RATIONALE: Zoledronate may delay or prevent the formation of bone metastases. It is not yet known whether chemotherapy and/or hormone therapy are more effective with or without zoledronate in preventing cancer recurrence and bone metastases in women who have breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of adjuvant chemotherapy and/or hormone therapy with or without zoledronate in preventing cancer recurrence and bone metastases in women who have stage II or stage III breast cancer.

Condition	Treatment or Intervention	Phase
bone metastases stage II breast cancer stage IIIA breast cancer stage IIIB breast cancer stage IIIC breast cancer	Drug: zoledronate  Procedure: adjuvant therapy  Procedure: bone metastases prevention	Phase III

OBJECTIVES: Primary

• Compare disease-free survival of women with stage II or III breast cancer at high risk of relapse treated with adjuvant chemotherapy and/or hormonal therapy with or without zoledronate.

Secondary

• Compare time to bone metastases, as first recurrence, in patients treated with these regimens.
• Compare time to bone metastases, per se, in patients treated with these regimens.
• Compare time to distant metastases in patients treated with these regimens.
• Compare overall survival in patients treated with these regimens.
• Compare the reduction in skeletal-related events (fractures, spinal cord compression, radiotherapy to the bone, surgery to the bone, and hypercalcemia) before and after the development of bone metastases in patients treated with these regimens.
• Determine the safety and toxicity of zoledronate in patients treated with these regimens.
• Correlate prognostic factors, such as estrogen-receptor and progesterone-receptor status, TNM stage, tumor grade, HER2/neu status, and menopausal status with treatment outcome in patients treated with these regimens.
• Determine more specific prognostic indicators for the development of bone metastases and factors that are able to predict specific benefit from bisphosphonate treatment using proteomics, tissue micro-array, and other modern techniques in these patients.

OUTLINE: This is a randomized, open-label, parallel-group, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive adjuvant chemotherapy and/or hormonal therapy. Patients also receive concurrent zoledronate IV over 15 minutes every 3-4 weeks for 6 doses, every 3 months for 8 doses, and then every 6 months for 5 doses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive adjuvant chemotherapy and/or hormonal therapy alone. Patients are followed annually for 5 years.

PROJECTED ACCRUAL: A total of 3,300 patients (1,650 per treatment arm) will be accrued for this study within 3 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of primary breast cancer, meeting 1 of the following staging criteria:
• Stage II
• Evidence of lymph node involvement
• Must have undergone prior complete primary tumor resection and treatment of the axillary lymph nodes within the past 60 days
• Stage III
• Tumor greater than 5 cm OR features of locally advanced disease (T4)
• Planning to receive neoadjuvant chemotherapy/endocrine therapy OR have undergone prior complete primary tumor resection and treatment of the axillary lymph nodes
• No more than 60 days since prior definitive surgery
• No more than 30 days between initiation of neoadjuvant chemotherapy/endocrine therapy and commencement of study drug in non-operative patients
• No more than 6 months between initiation of neoadjuvant chemotherapy/endocrine therapy and definitive surgery/radiotherapy
• No evidence of recurrent or metastatic disease
• No prior breast cancer
• Suitable candidate for definitive local therapy
• Hormone receptor status:
• Not specified

PATIENT CHARACTERISTICS: Age

• 18 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• Karnofsky 60-100% OR
• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Creatinine no greater than 1.5 times upper limit of normal

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years (including prior contralateral breast cancer) except nonmelanoma skin cancer or curatively treated carcinoma in situ of the cervix
• No history of disease with influence on bone metabolism, including any of the following:
• Paget’s disease of the bone
• Primary hyperparathyroidism
• Osteoporosis requiring treatment or likely to require treatment within the next 6 months
• No other concurrent severe physical or psychological disease that would preclude study compliance
• No known hypersensitivity to bisphosphonates

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics

Surgery

• See Disease Characteristics

Other

• More than 1 year since prior bisphosphonates
• More than 30 days since prior investigational drugs
• No concurrent investigational drugs (i.e., not locally approved for any indication)

United Kingdom, England
      Cancer Research Centre at Weston Park Hospital, Sheffield,  England,  S1O 2SJ,  United Kingdom; Recruiting
      Clatterbridge Centre for Oncology NHS Trust, MERSEYSIDE,  England,  CH63 4JY,  United Kingdom; Recruiting
      Cookridge Hospital at Leeds Teaching Hospital NHS Trust, Leeds,  England,  LS16 6QB,  United Kingdom; Recruiting
      North Tyneside Hospital, North Shields,  England,  NE29 8NH,  United Kingdom; Recruiting
      South Tyneside District Hospital, South Shields,  England,  NE34 0PL,  United Kingdom; Recruiting
      Southend NHS Trust Hospital, Westcliff-On-Sea,  England,  SS0 0RY,  United Kingdom; Recruiting
United Kingdom, Wales
      Glan Clywd District General Hospital, Rhyl, Denbighshire,  Wales,  LL 18 5UJ,  United Kingdom; Recruiting

Study chairs or principal investigators

Robert E. Coleman, MD, FRCP,  Cancer Research Centre at Weston Park Hospital   

Study ID Numbers:  CDR0000335111; SHEFF-AZURE; EU-20315; ISRCTN-79831382; BIG-1-04
Record last reviewed:  October 2003
Record first received:  November 4, 2003
ClinicalTrials.gov Identifier:  NCT00072020
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-05