Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial
Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial
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DOI：
10.1016/s1470-2045(14)70302-x
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发表时间：
2014-08-01
期刊：
影响因子：
51.1
通讯作者：
Marshall, Helen
中科院分区：
文献类型：
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作者：
Coleman, Robert;Cameron, David;Marshall, Helen
背景 双磷酸盐佐剂在早期乳腺癌中的作用尚不确定。因此，我们进行了一项大型随机试验，以研究佐来膦酸辅助使用对早期乳腺癌高危患者无病生存 (DFS) 的影响。 方法 在 AZURE 试验中，这是一项开放标签、国际、多中心、随机、对照、平行组 3 期试验，患有 II 期或 III 期乳腺癌的女性（年龄 >= 18 岁）由中央自动 24 小时随机分配（1:1） 计算机生成的电话最小化系统（平衡涉及腋窝淋巴结的数量、肿瘤分期、雌激素受体状态、全身治疗的类型和时间、绝经状态、他汀类药物的使用和治疗中心）单独接受标准辅助全身治疗（对照组）或每 3-4 周静脉注射 4 mg 唑来膦酸，共六剂，然后每 3 个月一次，共八剂，随后每 6 个月一次，共五剂 剂量，总共 5 年的治疗。主要终点是无病生存期（DFS）。次要终点是侵入性 DFS (IDFS)、总生存期、骨转移时间、远处复发时间以及随机分组中包含的变量的亚组分析。所有患者均已完成研究治疗。这项完全招募的研究的意向治疗最终分析结果在中位随访 84 个月后公布（IQR 66-93）。最终功效分析计划在 940 次 DFS 事件后进行。该试验在 ClinicalTrials.gov 注册，NCT00072020。结果从 2003 年 9 月 4 日至 2006 年 2 月 16 日期间，从七个国家的 174 个中心招募了 3360 名女性。各组之间的 DFS 事件数量没有差异：对照组为 493 例，唑来膦酸组为 473 例（调整后的风险比 [HR] 0.94， 95% CI 0.82-1.06；p = 0.30）。两组的 IDFS（HR 0.93，95% CI 0.82-1.05；p = 0.22）、总生存率（0.93，0.81-1.08；p = 0.37）和远处复发（0.93，0.81-1.07；p = 0.29）基本相同。唑来膦酸可减少骨转移的发生，无论是首次发生（HR 0.78，95% CI 0.63-0.96；p = 0.020）还是随访期间的任何时间（0.81，0.68-0.97；p = 0.022）。唑来膦酸对 DFS 的影响不受雌激素受体状态的影响。然而，唑来膦酸改善了试验入组时绝经后 5 年以上患者的 IDFS（n = 1041；HR 0.77，95% CI 0.63-0.96），但没有改善所有其他（绝经前、围绝经期和未知状态）绝经组（n = 2318；HR 1.03，95% CI） 0.89-1.20）。已报告 33 例疑似颌骨坏死病例，其中 26 例经中心审查确认，全部属于唑来膦酸组（1.7%，95% CI 1.0-2.4）。 解释 这些结果表明，在早期乳腺癌的标准辅助治疗中添加唑来膦酸并没有总体获益。然而，唑来膦酸确实可以减少骨转移的发生，并且对于已绝经的女性来说，可以改善疾病结果。
Background The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer.Methods In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age >= 18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020.Findings 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0.94, 95% CI 0.82-1.06; p = 0.30). IDFS (HR 0.93, 95% CI 0.82-1.05; p = 0.22), overall survival (0.93, 0.81-1.08; p = 0.37), and distant recurrences (0.93, 0.81-1.07; p = 0.29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0.78, 95% CI 0.63-0.96; p = 0.020) and at any time during follow-up (0.81, 0.68-0.97; p = 0.022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n = 1041; HR 0.77, 95% CI 0.63-0.96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n = 2318; HR 1.03, 95% CI 0.89-1.20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1.7%, 95% CI 1.0-2.4).Interpretation These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes.