Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4Weeks inWomen With Breast Cancer Metastatic to Bone The OPTIMIZE-2 Randomized Clinical Trial
Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4Weeks inWomen With Breast Cancer Metastatic to Bone The OPTIMIZE-2 Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2016.6316
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发表时间：
2017-07-01
期刊：
影响因子：
28.4
通讯作者：
Lipton, Allan
中科院分区：
文献类型：
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作者：
Hortobagyi, Gabriel N.;Van Poznak, Catherine;Lipton, Allan
唑来膦酸是一种有效的双膦酸盐，通常用于骨转移患者，以降低肿瘤相关事件（SRE）的风险。然而，长期每月一次给药的问题一直存在。目的：研究唑来膦酸每12周一次是否非劣效于唑来膦酸每4周一次，用于既往接受过唑来膦酸和/或帕米膦酸二钠标准给药方案的转移性乳腺癌患者。意向治疗（全分析集）、可评价（符合方案）和安全性人群的多中心III期试验。患者随机（1：1）接受4.0mg唑来膦酸静脉注射，每4周或每12周与安慰剂进行1年的中期输注。该研究于2006年3月3日至2013年7月25日在美国的102个临床试验中心进行。从2013年10月7日至2014年3月24日进行数据分析。该研究随机选择了416名乳腺癌骨转移妇女（≥ 18岁），这些妇女在治疗的前10 - 15个月内接受了9剂或更多剂量的唑来膦酸和/或帕米膦酸盐。主要结果和指标主要终点是研究中有1个或更多SRE的患者比例（SRE率）。关键的次要终点包括首次SRE的时间和骨骼发病率（SMR）。结果共有416名女性被随机分组：200名患者每4周接受唑来膦酸治疗（平均[SD]年龄，59.2 [11.1]岁; 173例为白色[86.5%]），203例患者每12周接受唑来膦酸治疗（平均[SD]年龄，58.6 [11.2]岁; 178例为白色[87.7%]），13例患者接受安慰剂（平均[SD]年龄，60.8 [12.2]岁; 13例为白色[100%]）。两个唑来膦酸治疗组的基线特征相似。随访1年后，唑来膦酸每4周一次组中有44例患者（22.0%）发生SRE，唑来膦酸每12周一次组中有47例患者（23.2%）发生SRE（比例差异为-1.2%;组间SRE率差异的单侧97.5%CI界限为-9.8%;非劣效性P = 0.02）。治疗组间至首次SRE的时间无统计学显著差异（风险比[HR]，1.06; 95% CI，0.70-1.60; P = 0.79）。每4周一次组与每12周一次组的平均（SD）SMR为0.46（1.06）vs 0.50（1.50）起事件/年（P = 0.85）。每4周一次组和每12周一次组的安全性特征相当，每4周一次组中有189例患者（95.5%）至少发生1起不良事件，而每12周一次组中有189例患者（93.5%）至少发生1起不良事件。4结论与相关性唑来膦酸每12周给药一次的治疗方案在发生1次或1次以上SRE的患者比例上不劣于每4周给药一次的治疗方案。这些结果可能对目前乳腺癌骨转移患者的治疗临床实践产生重大影响。
IMPORTANCE Zoledronic 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.OBJECTIVE To examine whether zoledronic acid every 12 weeks was noninferior to zoledronic acid every 4weeks 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 PARTICIPANTS OPTIMIZE-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 4.0mg 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 MEASURES The 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).RESULTS A 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 RELEVANCE The 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.