Osteoncology and Rare Tumors Center, IRCCS Scientific Institute of Romagna for the Study and Treatment of Cancer (IRST IRCCS), Meldola, Italy.
Lancet Oncol. 2013 Jun;14(7):663-70. doi: 10.1016/S1470-2045(13)70174-8. Epub 2013 May 16.
Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid.
We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12-15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0.19. The trial is registered with EudraCT, number 2005-004942-15.
We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0.26 (95% CI 0.15-0.37) in the 12-week group versus 0.22 (0.14-0.29) in the 4-week group. The between-group difference was 0.04 and the upper limit of one-tailed 97.5% CI was 0.17, which is lower than the non-inferiority margin. The most common grade 3-4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12.2% vs 0.0%; p=0.011).
Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice.
Novartis Farma.
唑来膦酸可降低乳腺癌患者的骨骼相关事件，但人们对每月持续给药的长期影响表示担忧。我们评估了在先前接受唑来膦酸每月治疗的患者中减少唑来膦酸给药频率的疗效和安全性。
我们在意大利的 62 个中心进行了这项非劣效性、3 期试验。我们招募了患有 1 或多个骨转移且已完成 12-15 个月唑来膦酸每月治疗的乳腺癌患者。患者按照中心（大小 4 至 8）进行随机分组，按 1:1 比例随机分配至唑来膦酸 4 mg 每 12 周一次或每 4 周一次，并至少随访 1 年。患者和研究者均未对治疗分配进行设盲。主要结局是在意向治疗人群中骨骼发病率（每位患者每年的骨骼相关事件）。我们使用了 0.19 的非劣效性边界。该试验在 EudraCT 注册，编号为 2005-004942-15。
我们筛选了 430 名患者，纳入了 425 名患者，其中 209 名被分配至 12 周组，216 名被分配至 4 周组。12 周组的骨骼发病率为 0.26（95%CI 0.15-0.37），4 周组为 0.22（0.14-0.29）。两组间的差异为 0.04，单侧 97.5%CI 的上限为 0.17，低于非劣效性边界。最常见的 3-4 级不良事件为骨痛（12 周组 56 例[27%]，4 周组 65 例[30%]）、恶心（24 例[11%]，33 例[15%]）和乏力（18 例[9%]，33 例[15%]）。12 周组有 1 例（<1%）患者发生肾脏不良事件，4 周组有 2 例（1%）。4 周组有 1 例（<1%）患者发生 1 级急性肾衰竭。12 周组有 4 例（<1%）患者发生颌骨坏死，4 周组有 3 例。无治疗相关死亡报告。12 个月后，12 周组的 N 端肽浓度较基线变化更大（12.2% vs 0.0%；p=0.011）。
我们的结果表明，有可能将唑来膦酸的给药频率减少至每 12 周一次，以减少第二年的暴露量，同时保持其治疗效果。然而，在改变当前实践之前，应该进一步研究对 N 端肽的影响。
诺华制药。
