.: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26 (5): 778-85, 2008.[PUBMED Abstract]

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]

Mamounas EP, Fisher B: Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. Semin Oncol 28 (4): 389-99, 2001.[PUBMED Abstract]

Mamounas EP, Fisher B: Preoperative chemotherapy for operable breast cancer. Cancer Treat Res 103: 137-55, 2000.[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.

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

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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