辅助卵巢抑制在绝经前乳腺癌适宜人群选择及疗效评价：荟萃分析

发布时间：2018-05-30 06:29

本文选题：卵巢抑制 + GnRHα　；参考：《浙江大学》2016年博士论文

【摘要】：目的：现乳腺癌位居女性恶性肿瘤发病率第一位,同时是女性常见肿瘤相关死亡原因之一。目前最常见的乳腺癌亚型仍然是激素受体阳性亚型,绝经前女性患者在其中占了相当大的比例,因此,进一步改进绝经前乳腺癌患者综合治疗方案具有重要临床意义。五年他莫昔芬(TAM)治疗是目前绝经前激素受体阳性乳腺癌治疗的基石,目前有研究认为,在标准他莫昔芬治疗基础上加用GnRHα卵巢抑制(OFS),或者芳香化酶抑制剂(AI)联合GnRHα卵巢抑制,可以产生更多的生存获益。近年来不管是st Gallen会议还是ASCO指南,均对加入GnRHα卵巢抑制的治疗方案进行了一定的讨论。本研究的主要目的是对绝经前乳腺癌术后辅助治疗中加入GnRHα卵巢抑制的生存获益进行系统评价,并探讨最优获益人群的临床特征。此外,运用网络meta的分析方法,对不同药物组合和疗程进行比较,研究GnRHα卵巢抑制最佳药物组合和最佳疗程。方法：利用计算机检索PubMed、EBSCO、Embase、Scopus、Cochrane library等知名国外数据库及知网、万方维普等国内相应数据库,同时手工检索相关文献作为补充。检索日期为自1980年至2016年3月,检索所有已公开发表的随机对照研究和半随机对照研究。采用风险比(Hazard ratio, HR)作为疗效分析统计量,各效应量均以95%可信区间表示。观测的结局指标包括：患者的总生存率(Overall survival, OS),无病生存率(Disease free survival, DFS),治疗反应率(Response rate, RR)。应用Stata软件进行效应量Meta分析及亚组分析,应用R软件Netmeta程序包进行网络Meta分析,比较不同药物组合及疗程评价。结果：本研究一共纳入34个文献,包括61724例患者,Meta分析提示,卵巢抑制联合他莫昔芬优于他莫昔芬单药5年治疗,5年DFS HR为0.89(95% CI0.80-0.98),5年OS HR为0.87(95% CI0.77-1.00)。在激素受体阳性亚组,卵巢抑制联合他莫昔芬显著优于他莫昔芬单药5年治疗,5年OS HR为0.75(95% CI0.58-0.98)。对大于40岁亚组,卵巢抑制联合他莫昔芬较之他莫昔芬单药5年OS HR为1.10(95%CI0.82-1.48),对于小于40岁亚组,卵巢抑制联合他莫昔芬较之他莫昔芬单药5年OS HR为0.81(95% CI0.54-1.24),就绝对值而言,卵巢抑制联合他莫昔芬较之他莫昔芬单药5年在大于40岁亚组可以取得部分获益。比较芳香化酶抑制剂与他莫昔芬和卵巢抑制联合使用的疗效,卵巢抑制联合阿那曲唑不优于卵巢抑制联合他莫昔芬,5年DFS HR为0.97(95% CI0.74-1.28),卵巢抑制联合依西美坦优于卵巢抑制联合他莫昔芬,5年DFS HR为0.63(95% CI0.46-1.86),在Ki-6720%亚组,卵巢抑制联合芳香化酶抑制剂优于卵巢抑制联合他莫昔芬,治疗反应率HR为0.36(95% CI0.26-0.50),而在Ki-6720%亚组,卵巢抑制联合芳香化酶抑制剂优于卵巢抑制联合他莫昔芬,治疗反应率HR为0.60(95% CI0.36-1.00),HR高于Ki-6720%亚组,提示保护性效果减弱。网络Meta分析提示,他莫昔芬联合布舍瑞林、戈舍瑞林、曲普瑞林对应5年DFS HR分别为0.71 (95% CI 0.54-0.94)、0.81 (95% CI 0.75-0.87)、0.79 (95% CI 0.71-0.88),阿那曲唑联合戈舍瑞林、曲普瑞林对应5年DFS HR分别为0.84 (95% CI 0.73-0.96)、0.89 (95% CI 0.75-1.05),依西美坦联合曲普瑞林对应5年DFS HR为0.66(95% CI0.58-0.76),优于其他药物组合。他莫昔芬联合布舍瑞林、戈舍瑞林、曲普瑞林对应5年OS HR分别为：0.69 (95% CI 0.50-0.94)、0.82 (95% CI 0.75-0.90)、0.74 (95% CI 0.63-0.86), 阿那曲唑联合戈舍瑞林对应5年OS HR为1.15(95% CI0.31-4.30),5年DFS取得的优势未能转换为5年OS获益。他莫昔芬联合卵巢抑制2年、3年、5年对应5年OS HR分别为：0.81 (95% CI 0.74-0.88)、0.74 (95% CI 0.62-0.89)、0.76 (95% CI 0.57-1.02),他莫昔芬联合卵巢抑制治疗3年优于2年和5年。结论：研究显示,年龄小于40岁或Ki-67表达大于20%是预示患者可能从GnRHα卵巢抑制治疗中获益的可能因素,提示年轻的Luminal B型乳腺癌患者可能从GnRHα卵巢抑制治疗中获益,但需要把年龄和Ki-67表达两个因素整合后做进一步研究。就药物选择而言,就5年DFS而言,依西美坦联合曲普瑞林治疗存在一定优势,就5年OS而言,他莫昔芬联合布舍瑞林、戈舍瑞林或曲普瑞林均可使患者获益,因此,建议他莫昔芬联合任意一种GnRHα药物联合治疗。就GnRHα卵巢抑制治疗疗程而言,治疗5年并不能就治疗3年增加生存获益,治疗3年疗效优于治疗2年,因此,建议GnRHα卵巢抑制治疗3年。目前关于绝经前芳香化酶抑制剂联合卵巢抑制的研究数目较少,需要更多的临床试验来支持和佐证现有的临床证据。
[Abstract]:Objective: breast cancer is the first in female malignant tumor and one of the causes of common cancer related deaths in women. The most common subtype of breast cancer is still the hormone receptor positive subtype, and the premenopausal women have a considerable proportion. Therefore, the comprehensive treatment of premenopausal breast cancer patients is further improved. The five years of tamoxifen (TAM) therapy is the cornerstone of the treatment of premenopausal hormone receptor positive breast cancer. There is a study that more survival benefits can be produced by adding GnRH alpha ovarian suppression (OFS), or aromatase inhibitor (AI) combined with GnRH alpha ovarian suppression on the basis of standard tamoxifen therapy. The main purpose of this study is to systematically evaluate the survival benefits of GnRH alpha ovarian suppression after premenopausal breast cancer and to explore the clinical features of the optimal benefiting population in the St Gallen and ASCO guidelines. Using the analysis method of network meta to compare different drug combinations and treatment courses, study the best combination and best course of GnRH alpha ovarian suppression. Methods: using computer to retrieve well-known foreign databases and knowledge networks such as PubMed, EBSCO, Embase, Scopus, Cochrane library, and other domestic relevant databases such as Wan Fang Weipu and so on. The literature was supplemented. The retrieval