Safety/Efficacy of Letrozole Monotherapy or in Combination With Zoledronic Acid as Extended Adjuvant Treatment of Postmenopausal Patients With Primary Breast Cancer

Study Overview
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Brief Summary
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This was a prospective, randomized, open-label, two arm phase III trial designed to evaluate the efficacy and safety of zoledronic acid in preventing bone loss in postmenopausal women with operable breast cancer who had received 4 to 6 years of adjuvant tamoxifen therapy after resection of the tumor. Patients were treated with letrozole 2.5 mg orally per day or letrozole 2.5 mg orally per day in combination with zoledronic acid 4 mg/6 months as an infusion. This trial did not recruit patients in the United States.

Official Title
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An Open Phase III Trial With Letrozole Alone or in Combination With Zoledronic Acid as Extended Adjuvant Treatment of Postmenopausal Patients With Primary Breast Cancer

Conditions
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Osteoporosis, Postmenopausal

Intervention / Treatment
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* Drug: Letrozole
* Drug: Zoledronic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Compliant postmenopausal women with primary operable breast cancer after 4 to 6 years of therapy with tamoxifen (end of tamoxifen therapy within last 6 months) Performance status 0-2 (Eastern Cooperative Oncology Group) Patients without severe osteoporosis at study entry No evidence of relapse at the time of randomization Adequate function of bone marrow, kidney, and liver Exclusion Criteria: Estrogen- and progesterone-receptor status negative or unknown Completion of adjuvant tamoxifen therapy more than 6 months prior to study start Inflammatory breast cancer Current/active dental problems including infection of the teeth or jawbone, dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw, of exposed bone in the mouth, or of slow healing after dental procedures. Recent (within 6 weeks) or planned dental or jaw surgery History of diseases with influence on bone metabolism such as Paget's disease and primary overactive parathyroid Prior or concomitant therapies: chemotherapy within the last 12 months, intravenous or oral bisphosphonates, systemic corticosteroids, anabolic steroids or growth hormones, Tibolone, parathyroid hormone, systemic sodium fluoride or any drugs known to affect the skeleton (such as calcitonin, mithramycin, or gallium nitrate) Patients with previous or concomitant cancers (not breast cancer) within the past 5 years EXCEPT adequately treated basal or squamous cell skin cancers or in situ cancer of the cervix. Patients with previous other cancer(s) must have been disease-free for at least 5 years. Patients currently receiving oral bisphosphonates must discontinue these at least 3 weeks prior to study start. Additional protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole<br>Letrozole orally 2.5 mg/day for 3 years | Drug: Letrozole<br>* 2.5 mg/day for 3 years<br>|
| Experimental: Letrozole + Zoledronic Acid<br>Letrozole orally 2.5mg/day for 3 years; Zoledronic acid 4mg every 6 months by infusion | Drug: Letrozole<br>* 2.5 mg/day for 3 years<br>Drug: Zoledronic acid<br>* 4 mg every 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bone Mineral Density (BMD) From Baseline to Month 36 | Change in bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) in lumbar spine (L1-L4). Change calculated by (Month 36 BMD-Baseline BMD)/Baseline BMD*100. | at 36 months as compared to baseline | 
| Percent Change in Bone Mineral Density (BMD) From Baseline to Month 36 | Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA) scan. ANCOVA model was used in the analysis where: Variable = Baseline, Center, Treatment BMD = (Month 36 BMD-Baseline BMD)/Baseline BMD*100. | Baseline, Month 36 | 
| Change in T-score From Baseline to Month 36 | BMD measured by DXA (dual energy x-ray absorptiometry) at lumbar spine, L1-L4. The T-Score is a comparison of a patient's BMD to that of a healthy 30 year of the same sex and ethnicity. The criteria of the World Health Organization are Normal is a T-Score of 1.0 or higher. Osteopenia is defined as between - 1.0 and -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and half standard deviations below the mean of a 30 year old man/woman. | Baseline and Month 36 | 
| Change in Z Score From Baseline to Month 36 | Bone Mineral Density is measured by dual energy x-ray absorptiometry (DXA). The Z-Score is the number of standard deviations a patient's BMD differs from the average BMD of their age, sex and ethnicity. A Z-score of less than minus -1.5 raises concern of factors other than aging as contributing to osteoporosis. | Baseline, month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bone Mineral Density From Baseline to 12 Months | Change in bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) in lumbar spine (L1-L4). Change calculated by (Month 36 BMD-Baseline BMD)/Baseline BMD*100. | Baseline, 12 months | 
| Number of Participants With Any Kind of Fractures, by Visit. | Number of participants with fractures of any type since the last visit | Baseline, Month 6, 12, 18, 24 , 30 and 36 | 
| Median Disease Free Survival (DFS) | Disease Free Survival is measured in days and represents the number of days participants were progression free. Progression free survival is defined as the time from randomization to the date of the first documented progression or recurrence of disease or death from any cause. Median disease free survival is the time when 50% of the patients had a recurrence. | 36 months | 
| Change in T-Score From Baseline to Month 12 | BMD measured by DXA (dual energy x-ray absorptiometry) at lumbar spine, L1-L4. The T-Score is a comparison of a patient's BMD to that of a healthy 30 year of the same sex and ethnicity. The criteria of the World Health Organization are Normal is a T-Score of 1.0 or higher. Osteopenia is defined as between - 1.0 and -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and half standard deviations below the mean of a 30 year old man/woman. | Baseline, Month 12 | 
| Change in Z-Score From Baseline to Month 12 | (DXA). The Z-Score is the number of standard deviations a patient's BMD differs from the average BMD of their age, sex and ethnicity. A Z-score of less than minus -1.5 raises concern of factors other than aging as contributing to osteoporosis | Baseline, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, postmenopausal, bone mineral density, Zoledronic acid, Letrozole, extended adjuvant treatment., Postmenopausal women with primary hormone receptor positive breast cancer