Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Sheffield, UK.
Deakin University, Geelong, Australia.
Eur J Cancer. 2018 May;94:70-78. doi: 10.1016/j.ejca.2018.02.004. Epub 2018 Mar 20.
The fracture impact of adjuvant bisphosphonates in breast cancer is not defined with most trials reporting changes in bone mineral density as a surrogate. The AZURE trial (ISRCTN79831382) evaluated the impact of adjuvant zoledronic acid (ZOL) on fractures. The AZURE trial is an academic, multi-centre, randomised phase III study evaluating the addition of ZOL 4 mg to standard therapy (neo/adjuvant chemotherapy and/or endocrine therapy) for 5 years (administered by intravenous (iv) infusion every 3-4 weeks for 6 doses, then 3 monthly × 8 and 6 monthly × 5) in patients with stage II/III early breast cancer. Fracture data collected as part of skeletal-related adverse event reporting were analysed after a median of 84.2 months of follow-up and 966 disease-free survival (DFS) events. We assessed number of fractures, time-to-first fracture and the incidence of fractures before and after disease recurrence. Two hundred forty-four patients reported ≥1 fracture, 140 (8.3%) in the control arm (171 fractures) and 104 (6.2%) in the ZOL arm (120 fractures). Of the 291 fractures reported, 207 fractures occurred in the absence of recurrence (control 111, ZOL 96), 80 after recurrence (control 59, ZOL 21). The 5-year fracture rate was reduced from 5.9% (95%CI 4.8, 7.1%; control) to 3.8% (95%CI 2.9, 4.7%) with ZOL. ZOL significantly increased time-to-first fracture (HR 0.69, 95%CI 0.53-0.90; P = 0.0053) but the majority of fracture prevention benefit occurred after a DFS event (HR 0.3; 95%CI 0.17, 0.53; P < 0.001). Fracture benefits from ZOL were similar across menopausal sub-groups. In conclusion, adjuvant ZOL reduced the risk of clinical fractures, the majority of this protection occurred after disease recurrence.
辅助性双膦酸盐对乳腺癌骨折的影响尚未明确，大多数试验均以骨密度变化作为替代指标进行报告。AZURE 试验（ISRCTN79831382）评估了辅助唑来膦酸（zoledronic acid，ZOL）对骨折的影响。该试验是一项由学术机构开展的、多中心、随机 III 期研究，评估了 ZOL 4mg 联合标准治疗（新辅助/辅助化疗和/或内分泌治疗）5 年（静脉输注，每 3-4 周 1 次，共 6 次，然后每 3 个月 1 次×8 次，每 6 个月 1 次×5 次）对 II/III 期早期乳腺癌患者的影响。在中位随访 84.2 个月、发生 966 例无疾病生存（disease-free survival，DFS）事件后，分析了作为骨骼相关不良事件报告一部分而收集的骨折数据。在接受治疗的 547 例患者中，244 例（44.5%）报告发生了≥1 次骨折，其中对照组 140 例（8.3%，171 次骨折），ZOL 组 104 例（6.2%，120 次骨折）。在报告的 291 次骨折中，207 次发生在无复发时（对照组 111 次，ZOL 组 96 次），80 次发生在复发后（对照组 59 次，ZOL 组 21 次）。ZOL 使 5 年骨折率从 5.9%（95%CI 4.8，7.1%；对照组）降至 3.8%（95%CI 2.9，4.7%）。ZOL 显著延长了首次骨折时间（HR 0.69，95%CI 0.53-0.90；P=0.0053），但大多数骨折预防获益发生在 DFS 事件之后（HR 0.3；95%CI 0.17，0.53；P<0.001）。在绝经亚组中，ZOL 对骨折的获益相似。总之，辅助 ZOL 降低了临床骨折风险，大部分获益发生在疾病复发后。
