Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Four versus Six Cycles of Cyclophosphamide/Doxorubicin or Paclitaxel in Adjuvant Breast Cancer

Basic Trial Information

Special Category: CTSU trial, NCI Web site featured trial

Objectives

Primary

1. Compare the disease-free survival of women with operable breast cancer and 0-3 positive axillary lymph nodes treated with two different schedules (4 vs 6 courses) of adjuvant cyclophosphamide and doxorubicin vs paclitaxel. (Arms II and IV closed to accrual as of 1/30/2008)
2. Compare the disease-free survival of patients treated with these regimens.

Secondary

1. Compare overall survival, local control, and time to distant metastasis in patients treated with these regimens.
2. Compare the toxic effects of these regimens in these patients.
3. Compare the effect of these regimens on the induction of menopause in premenopausal patients.
4. Determine the discrepancy of myelosuppression in patients with MDR1 haplotypes on the CA treatment arm.
5. Compare the disease-free survival of patients with MDR1 haplotypes treated with these regimens.
6. Correlate CYP3A5, CYP2C8, and CYP2B6 polymorphisms with disease-free survival and toxicity in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Histologically confirmed invasive carcinoma of the breast with 0-3 positive axillary lymph nodes
  • Meets 1 of the following criteria for node-negative disease:
    • Negative sentinel lymph node biopsy
    • At least 6 negative axillary lymph nodes removed and determined to be negative by axillary dissection
  • Meets 1 of the following criteria for node-positive disease (1-3 positive axillary lymph nodes):
    • At least 1 positive lymph node by sentinel lymph node biopsy AND at least 6 axillary lymph nodes removed by axillary dissection; of all the nodes removed from both the sentinel lymph node biopsy and the axillary dissection, 1-3 must be positive
    • At least 6 lymph nodes removed by axillary dissection; 1-3 nodes from the axillary dissection must be positive

• "High-risk" disease that warrants chemotherapy (ultimately determined by the treating physician)
• Modified radical mastectomy or lumpectomy within the past 84 days required
  • Negative tumor margins for invasive cancer and ductal carcinoma in situ (DCIS)
  • Lobular carcinoma in situ (LCIS) at the margin allowed
• Multicentric disease allowed provided margins and axillary nodes are negative after resection
• Bilateral synchronous disease allowed
• Invasive cancer on one side and DCIS or LCIS on the contralateral side is allowed provided all other eligibility criteria are met
• No locally advanced, inflammatory, or metastatic breast cancer
• No dermal lymphatics involvement, even if there are no clinical signs of inflammatory cancer
• HER2/neu positive, negative, or unknown
• Hormone receptor status:
  • Any estrogen and/or progesterone receptor status

Prior/Concurrent Therapy:

Biologic therapy:

• No prior trastuzumab (Herceptin^®) for this malignancy

Chemotherapy:

• See Disease Characteristics
• No prior chemotherapy for this malignancy
• No other concurrent chemotherapy

Endocrine therapy:

• No prior hormonal therapy for this malignancy except tamoxifen given for up to 4 weeks
• Prior tamoxifen or other selective estrogen receptor modulators (SERMs) for prevention or other indications (e.g., osteoporosis) allowed
• No concurrent exogenous hormonal therapy (including oral contraceptives, postmenopausal hormone replacement therapy, or raloxifene) except:
  • Steroids for adrenal failure
  • Hormonal agents for nondisease-related conditions (e.g., insulin for diabetes or synthroid for hypothyroidism)
  • Intermittent dexamethasone as an antiemetic and premedication for paclitaxel
• No concurrent tamoxifen or other SERMs

Surgery:

• See Disease Characteristics

Other:

• No concurrent dexrazoxane
• No concurrent raloxifene
• Concurrent bisphosphonates for osteoporosis allowed
• Concurrent trastuzumab (Herceptin^®) allowed for patients with HER2-positive disease
• Concurrent enrollment on adjuvant bisphosphonate studies allowed
• Concurrent enrollment on adjuvant hormonal studies allowed provided hormonal therapy does not commence until completion of study chemotherapy

Patient Characteristics:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Premenopausal or postmenopausal

Performance status:

• CTC 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,000/mm³
• Platelet count at least 100,000/mm³

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal

Renal:

• Creatinine no greater than 2.0 mg/dL

Cardiovascular:

• No active congestive heart failure
• No myocardial infarction within the past 6 months

Other:

• Not pregnant or nursing
• Fertile patients must use effective nonhormonal contraception during and for at least 2 months after study participation
• No other malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

Expected Enrollment

A total of 4,646 patients will be accrued for this study within 29 months.

Outcomes

Disease-free survival

Overall survival
Toxicity
Myelosuppression in patients with MDR1 haplotypes
CYP3A5, CYP2C8, and CYP2B6 polymorphisms

Outline

This is a randomized study. Patients are stratified according to menopausal status (premenopausal vs postmenopausal), estrogen receptor (ER)/progesterone receptor (PR) status (ER and/or PR positive or unknown vs ER and PR negative), and HER2/neu status (negative vs unknown vs positive [by immunohistochemistry 3+ staining or gene amplification by fluorescence in situ hybridization]). Patients are randomized to 1 of 4 treatment arms (arms II and IV closed to accrual as of 1/30/2008).

• Arm I: Patients receive doxorubicin IV and cyclophosphamide IV on day 1. Treatment repeats every 14 days for 4 courses.
• Arm II (closed to accrual as of 1/30/2008): Patients receive doxorubicin and cyclophosphamide as in arm I. Treatment repeats every 14 days for 6 courses.
• Arm III: Patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 14 days for 4 courses.
• Arm IV (closed to accrual as of 1/30/2008): Patients receive paclitaxel as in arm III. Treatment repeats every 14 days for 6 courses.

Treatment in all arms continues in the absence of disease progression or unacceptable toxicity.

Lumpectomy patients must then undergo radiotherapy. Mastectomy patients undergo radiotherapy at the discretion of the treating physician.

Patients are followed every 6 months for 2 years and then annually for 15 years.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Lawrence Shulman, MD, Protocol chair		Ph: 617-632-2277; 866-790-4500 Email: Lawrence_Shulman@dfci.harvard.edu

Related Information

Featured trial article

Registry Information
Official Title		Cyclophosphamide And Doxorubicin (CA) (4 VS 6 Cycles) Versus Paclitaxel (4 VS 6 Cycles) As Adjuvant Therapy For Breast Cancer in Women With 0-3 Positive Axillary Lymph Nodes:A 2X2 Factorial Phase III Randomized Study
Trial Start Date		2002-05-15
Trial Completion Date		2004-10-02 (estimated)
Registered in ClinicalTrials.gov		NCT00041119
Date Submitted to PDQ		2002-05-10
Information Last Verified		2010-08-02
NCI Grant/Contract Number		CA31946

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