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

Alternate Title

Zoledronate in Preventing Bone Loss in Postmenopausal Women Who Are Receiving Letrozole for Stage I, Stage II, or Stage IIIA Breast Cancer

Basic Trial Information

Objectives

1. Compare the effectiveness of zoledronate vs standard care in reducing bone loss during the first 12 months of study treatment in postmenopausal women with stage I-IIIA breast cancer initiating letrozole after prior treatment with tamoxifen.
2. Compare the effect of immediate vs delayed zoledronate, annually at 2-5 years post-baseline, in reducing bone loss in these patients.

Entry Criteria

Disease Characteristics:

• Diagnosis of breast cancer
  • Stage I, II, or IIIA disease
• Completed ≤ 6 years of adjuvant tamoxifen therapy
• Total baseline lumbar spine or femoral neck bone mineral density T-score below -2.0 standard deviation (e.g., a patient with a T-score of -2.1 in ineligible; a patient with a T-score of -1.9 is eligible)
• No clinical or radiological evidence of recurrent or metastatic disease
• Hormone receptor status:
  • Estrogen receptor- and/or progesterone receptor-positive

Prior/Concurrent Therapy:

Biologic therapy

• Not specified

Chemotherapy

• No concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics
• Prior parathyroid hormone allowed provided it was not administered for > 1 week
• More than 6 months since prior anabolic steroids or growth hormone
• More than 12 months since prior endocrine therapy (including estrogen) except for the following:
  • Tamoxifen
  • Insulin
  • Oral hypoglycemics
  • Thyroid hormone
  • Steroid inhalers
• More than 12 months since prior systemic corticosteroids except short-term corticosteroids to prevent or treat chemotherapy-induced nausea and vomiting or acute respiratory illness
  • Concurrent short-term corticosteroids allowed
• No other concurrent hormonal therapy
• No concurrent parathyroid hormone

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• Prior systemic sodium fluoride allowed provided it was not administered for > 3 months within the past 2 years
• More than 3 weeks since prior oral bisphosphonates
• More than 2 weeks since prior and no concurrent drugs known to affect the skeleton (e.g., calcitonin, mithramycin, or gallium nitrate)
• More than 30 days since prior systemic investigational drugs and/or devices
• More than 7 days since prior topical investigational drugs
• No prior IV bisphosphonates
• No prior aromatase inhibitor therapy
• No concurrent calcitonin, sodium fluoride, or Tibolone
• No other concurrent anticancer therapy
• No other concurrent bisphosphonates
• No other concurrent investigational drugs or devices

Patient Characteristics:

Age

• Postmenopausal

Sex

• Female

Menopausal status

• Postmenopausal, defined by 1 of the following:
  • Over 55 years of age with cessation of menses
  • 55 years of age and under with spontaneous cessation of menses for > 1 year
  • 55 years of age and under with spontaneous cessation of menses for ≤ 1 year, but amenorrheic (e.g., spontaneous or secondary to hysterectomy) with postmenopausal estradiol levels (< 5 ng/dL)
  • Undergone bilateral oophorectomy

Performance status

• ECOG 0-2

Life expectancy

• At least 5 years

Hematopoietic

• WBC ≥ 3,000/mm³
• Platelet count ≥ 100,000/mm³

Hepatic

• Alkaline phosphatase ≤ 3 times upper limit of normal (ULN)
• AST ≤ 3 times ULN

Renal

• Creatinine < 2.0 mg/dL
• No hypercalcemia (i.e., calcium > 1 mg/dL above ULN within the past 6 months)
• No hypocalcemia (i.e., calcium > 0.5 mg/dL below lower limit of normal within the past 6 months)

Other

• No uncontrolled infection
• No uncontrolled diabetes mellitus
• No uncontrolled thyroid dysfunction
• No disease affecting bone metabolism (e.g., hyperparathyroidism, hypercortisolism, Paget's disease, or osteogenesis imperfecta)
• No malabsorption syndrome
• No uncontrolled seizure disorder associated with falls
• No known hypersensitivity to zoledronate or other bisphosphonates, letrozole, calcium, or cholecalciferol (vitamin D)
• No mental illness that would preclude giving informed consent
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No other non-malignant systemic disease
• No clinical or radiologic evidence of existing fracture in the lumbar spine and/or total hip
• No history of fracture with low intensity or not associated with trauma
• No contraindication to spinal dual energy x-ray absorptiometry (DEXA) due to any of the following:
  • History of surgery at the lumbosacral spine, with or without implantable devices
  • Scoliosis with a Cobb angle > 15° at the lumbar spine
  • Immobility, hyperostosis, or sclerotic changes at the lumbar spine
  • Evidence of sufficient sclerotic abdominal aorta that would interfere with DEXA scan
  • Any disease of the spine that would preclude proper acquisition of a lumbar spine DEXA
• Considered reliable

Expected Enrollment

A total of 550 patients (275 per treatment arm) will be accrued for this study within 28 months.

Outcomes

Average intra-patient change in total lumbar spine (L1-L4) bone mineral density (BMD) as measured by dual energy x-ray absorptiometry at baseline and 1 year after completion of study treatment

BMD (lumbar spine) annually for 5 years after completion of study treatment
Incidence of osteoporosis
Loss of bone density
Hip (femoral neck) BMD
Incidence of bone fractures
Toxicity
Time to disease progression
N-telopeptide and bone-specific alkaline phosphatase at 3, 6, and 12 months

Outline

This is a randomized, open-label, multicenter study. Patients are stratified according to duration of prior tamoxifen therapy (≤ 2 years vs > 2 years); time since tamoxifen therapy was discontinued (< 1 vs ≥ 1 year); prior adjuvant chemotherapy (yes vs no); and baseline total lumbar spine or femoral neck bone mineral density (BMD) T-score (> -1 standard deviation [SD] vs between -1 to -2 SD). Patients are randomized to 1 of 2 treatment arms.

• Arm I (immediate therapy): Patients receive oral letrozole once daily. Patients also receive zoledronate IV over 15 minutes once every 6 months.
• Arm II (delayed therapy): Patients receive oral letrozole as in arm I. Patients with radiologic evidence of bone loss after 1 year of letrozole therapy receive zoledronate as in arm I.

In both arms, treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

Hines SL, Mincey B, Dentchev T, et al.: Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC. Breast Cancer Res Treat 117 (3): 603-9, 2009.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Stephanie Hines, MD, Protocol chair		Ph: 507-284-4798
Edith Perez, MD, Protocol co-chair		Ph: 507-284-1159 Email: perez.edith@mayo.edu

Registry Information
Official Title		A Randomized, Controlled, Open-Label Trial of Empiric Prophylactic vs. Delayed Use of Zoledronic Acid for Prevention of Bone Loss in Postmenopausal Women with Breast Cancer Initiating Therapy with Letrozole After Tamoxifen
Trial Start Date		2005-01-28
Registered in ClinicalTrials.gov		NCT00107263
Date Submitted to PDQ		2004-12-30
Information Last Verified		2006-03-28
NCI Grant/Contract Number		CA25224

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