乳腺癌骨转移：唑来膦酸每三个月不亚于每月用药
JAMA Oncology
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骨骼相关事件（SRE）的风险。然而，对其需要长期每月用药存在顾虑。
2017年1月26日，《美国医学会杂志肿瘤学分册》在线发表德克萨斯大学MD安德森癌症中心、密歇根大学、犹他癌症专家协会、西北大学范伯格医学院、戴维斯加利福尼亚大学萨克拉门托综合癌症中心、堪萨斯癌症中心、德克萨斯大学西南医学中心、新泽西诺华制药、英国阿斯利康、纽约万春药业、宾夕法尼亚州密尔顿·史内夫里·赫尔希医学中心的研究报告，调查了既往接受唑来膦酸和/或帕米膦酸二钠标准给药方案的乳腺癌骨转移患者接受唑来膦酸每12周1次是否非劣效于每12周1次。
该意向治疗（全分析组）可评估（每个方案）安全性人群的前瞻随机双盲多中心Ⅲ期研究（OPTIMIZE-2）于2006年3月3日～2013年7月25日，在美国102个临床研究中心入组年龄≥18岁曾经接受10～15个月唑来膦酸和/或帕米膦酸≥9次的乳腺癌骨转移女性患者416例，按1∶1随机分组，每4或12周接受静脉注射唑来膦酸4.0mg共1年。2013年10月7日～2014年3月24日进行数据分析。
主要衡量指标为研究期间SRE≥1次的患者比例（SRE率）。关键次要衡量指标包括入组后至首次SRE的时间和骨骼发病率（SMR）。
结果，每4、12周组分别有200、203例，平均年龄分别为59.2±11.1、58.6±11.2岁，白人分别为173、178例（86.5%、87.7%），两个唑来膦酸治疗组的基础特征相似。
随访1年后，每4、12周组的SRE率分别为22.0%、23.2%（44、47例，比例相差-1.2%，组间SRE率差异单侧97.5%置信区间下限：-9.8%，非劣效性P=0.02）。
治疗组之间入组至首次SRE的时间无统计学显著差异（风险比：1.06，95%置信区间：0.70～1.60，P=0.79）。
每4、12周组的平均SMR为每年0.46±1.06、0.50±1.50（P=0.85）。
每4、12周组的安全性情况相似，不良事件≥1的患者各有189例（95.5%、93.5%）。
因此，唑来膦酸每12周方案与每4周方案相比，患者发生SRE的比例相似，这些结果可能对于目前治疗乳腺癌骨转移患者的临床实践具有实质性影响。
对此，纽约纪念斯隆凯特林癌症中心、威尔康奈尔医学院的专家发表同期评论：骨代谢调节剂的低密度给药方案。
JAMA Oncol. 2017 Jan 26. [Epub ahead of print]
Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial.
Hortobagyi GN, Van Poznak C, Harker WG, Gradishar WJ, Chew H, Dakhil SR, Haley BB, Sauter N, Mohanlal R, Zheng M, Lipton A.
University of Texas, MD Anderson Cancer Center, Houston; University of Michigan, Ann Arbor; Utah Cancer Specialists, Salt Lake City, Utah; Northwestern University Feinberg School of Medicine, Chicago, Illinois; UC Davis Comprehensive Cancer Center, Sacramento, California; Cancer Center of Kansas, Wichita; University of Texas Southwestern Medical Center, Dallas; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey; AstraZeneca, London, England; BeyondSpring Pharmaceuticals, New York, New York; Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania.
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 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 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 4.0 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 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.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00320710
PMID: 28125763
DOI: 10.1001/jamaoncol.2016.6316
JAMA Oncol. 2017 Jan 26. [Epub ahead of print]
Less Intense Dosing Schedule for a Bone-Modifying Agent.
Fornier MN.
Memorial Sloan Kettering Cancer Center; Weill Cornell Medical College, New York, New York.
PMID: 28125761
DOI: 10.1001/jamaoncol.2016.6240