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Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.

ABSTRACT: Importance:Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. Objective:To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Design, Setting, Participants:Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n?=?1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Interventions:Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n?=?911) vs every 12 weeks (n?=?911) for 2 years. Main Outcomes and Measures:The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Results:Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ?]; P?

SUBMITTER: Himelstein AL

PROVIDER: S-EPMC5321662 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.

Himelstein Andrew L AL Foster Jared C JC Khatcheressian James L JL Roberts John D JD Seisler Drew K DK Novotny Paul J PJ Qin Rui R Go Ronald S RS Grubbs Stephen S SS O'Connor Tracey T Velasco Mario R MR Weckstein Douglas D O'Mara Ann A Loprinzi Charles L CL Shapiro Charles L CL

JAMA 20170101 1

<h4>Importance</h4>Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain.<h4>Objective</h4>To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks.<h4>Design, setting, participants</h4>Randomized, open-label clinical trial conducted at 269 academic and community sites in th ...[more]

PMID: 28030702

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Project description:Introduction In patients with metastatic disease involving weight-bearing bones, postoperative radiotherapy (PORT) is commonly administered following surgical stabilization of an impending or confirmed pathologic fracture to reduce the risk of a seeded local recurrence. The goal was to re-evaluate the beneficial effect of PORT in a modern cohort of patients and determine any potential clinical predictors of skeletal-related events (SREs) which were defined as a pathologic fracture or the necessity for radiation or surgery to the affected bone. Methods Consecutive patients undergoing surgical stabilization of metastatic disease to weight-bearing bones of the extremities between 2012 and 2019 were reviewed. Patient, disease, and treatment factors were abstracted. The cumulative incidence of SREs was determined using competing risks methodology; overall survival (OS) was estimated using the Kaplan-Meier method. Results A total of 82 patients were identified, 74% of whom had undergone intramedullary nail fixation and 26% internal fixation or replacement. The femur was the most commonly involved bone (94%). A majority (78%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1-2. Bone-strengthening agents were given to 38% and PORT to 54%. The median PORT dose was 30 Gy in 10 fractions and the median percent coverage of surgical hardware was 100% (range, 25-100). SREs occurred in 10 of 82 patients. There were no differences between no RT and RT groups for the two-year cumulative incidence of SREs (8.2% vs 11.5%, p=0.59) or two-year cumulative incidence of local failure (10.8% vs 4.6%, p=0.53). The only identified predictors of SREs were the use of bone-strengthening agents (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.05-1.06, p=0.06) and malnutrition (HR 3.69, 95% CI 0.91-14.93, p=0.07). For patients treated with PORT, a biologically effective dose or percent coverage of surgical hardware was not associated with SREs. Conclusion In this series, the addition of PORT following surgery for metastatic disease involving weight-bearing bones does not significantly affect the rate of SREs. The use of bone-strengthening agents appears protective, and malnourished patients appear particularly at high risk for future SRE.

Project description:ImportanceZoledronic acid, a potent bisphosphonate, is commonly administered to patients with bone metastases to reduce the risk of skeletal-related events (SREs). However, there have been concerns regarding its long-term monthly administration.ObjectiveTo examine whether zoledronic acid every 12 weeks was noninferior to zoledronic acid every 4 weeks in patients with metastatic breast cancer that involved the bone who had previously received a standard dosing regimen of zoledronic acid and/or pamidronate disodium.Design, setting, and participantsOPTIMIZE-2 was a prospective, randomized, double-blind, multicenter phase 3 trial of intention-to-treat (full analysis set), evaluable (per protocol), and safety populations. Patients were randomized (1:1) to receive 4.0 mg of intravenous zoledronic acid every 4 or every 12 weeks with placebo for interim infusions for 1 year. The study was conducted at 102 clinical trial centers in the United States from March 3, 2006, to July 25, 2013. Data analysis was performed from October 7, 2013, to March 24, 2014. The study randomized 416 women (≥18 years old) with bone metastases from breast cancer who previously received 9 or more doses of zoledronic acid and/or pamidronate during the first 10 to 15 months of therapy.Main outcomes and measuresThe primary end point was the proportion of patients with 1 or more SRE on study (SRE rate). The key secondary end points included time to first SRE and skeletal morbidity rate (SMR).ResultsA total of 416 women were randomized: 200 patients received zoledronic acid every 4 weeks (mean [SD] age, 59.2 [11.1] years; 173 were white [86.5%]), 203 patients received zoledronic acid every 12 weeks (mean [SD] age, 58.6 [11.2] years; 178 were white [87.7%]), and 13 patients received placebo (mean [SD] age, 60.8 [12.2] years; 13 were white [100%]). Baseline characteristics were similar in both zoledronic acid treatment arms. After 1 year of follow-up, SREs occurred in 44 patients (22.0%) in the zoledronic acid every 4 weeks group and 47 patients (23.2%) in the zoledronic acid every 12 weeks group (proportional difference of -1.2%; 1-sided 97.5% CI bound of the difference in SRE rate between arms, -9.8%; noninferiority P = .02). The time to first SRE between treatment groups was not statistically significantly different (hazard ratio [HR], 1.06; 95% CI, 0.70-1.60; P = .79). The mean (SD) SMR was 0.46 (1.06) vs 0.50 (1.50) events per year in the every 4 weeks vs every 12 weeks groups (P = .85). The safety profiles of the every 4 weeks and every 12 weeks groups were comparable, with 189 patients (95.5%) in the every 4 weeks group having at least 1 adverse event compared with 189 (93.5%) in the every 12 weeks group.Conclusions and relevanceThe every 12 weeks regimen of zoledronic acid was noninferior to the every 4 weeks regimen for the proportion of patients experiencing 1 or more SRE. These results may have a substantial influence on current clinical practice for treatment of patients with bone metastasis from breast cancer.Trial registrationclinicaltrials.gov Identifier: NCT00320710.

Dataset Information

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.

Publications

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.

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