Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy plus trastuzumab is more effective than combination chemotherapy alone for treating breast cancer.

PURPOSE: This randomized phase III trial is studying how well giving combination chemotherapy together with trastuzumab works compared to combination chemotherapy alone in treating women with node-positive stage II or stage IIIA breast cancer that overexpresses HER2.

Further Study Information

OBJECTIVES:

• Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin®) in women with operable, node-positive breast cancer that overexpresses HER2.

• Compare the effect of these regimens on disease-free and overall survival of these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive nodes (1-3 vs 4-9 vs 10 or more), administration of hormonal therapy (tamoxifen vs anastrozole vs neither), surgery/radiotherapy (lumpectomy plus breast irradiation vs lumpectomy plus breast irradiation plus regional irradiation vs mastectomy without radiotherapy vs mastectomy with radiotherapy), paclitaxel schedule (every 3 weeks vs weekly), and participating center. Patients are randomized to one of two treatment arms.

• Arm I: Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses. Approximately 3 weeks after the last course, patients receive paclitaxel IV over 3 hours every 21 days for 4 courses OR paclitaxel IV over 1 hour once weekly for 12 weeks (12 doses).

• Arm II: Patients receive chemotherapy as in arm I and trastuzumab (Herceptin®) IV over 90 minutes on day 1 of the first course of paclitaxel. Trastuzumab is then administered IV over 30 minutes weekly for 51 weeks, beginning on day 8.

All patients with estrogen or progesterone receptor-positive tumors receive hormonal therapy* for at least 5 years, beginning within 3-12 weeks after the last dose of chemotherapy. Patients who have received prior tamoxifen for prevention may be treated with additional tamoxifen for no more than 5 years at the discretion of the principal investigator (PI).

NOTE: *Other hormonal therapeutic agents are allowed in sequence with or as an alternative to tamoxifen therapy.

All patients previously treated with lumpectomy undergo breast irradiation beginning after completion of chemotherapy and concurrently with trastuzumab (in arm II) administration. Patients previously treated with mastectomy may also receive radiotherapy. Radiotherapy is administered daily for 5-6 weeks.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,700 patients will be accrued for this study within 4.75 years.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically proven invasive adenocarcinoma of the breast

• Stage IIA, IIB, or IIIA

• Confined to the breast and ipsilateral axilla (cN0-1) on clinical examination

• At least 1 histologically positive axillary node

• No lymph nodes clinically fixed to each other or to other structures (cN2)

• HER2 strongly positive (3+ by immunostain OR gene amplification by fluorescent in situ hybridization)

• Submission of tumor block required

• Must have undergone axillary dissection and either total mastectomy OR lumpectomy

• Sentinel node dissection allowed, if followed by axillary dissection

• No diffuse tumors by mammography in patients treated with lumpectomy

• No more than 84 days since prior surgery for breast cancer (e.g., lumpectomy, mastectomy, axillary dissection, or re-excision of lumpectomy margins)

• No bilateral malignancy, contralateral mass, or mammographic abnormality unless histologically proven as benign

• No suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or infraclavicular nodes unless histologically proven not to be involved with tumor

• No primary T4 tumors (for any reason)

• No prior breast cancer, including ductal carcinoma in situ

• Prior lobular carcinoma in situ allowed

• Bone pain allowed provided there is no metastatic disease by x-ray, MRI, or biopsy

• Hormone receptor status:

• Estrogen and progesterone status known

PATIENT CHARACTERISTICS:

Age:

• Not specified

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Not specified

Life expectancy:

• At least 10 years, excluding diagnosis of breast cancer

Hematopoietic:

• Platelet count at least 100,000/mm^3*

• Absolute neutrophil count at least 1,500/mm^3 (unless determined by the investigator to be normal for ethnic or racial variation) NOTE: *Significant underlying hematologic disorders must be excluded if above upper limit of normal (ULN)

Hepatic:

• Bilirubin no greater than ULN

• SGOT less than 1.5 times ULN

• Alkaline phosphatase less than 2.5 times ULN

• No systemic hepatic disease that would preclude study participation

Renal:

• Creatinine normal

• No systemic renal disease that would preclude study participation

Cardiovascular:

• LVEF at least lower limit of normal by MUGA

• No cardiovascular disease that would preclude study participation

• No angina pectoris requiring treatment

• No cardiomegaly on chest x-ray

• No prior myocardial infarction by clinical diagnosis or by EKG or other test

• No prior congestive heart failure

• No prior cardiomyopathy

• No cardiac arrhythmia requiring medication

• No severe conduction abnormality

• No clinically significant valvular disease

• No poorly controlled hypertension (diastolic greater than 100 mm Hg), unless adequately controlled by medication

• No ventricular hypertrophy on EKG

Other:

• Not pregnant or nursing

• Fertile patients must use effective barrier contraception

• No other prior malignancy within the past 5 years except effectively treated carcinoma in situ of the cervix, melanoma in situ, or basal cell or squamous cell skin cancer

• No psychiatric or addictive disorders that would preclude informed consent

• No sensory or motor neuropathy grade 2 or greater

• No contraindications to corticosteroids

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy for this breast cancer

Chemotherapy:

• No prior chemotherapy for this breast cancer

• No prior anthracycline or taxane therapy for any cancer

Endocrine therapy:

• No prior hormonal therapy for this breast cancer

• No concurrent hormonal therapy (e.g., birth control pills or ovarian hormone replacement therapy)

• No concurrent raloxifene or other selective estrogen-receptor modulators

Radiotherapy:

• No prior radiotherapy for this breast cancer

• No concurrent radiotherapy to internal mammary nodes

• No other concurrent radiotherapy except as specified in study

Surgery:

• See Disease Characteristics

Other:

• No other concurrent investigational agents

Trial Contact Information

Trial Lead Organizations/Sponsors

National Surgical Adjuvant Breast and Bowel Project

Edward H. Romond

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00004067
Information obtained from ClinicalTrials.gov on January 05, 2012

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