Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, United Kingdom.
N Engl J Med. 2011 Oct 13;365(15):1396-405. doi: 10.1056/NEJMoa1105195. Epub 2011 Sep 25.
Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients.
In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed.
At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups.
These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).
数据表明，辅助使用双膦酸盐可降低早期乳腺癌患者的复发率和死亡率。我们开展了一项研究，旨在确定在标准辅助治疗的基础上加用唑来膦酸是否可改善此类患者的疾病转归。
在这项开放标签的 3 期研究中，我们将 3360 例患者随机分配，分别接受标准辅助全身治疗联合或不联合唑来膦酸治疗。唑来膦酸每 3-4 周给药 1 次，共 6 次，然后每 3-6 个月给药 1 次，完成 5 年治疗。研究的主要终点为无病生存。第二次中期分析显示，无获益预设边界已被突破。
中位随访 59 个月时，两组间主要终点无显著差异，两组无病生存率分别为 77%（唑来膦酸组调整后的危险比为 0.98；95%置信区间为 0.85 至 1.13；P=0.79）。唑来膦酸组有 377 例患者发生疾病复发或死亡，对照组有 375 例患者发生疾病复发或死亡。唑来膦酸组死亡 243 例，对照组死亡 276 例，两组总生存率分别为 85.4%和 83.1%（调整后的危险比为 0.85；95%置信区间为 0.72 至 1.01；P=0.07）。唑来膦酸组有 17 例经确认发生颌骨坏死（累积发生率为 1.1%；95%置信区间为 0.6 至 1.7；P<0.001），9 例疑似病例；对照组无病例。两组的其他不良事件发生率相似。
这些结果不支持在乳腺癌辅助治疗中常规使用唑来膦酸。（由诺华制药公司和国家癌症研究网络资助；AZURE 当前对照试验编号，ISRCTN79831382。）
