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

Study Overview
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Brief Summary
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RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. Zoledronate may prevent bone loss in patients who are receiving letrozole. It is not yet known which schedule of zoledronate is more effective in preventing bone loss in patients with breast cancer. PURPOSE: This randomized phase III trial is studying two different schedules of zoledronate to compare how well they work in preventing bone loss in postmenopausal women who are receiving letrozole for stage I, stage II, or stage IIIA breast cancer.

Detailed Description
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OBJECTIVES: 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. Compare the effect of immediate vs delayed zoledronate, annually at 2-5 years post-baseline, in reducing bone loss in these patients. 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. PROJECTED ACCRUAL: A total of 550 patients (275 per treatment arm) will be accrued for this study within 28 months.

Official Title
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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

Conditions
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Breast Cancer, Osteoporosis

Intervention / Treatment
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* Drug: letrozole
* Drug: zoledronic acid


Participation Criteria
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Eligibility Criteria
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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 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/mm^3 Platelet count ≥ 100,000/mm^3 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: letrozole + zoledronate<br>Patients receive oral letrozole once daily. Patients also receive zoledronate IV over 15 minutes once every 6 months. Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity. | Drug: letrozole<br> <br> Drug: zoledronic acid<br> <br> |
| Experimental: Arm II: letrozole + zoledronate<br>Patients receive oral letrozole once daily. Patients with radiologic evidence of bone loss after 1 year of letrozole therapy receive zoledronate as in arm I. Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity. | Drug: letrozole<br> <br> Drug: zoledronic acid<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | at 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMD (lumbar spine) annually for 5 years after completion of study treatment |  | Up to 5 years | 
| Incidence of osteoporosis |  | Up to 5 years | 
| Loss of bone density |  | Up to 5 years | 
| Incidence of bone fractures |  | Up to 5 years | 
| Time to disease progression |  | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteoporosis, stage I breast cancer, stage II breast cancer, stage IIIA breast cancer