Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University of Vienna, A-1090 Vienna, Austria.
Lancet Oncol. 2011 Jul;12(7):631-41. doi: 10.1016/S1470-2045(11)70122-X. Epub 2011 Jun 5.
Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid.
ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3.6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing.
At a median follow-up of 62 months (range 0-114.4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0.68, 95% CI 0.51-0.91; p=0.009), although the difference was not significant in the tamoxifen (HR 0.67, 95% CI 0.44-1.03; p=0.067) and anastrozole arms (HR 0.68, 95% CI 0.45-1.02; p=0.061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0.67, 95% CI 0.41-1.07; p=0.09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1.08, 95% CI 0.81-1.44; p=0.591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1.75, 95% CI 1.08-2.83; p=0.02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121).
Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer.
AstraZeneca; Novartis.
奥地利乳腺癌和结直肠癌研究组试验-12（ABCSG-12）在 48 个月的随访中显示，佐来膦酸联合辅助内分泌治疗可显著改善无病生存期。我们现在评估了长期临床疗效，包括接受阿那曲唑或他莫昔芬联合或不联合唑来膦酸治疗的患者的无病生存期和疾病结局。
ABCSG-12 是一项随机、对照、开放标签、两因素、两水平、多中心试验，纳入了 1803 例接受戈舍瑞林（每 28 天 3.6mg）治疗的绝经前内分泌受体阳性早期（I-II 期）乳腺癌患者，比较了阿那曲唑（每天 1mg）或他莫昔芬（每天 20mg）联合或不联合唑来膦酸（每 6 个月 4mg）的疗效和安全性，治疗时间为 3 年。随机分组（1:1:1:1 比例）采用计算机化和 Pocock 和 Simon 最小化方法，根据 8 个预后变量（年龄、新辅助化疗、病理肿瘤分期；淋巴结受累、手术或局部区域治疗类型、完全腋窝清扫术、术中放疗和地理区域）平衡四个治疗组。治疗分配未设盲。主要终点是无病生存期（定义为疾病复发或死亡），并采用意向治疗进行分析。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00295646；随访仍在进行中。
中位随访时间为 62 个月（范围 0-114.4 个月），在治疗完成后 2 年多的时间里，报告了 186 例无病生存事件（53 例发生在单独使用他莫昔芬的 450 例患者中，57 例发生在单独使用阿那曲唑的 453 例患者中，36 例发生在他莫昔芬联合唑来膦酸的 450 例患者中，40 例发生在阿那曲唑联合唑来膦酸的 450 例患者中）。唑来膦酸降低了无病生存事件的风险（总体 HR 0.68，95%CI 0.51-0.91；p=0.009），尽管在他莫昔芬（HR 0.67，95%CI 0.44-1.03；p=0.067）和阿那曲唑组（HR 0.68，95%CI 0.45-1.02；p=0.061）中差异无统计学意义。唑来膦酸并没有显著影响死亡风险（使用唑来膦酸 30 例死亡，未使用 43 例死亡；HR 0.67，95%CI 0.41-1.07；p=0.09）。单独使用他莫昔芬与单独使用阿那曲唑的患者无病生存期无差异（HR 1.08，95%CI 0.81-1.44；p=0.591），但阿那曲唑组的总生存期比他莫昔芬组差（46 例死亡 vs 27 例死亡；HR 1.75，95%CI 1.08-2.83；p=0.02）。治疗总体耐受性良好，无肾功能衰竭或颌骨坏死的报告。报告有骨痛的患者为 601 例（33%；使用唑来膦酸的 349 例 vs 未用药物的 252 例），疲劳的患者为 361 例（20%；使用唑来膦酸的 192 例 vs 未用药物的 169 例），头痛的患者为 280 例（16%；使用唑来膦酸的 147 例 vs 未用药物的 133 例），关节痛的患者为 266 例（15%；使用唑来膦酸的 145 例 vs 未用药物的 121 例）。
唑来膦酸的加入改善了接受阿那曲唑或他莫昔芬治疗的患者的无病生存期。接受阿那曲唑和他莫昔芬治疗的患者无病生存期总体无差异，但单独使用阿那曲唑的患者总生存期较差。这些数据显示唑来膦酸具有持续获益，并支持在绝经前早期乳腺癌患者中添加辅助内分泌治疗。
阿斯利康；诺华。
