Combination Chemotherapy in Treating Women With Stage I, Stage II, or Stage IIIA (cT1-3, N0-1, M0) Breast Cancer and Positive Axillary Lymph Nodes

National Surgical Adjuvant Breast and Bowel Project Foundation (NSABP)

Status and phase: Completed; Phase 3

Conditions: Breast Cancer

Treatments: Drug: cyclophosphamide; Drug: docetaxel; Drug: doxorubicin

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00003782

CDR0000066914

NSABP B-30

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving combination chemotherapy after surgery may kill any tumor cells remaining following surgery. It is not yet known which regimen of combination chemotherapy is more effective in treating breast cancer with positive axillary lymph nodes.

PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy in treating women who have undergone surgery for stage I, stage II, or stage IIIA breast cancer with positive axillary lymph nodes.

Full description

OBJECTIVES:

• Compare the efficacy of adjuvant doxorubicin, cyclophosphamide, and docetaxel given concurrently vs adjuvant doxorubicin and cyclophosphamide followed by docetaxel, in terms of overall survival and disease-free survival, of women with breast cancer and positive axillary lymph nodes.
• Compare the efficacy of adjuvant doxorubicin and docetaxel vs regimens containing cyclophosphamide in these patients.
• Compare the toxic effects of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens. (Quality of life substudy closed to accrual as of 7/20/01.)
• Compare the differences in amenorrhea in premenopausal women in each treatment arm and its relationship to symptoms, quality of life (quality of life substudy closed to accrual as of 7/20/01), disease-free survival, and overall survival.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, number of positive nodes (1-3 vs 4-9 vs at least 10), sequential tamoxifen or anastrozole administration (yes vs no), and type of prior surgery and radiotherapy plan (mastectomy with no local or regional radiotherapy vs mastectomy with local and/or regional radiotherapy vs lumpectomy with local radiotherapy vs lumpectomy with local and regional radiotherapy). Patients are randomized to one of three treatment arms.

• Arm 1: Patients receive doxorubicin IV over 15 minutes and cyclophosphamide IV over 30 minutes every 21 days for 4 courses. Three weeks after the last dose of this combination, patients receive docetaxel IV over 1 hour every 21 days for 4 courses.
• Arm 2: Patients receive doxorubicin IV over 15 minutes and docetaxel IV over 1 hour every 21 days for 4 courses.
• Arm 3: Patients receive doxorubicin IV over 15 minutes, cyclophosphamide IV over 30 minutes, and docetaxel IV over 1 hour every 21 days for 4 courses.

Patients in all arms who are estrogen receptor-positive and/or progesterone receptor-positive receive oral tamoxifen daily for 5 years beginning within 3-12 weeks of completion of chemotherapy. Patients who are postmenopausal may receive alternative hormonal therapy at the discretion of the treating physician.

Some patients may receive postmastectomy radiotherapy on SWOG-S9927 or NCIC-MA.20 after recovery from chemotherapy.

Quality of life and menstrual history are assessed before randomization, on day 1 of course 4, and at 6, 12, 18, and 24 months. (Quality of life substudy closed to accrual as of 7/20/01.)

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

PROJECTED ACCRUAL: A total of 5,300 patients will be accrued for this study within 4-5 years.

Enrollment: 5,351 patients

Sex: Female

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive adenocarcinoma of the breast

  • Confined to the breast and ipsilateral axilla on clinical exam

    • Stage I, II, or IIIA (cT1-3, N0-1, M0)

• At least one axillary lymph node with evidence of tumor on histologic exam

  • Sentinel node biopsy allowed if followed by axillary dissection
  • No suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or infraclavicular nodes, unless proven on biopsy to not be involved with tumor

• No bilateral malignancy or mass in the opposite breast, unless mass is histologically proven to be benign

• Must have undergone either a prior total mastectomy and axillary dissection (modified radical mastectomy) OR

• Prior lumpectomy and axillary dissection

  • Patients must receive radiotherapy after randomization (not before) AND after chemotherapy

  • Margins must be clear

  • No ipsilateral lymph nodes that are fixed to one another or to other structures (N2 disease) and/or any positive nonaxillary lymph nodes (intramammary nodes are considered axillary nodes)

  • No histologically evident invasive tumor or ductal carcinoma in situ

  • No diffuse tumors by mammography that would not be surgically amenable to lumpectomy

  • No other dominant mass in the ipsilateral breast remnant unless one of the following is true:

    • Histologically benign
    • Surgically removed with clear margins if malignant

• No ulceration, erythema, infiltration of the skin or underlying chest wall (complete fixation), peau d'orange, or skin edema of any magnitude

  • Tethering or dimpling of the skin or nipple inversion allowed

• No metastatic disease

  • Skeletal pain allowed if bone scan negative for metastases

• Hormone receptor status:

  • Estrogen and progesterone status determined

PATIENT CHARACTERISTICS:

Age:

• greater than or equal to 18 years

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Not specified

Life expectancy:

• At least 10 years, excluding diagnosis of cancer

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3 (may be less, if in the opinion of the investigator, this represents an ethnic or racial variation)
• Platelet count at least 100,000/mm^3* NOTE: *If platelet count is above the upper limit of normal (ULN), significant underlying hematologic disorders must be excluded

Hepatic:

• Bilirubin no greater than ULN
• Alkaline phosphatase less than 2.5 times ULN*
• SGOT less than 1.5 times ULN*
• No nonmalignant systemic hepatic disease that would preclude study participation NOTE: *Alkaline phosphatase and SGOT cannot both be greater than ULN

Renal:

• Creatinine no greater than normal
• No nonmalignant systemic renal disease that would preclude study participation

Cardiovascular:

• No nonmalignant systemic cardiovascular disease that would preclude study participation

• LVEF at least lower limit of normal (LLN) by MUGA or echocardiogram

• No active cardiac disease that would preclude use of doxorubicin or docetaxel, including the following:

  • Any prior myocardial infarction
  • Angina pectoris requiring anti-anginal medication
  • History of congestive heart failure
  • Cardiac arrhythmia requiring medication
  • Severe conduction abnormality
  • Valvular disease with documented cardiac function compromise
  • Cardiomegaly on chest x-ray or ventricular hypertrophy on EKG, unless LVEF at least LLN
  • Poorly controlled hypertension (diastolic greater than 100 mm/Hg)
  • Hypertension well controlled by medication allowed

Other:

• No grade 2 or greater peripheral neuropathy

• No other prior malignancy within the past 5 years except:

  • Effectively treated squamous cell or basal cell skin cancer
  • Surgically treated carcinoma in situ of the cervix
  • Segmentally resected lobular carcinoma in situ of the ipsilateral or contralateral breast

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception

• No nonmalignant systemic disease that would preclude study participation

• No diabetes with morning fasting blood glucose of 200 mg/dL or greater

• No psychiatric or addictive disorders that would preclude informed consent

• No contraindication to corticosteroids that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior immunotherapy for breast cancer

Chemotherapy:

• No prior chemotherapy for breast cancer
• No prior anthracyclines or taxanes
• No other concurrent investigational chemotherapy

Endocrine therapy:

• No prior hormonal therapy for breast cancer
• No concurrent hormonal birth control methods or other hormonal therapy
• No concurrent raloxifene, including for osteoporosis
• Concurrent low-dose topical estrogen in the form of conjugated estrogen ring or conjugated estrogen vaginal cream (dose no more than 0.3 mg or 1/8 of an applicator applied vaginally 3 times a week) allowed

Radiotherapy:

• See Disease Characteristics
• No prior radiotherapy for this malignancy

Surgery:

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

Other:

• No prior systemic therapy for this malignancy
• No concurrent medications that alter cardiac conduction (e.g., digitalis, beta blockers, or calcium-channel blockers) for cardiac arrhythmia, angina, or congestive heart failure (allowed if administered for other reasons [e.g., hypertension])
• Concurrent bisphosphonates allowed

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

5,351 participants in 3 patient groups

Arm 1: Doxorubicin + Cyclophosphamide, then Docetaxel

Experimental group

Description:

Doxorubicin + Cyclophosphamide, then Docetaxel

Treatment:

Drug: doxorubicin

Drug: cyclophosphamide

Drug: docetaxel

Arm 2: Doxorubicin + Docetaxel

Experimental group

Description:

Doxorubicin + Docetaxel

Treatment:

Drug: doxorubicin

Drug: docetaxel

Arm 3: Doxorubicin + Docetaxel + Cyclophosphamide

Experimental group

Description:

Doxorubicin + Docetaxel + Cyclophosphamide

Treatment:

Drug: doxorubicin

Drug: cyclophosphamide

Drug: docetaxel