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桓兴医讯 在内分泌敏感的乳腺癌中他莫昔芬2年治疗前或2年治疗后
文章来源:北京市朝阳区桓兴肿瘤医院 点击数: 发布时间:2018-03-07 08:53
《柳叶刀肿瘤分册》2018年2月23日在线先发
在内分泌敏感的乳腺癌中他莫昔芬2年治疗前或2年治疗后,阿那曲唑、依西美坦、来曲唑辅助治疗的对比研究(FATA-GIM3试验):一项随机化3期试验
背景
芳香化酶抑制剂辅助治疗乳腺癌的最佳方案仍不明确,据我们所知,尚无临床试验直接比较阿那曲唑、依西美坦和来曲唑这三种芳香化酶抑制剂。芳香化酶抑制剂作为激素受体阳性早期乳腺癌的辅助治疗,我们研究了芳香化酶抑制剂的类型和用药方案。
方法
FATA-GIM3是一项多中心、开放标签、随机化、3期临床试验,在激素受体阳性绝经后早期乳腺癌女性中,研究了6种不同的治疗方案。符合条件的患者为组织学证实为浸润性激素受体阳性乳腺癌、已手术完整切除、肿瘤大小和腋窝淋巴结状态不限。主要排除标准为激素替代治疗、复发或转移性乳腺癌、既往他莫昔芬治疗过、过去10年内有另一种恶性肿瘤。等比例将患者随机分配到6个治疗组中的一组:口服阿那曲唑(每天1mg)、依西美坦(每天25mg)、或来曲唑(每天2.5mg)先治疗5年(先期策略),或者口服他莫昔芬(每天20mg)2年后序贯口服这三种芳香化酶抑制剂中的一种治疗3年(切换策略)。按照计算机最小化程序进行随机化分组,并根据雌激素受体、孕激素受体、HER2状态、既往化疗和淋巴结病理状态进行随机化亚组分层。患者和医生对治疗分组均知晓。主要终点为无病生存。宣布先期策略优于切换策略的最小分界值设定为5年无病生存率相差2%。根据意向性治疗原则进行主要疗效分析,对完成了至少一次安全病例报告表的所有患者纳入安全性分析。随访仍在进行。这项试验已在欧洲临床试验数据库注册,注册号2006-004018-42,并在ClinicalTrials.gov网站注册,注册号NCT00541086。
发现
2007年3月9日至2012年7月31日,3697名患者入组了本研究。中位随访60个月(IQR,46–72)后,报告了401个无病生存事件,其中实施切换策略的1850名患者中有211(11%)个、实施先期策略的1847名患者中有190(10%)个。实施切换策略的5年无病生存率为88.5%(95%CI,86.7–90.0)、先期策略为89.8%(88.2-91.2)(风险比0.89,95%CI,0.73–1.08;p=0.23)。阿那曲唑组(124个事件)5年无病生存率为90.0%(95%CI,87.9–91.7)、依西美坦组(148个事件)为88.0%(85.8-89.9)、来曲唑组(129个事件,p=0.24)为89.4%(87.3-91.1)。未出现意料之外的严重不良反应或治疗相关性死亡。肌肉骨骼副作用是最常见的3-4级事件,在接受切换策略的1761名患者中有130名(7%)、接受先期策略的1766名患者中有128名(7%)报告了肌肉骨骼副作用事件。实施先期策略1级肌肉骨骼事件较实施切换策略更常见(1766名患者中924名[52%],对比1761名中745名[42%])。所有其他3-4级不良事件两组患者均不到2%。
解释
5年的芳香化酶抑制剂治疗并不优于2年他莫昔芬序贯3年芳香化酶抑制剂。就疗效而言,这三种芳香化酶抑制剂不存在孰优孰劣,因此,这种情况下,在决定最佳治疗方案时,应考虑患者意愿、耐受性和经济因素。
北京市朝阳区桓兴肿瘤医院 桓兴医讯编译组 王津京
2018年3月7日 星期三
Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial
Background
Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer.
Methods
FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086.
Findings
Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group.
Interpretation
5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting.

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