乳腺癌、前列腺癌、多发性骨髓瘤骨转移患者：唑来膦酸每三个月不亚于每月用药

　　2017年1月3日，《美国医学会杂志》正式发表海伦格雷厄姆癌症中心研究所、梅奥医院、弗吉尼亚癌症研究所、弗吉尼亚联邦大学梅西癌症中心、耶鲁大学、雷杰纳荣制药、冈德森医疗集团、美国临床肿瘤学会、罗斯威尔帕克癌症研究所、迪凯特纪念医院、新罕布什尔肿瘤与血液内科医院、美国国家癌症研究所、纽约西奈山伊坎医学院的研究报告，比较了唑来膦酸4、12周方案持续2年用于转移性乳腺癌、前列腺癌、多发性骨髓瘤。

　　该随机非盲研究于2009年5月～2012年4月在美国269家学术型和社区型医疗中心入组1822例骨转移患者（中位年龄65岁，女性980例、占53.8%，转移性乳腺癌855例、转移性前列腺癌689例、多发性骨髓瘤278例），随机分配接受唑来膦酸4或12周方案（各911例）治疗两年。随访截至2014年4月。

　　主要结局衡量指标为SRE（定义：临床骨折、脊髓压迫、骨放疗、骨手术）≥1次的所有患者比例，次要指标包括SRE≥1次的各个疾病患者比例、简要疼痛量表评分、东部肿瘤协作组织（ECOG）体力状态评分、颌骨坏死发生率、肾功能障碍发生率、骨病发生率、根据羧基末端端肽水平评估553例亚组患者的骨转换是否受到抑制。将绝对差7%作为两种方案非劣效阈值。

　　结果，795例入组第2年完成研究确定的治疗方案，随机后2年内，4、12周组SRE≥1次的患者比例分别为29.5%、28.6%（260、253例），风险差为-0.3%（单侧95%置信区间：-4%～∞，非劣效性P＜0.001）。

　　两组之间简要疼痛量表评分、ECOG体力状态评分、颌骨坏死发生率、肾功能障碍发生率、骨病发生率均无显著差异，但是12周方案的骨转换较明显（羧基末端端肽水平较高，提示骨吸收或骨形成速度升高）。

　　因此，对于乳腺癌、前列腺癌、多发性骨髓瘤所致骨转移患者，每12周使用唑来膦酸与每4周的标准给药间隔相比，不会造成2年内骨骼事件风险增加。对于患者，尤其对于外地患者，治疗间隔延长意味着减少往返医院的奔波，同时减少了静脉注射次数和住院天数、降低了医疗费用。较长间隔用药或是一种可接受的治疗选择。

JAMA. 2017 Jan 3;317(1):48-58.

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

Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, Qin R, Go RS, Grubbs SS, O'Connor T, Velasco MR Jr, Weckstein D, O'Mara A, Loprinzi CL, Shapiro CL.

Helen F. Graham Cancer Center & Research Institute, Newark, Delaware; Mayo Clinic, Rochester, Minnesota; Virginia Cancer Institute, Richmond; VCU Massey Cancer Center, Richmond, Virginia; Yale University, New Haven, Connecticut; Regeneron Pharmaceuticals, Basking Ridge, New Jersey; Gundersen Health System, La Crosse, Wisconsin; American Society of Clinical Oncology, Alexandria, Virginia; Roswell Park Cancer Institute, Buffalo, New York; Decatur Memorial Hospital, Decatur, Illinois; New Hampshire Oncology Hematology PA, Hooksett; National Cancer Institute, Bethesda, Maryland; Icahn School of Medicine at Mount Sinai, New York, New York.

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<.001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks.

CONCLUSIONS AND RELEVANCE: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00869206.

PMID: 28030702

DOI: 10.1001/jama.2016.19425