Comparison of Two Schedules of Zoledronic Acid in Treating Patients With Breast Cancer That Has Spread to the Bone

Study Overview
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Brief Summary
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RATIONALE: Zoledronic acid may help decrease the risk of broken bones, bone pain, and other symptoms caused by bone metastases. It may also help patients live more comfortably. PURPOSE: This randomized clinical trial is studying different schedules of zoledronic acid to compare how well they work in treating patients with breast cancer that has spread to the bone.

Detailed Description
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OBJECTIVES: Primary Compare the frequency and timing of serious related events (e.g., fractures, radiotherapy to bone, hypercalcemia of malignancy, orthopedic surgery, and spinal cord compression) in patients with advanced breast cancer metastatic to the bone treated with bone marker-directed schedule vs standard schedule zoledronic acid. Secondary Compare the quality of life of patients treated with these regimens. Compare the clinical burden of skeletal complications in these patients. Compare pain, performance status, and analgesic use (PPA score) in these patients. Compare the incidence of new bone metastases in these patients. Compare overall survival of these patients. Compare bisphosphonate use and expenditure on administration in these patients. OUTLINE: This is an open-label, randomized, controlled, parallel-group, multicenter study. Patients are stratified according to treatment center, gender, type of concurrent systemic therapy at study entry (endocrine therapy [with or without trastuzumab (Herceptin^®)] vs chemotherapy [with or without trastuzumab] vs trastuzumab alone vs chemotherapy and endocrine therapy [with or without trastuzumab] vs no systemic anticancer treatment), prior skeletal-related event (yes vs no), duration of bisphosphonate use for metastatic disease prior to study entry (4-6 months vs 6-12 months), type of metastases present at study entry (bone only vs bone and soft tissue vs bone and visceral metastases vs bone, soft tissue, and visceral metastases). Patients are randomized to 1 of 2 treatment arms. Arm I (standard schedule): Patients receive zoledronic acid IV over 15 minutes once every 3-4 weeks for 24 months. Arm II (bone marker-directed schedule): Patients receive zoledronic acid IV over 15 minutes once every 3-4, 8-9, or 15-16 weeks (based on serum N-telopeptide:creatinine ratio) for 24 months. Quality of life is assessed at baseline and at 3, 6, 9, 12, 18, and 24 months. After completion of study therapy, patients are followed periodically for up to 3 years. PROJECTED ACCRUAL: A total of 1,500 patients will be accrued for this study.

Official Title
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Cost-Effective Use of Bisphosphonates in Metastatic Bone Disease - A Comparison of Bone Marker Directed Zoledronic Acid Therapy to a Standard Schedule

Conditions
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Breast Cancer, Hypercalcemia of Malignancy, Metastatic Cancer, Musculoskeletal Complications, Pain

Intervention / Treatment
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* Drug: zoledronic acid
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary breast cancer Advanced disease Radiographic confirmation of bone metastases (≥ 1 bone scan lesion must be confirmed as metastatic by plain radiographs or CT scan/MRI) Must have received zoledronic acid to treat metastatic bone disease (i.e., ≥ 4 or 5 zoledronic acid treatments prior to study entry for patients receiving 4- or 3-weekly infusions, respectively) for ≥ 4 months prior to study entry Any bisphosphonate to treat metastatic bone disease allowed provided it was not given for more than 12 months prior to study entry No metabolic bone disease (e.g., Paget's disease of bone) Osteoporosis allowed No brain metastases Hormone receptor status not specified PATIENT CHARACTERISTICS: Male or female Menopausal status not specified WHO or ECOG performance status 0-2 Life expectancy ≥ 6 months Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception AST and ALT ≤ 3 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN Creatinine clearance ≥ 30 mL/min No poor venous access No concurrent active dental problems, including infection of the teeth or jawbone (maxilla or mandibular) No prior or current diagnosis of osteonecrosis of the jaw No other cancer within the past 5 years except nonmelanomatous skin cancer, carcinoma in situ of the uterine cervix, or superficial bladder cancer treated with curative intent PRIOR CONCURRENT THERAPY: See Disease Characteristics No other prior bisphosphonate treatment within the past 3 weeks No treatment with systemic bone-seeking radioisotopes (e.g., strontium chloride Sr 89, samarium Sm 153 lexidronam pentasodium) within the past 3 months No wide-field (hemibody) radiotherapy within the past 3 months Recent standard-field, localized radiotherapy allowed No dental or jaw surgery (e.g., extractions, implants) within the past 4 weeks No other concurrent bisphosphonates No concurrent medication with drugs known to affect bone metabolism (e.g., calcitonin or high-dose systemic corticosteroids [> 10 mg prednisolone/day or equivalent]) Systemic or oral corticosteroids allowed for clearly indicated conditions (e.g., chemotherapy-induced emesis, brain metastases, compression syndromes) Concurrent chemotherapy, biological therapy, or endocrine therapy allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: zoledronic acid|nan|
|Procedure: quality-of-life assessment|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fractures |  |  | 
| Radiotherapy to bone either for relief of pain or to treat or prevent pathological fractures or spinal cord compression |  |  | 
| Hypercalcemia of malignancy |  |  | 
| Orthopedic surgery to prevent or treat pathological fractures or spinal cord compression |  |  | 
| Spinal cord compression |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life as measured by QLQ-C30 and the QLQ-BR23 breast-specific module |  |  | 
| Clinical burden of skeletal complications |  |  | 
| Pain, performance status, and analgesic use |  |  | 
| Incidence of new bone metastases |  |  | 
| Overall survival |  |  | 
| Bisphosphonate use and expenditure on administration |  |  | 
| Health care utilization |  |  | 
| Clinical utility of the point of care test for N-telopeptides (NTx) excretion |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypercalcemia of malignancy, musculoskeletal complications, pain, stage IV breast cancer, male breast cancer, recurrent breast cancer, bone metastases