Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial
复制标题
DOI：
10.1016/s1470-2045(11)70122-x
复制
发表时间：
2011-07-01
期刊：
影响因子：
51.1
通讯作者：
Greil, Richard
中科院分区：
文献类型：
--
作者：
Gnant, Michael;Mlineritsch, Brigitte;Greil, Richard
奥地利乳腺癌和结直肠癌研究组试验-12 (ABCSG-12) 48个月随访分析显示，辅助内分泌治疗中添加唑来膦酸可显著提高无病生存率。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治疗合并或不合并唑来膦酸的患者的无病生存期和疾病结局。方法：abg -12是一项随机、对照、开放标签、二因子、多中心试验，纳入1803名绝经前内分泌受体阳性的早期（I-II期）乳腺癌患者，接受戈舍雷林（3.6 mg / 28天）治疗，比较阿那曲唑（1mg /天）或他莫昔芬（20mg /天）与唑来膦酸（4mg / 6个月）联合治疗3年的疗效和安全性。随机化（1:1:1:1比例）是计算机化的，基于Pocock和Simon最小化方法，在8个预后变量（年龄、新辅助化疗、病理肿瘤分期、淋巴结累及、手术类型或局部治疗、完全腋窝清扫、术中放射治疗和地理区域）上平衡4个治疗组。治疗分配没有被掩盖。主要终点是无病生存期（定义为疾病复发或死亡），分析的目的是治疗。该试验已在ClinicalTrials.gov注册，编号NCT00295646；后续工作正在进行中。在中位随访62个月（范围0-114.4个月），治疗结束后超过2年，报告了186例无病生存事件（单独他莫昔芬组450例53例，单独阿那曲唑组453例57例，他莫昔芬加唑来膦酸组450例36例，阿那曲唑加唑来膦酸组450例40例）。唑来膦酸总体上降低了无病生存事件的风险（HR 0.68, 95% CI 0.51-0.91; p=0.009），尽管在他莫昔芬组（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）中分别评估差异不显著。唑来膦酸对死亡风险没有显著影响（服用唑来膦酸组有30例死亡，未服用唑来膦酸组有43例死亡；HR 0.67, 95% CI 0.41-1.07; p=0.09）。单独使用他莫昔芬的患者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），但阿那曲唑的总生存期比单独使用他莫昔芬的患者差（46 vs 27例死亡；HR 1.75, 95% CI 1.08-2.83; p=0.02）。治疗通常耐受性良好，没有肾衰或颌骨骨坏死的报告。601例患者报告骨痛（33%，349例服用唑来膦酸，252例未服用唑来膦酸），361例患者报告疲劳（20%，192例对169例），280例患者报告头痛（16%，147例对133例），266例患者报告关节痛（15%，145例对121例）。解释唑来膦酸的加入提高了服用阿那曲唑或他莫昔芬的患者的无病生存期。总的来说，接受阿那曲唑和他莫昔芬治疗的患者的无病生存期没有差异，但单独接受阿那曲唑治疗的患者的总生存期较差。这些数据显示了唑来膦酸的持续益处，并支持将其加入绝经前早期乳腺癌患者的辅助内分泌治疗。
Background 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.Methods 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.Findings 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).Interpretation 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.