date was from 1980 to March 2016. All published randomized controlled studies and semi randomized controlled studies were retrieved. Hazard ratio (HR) was used as a therapeutic analysis statistics, each of which was expressed in a 95% confidence interval. The observational index included the total survival rate of the patient (Overall surviv) Al, OS), the disease free survival rate (Disease free survival, DFS), treatment response rate (Response rate, RR). Using Stata software for Meta analysis and subgroup analysis, we used the R software package for network analysis to compare different drug combinations and course of treatment. Results: This study included 34 documents, including 61724 patients. Meta analysis suggested that ovarian suppression combined with tamoxifen was better than tamoxifen for 5 years, 5 years DFS HR was 0.89 (95% CI0.80-0.98), 5 year OS HR was 0.87 (95% CI0.77-1.00). In the hormone receptor positive subgroup, ovarian suppression combined with tamoxifen was significantly better than tamoxifen single drug 5 years, and OS HR was 0.75 (95% CI0.58-0.98) for 5 years. It was greater than 40 years. Subgroup, ovarian suppression combined with tamoxifen compared with the tamoxifen single drug 5 years OS HR 1.10 (95%CI0.82-1.48), for less than 40 year old subgroup, ovarian suppression combined with tamoxifen compared with the tamoxifen 5 year OS HR 0.81 (95% CI0.54-1.24), in terms of absolute value, ovarian suppression combined with tamoxifen more than the tamoxifen 5 years older than 40 years old. Compared with the combined use of aromatase inhibitors and tamoxifen and ovarian inhibition, ovarian inhibition combined with ananzole was not superior to ovarian inhibition combined with tamoxifen, 5 years DFS HR was 0.97 (95% CI0.74-1.28), ovarian inhibition combined with etoxetam superior to ovarian inhibition combined with tamoxifen, and 5 year DFS HR was 0.63 (95% CI0.46-1.86), in the Ki-6720% subgroup, ovarian suppression combined with aromatase inhibitors is superior to ovarian inhibition combined with tamoxifen, and the reaction rate of HR is 0.36 (95% CI0.26-0.50), while in the Ki-6720% subgroup, ovarian inhibition combined with aromatase inhibitors is superior to ovarian suppression combined with tamoxifen, and the response rate of the treatment is 0.60 (95% CI0.36-1.00), and HR is high. Meta analysis suggested that tamoxifen combined with DFS HR for 5 years (95% CI 0.54-0.94), 0.81 (95% CI 0.75-0.87), 0.79 (95% CI 0.71-0.88), A Na trazole United Gore Sherry Lin, and trapririn 0.84 (95%) for 5 year DFS HR, respectively. CI 0.73-0.96), 0.89 (95% CI 0.75-1.05), IXI mestan combined with tripletin for 5 years DFS HR 0.66 (95% CI0.58-0.76), superior to other drug combinations. Tamoxifen combined with amoliolin, cestolin, and koji Pu Ruilin for 5 years OS HR respectively: 0.69 (95% CI 0.50-0.94), 0.82 (95% CI), 0.74 (95% 95%), 0.74 (95% 95%), 0.74 Trazole combined with Gore Sherry Lin for 5 years OS HR for 1.15 (95% CI0.31-4.30), 5 year DFS gain failed to convert to 5 year OS benefit. Tamoxifen combined ovarian inhibition for 2 years, 3 years, 5 years corresponding to 5 years OS HR, 0.81 (95% CI 0.62-0.89), 0.74 (CI CI), tamoxifen combined ovarian suppression treatment years of ovarian inhibition Better than 2 years and 5 years. Conclusions: studies have shown that age less than 40 years old or Ki-67 more than 20% is a potential factor for patients who may benefit from GnRH alpha ovarian suppression therapy, suggesting that young Luminal B breast cancer patients may benefit from GnRH alpha ovarian suppression therapy, but the integration of age and Ki-67 expression in two factors is required. One step of the study. As far as drug selection is concerned, in terms of 5 years of DFS, there is a certain advantage in the treatment of etoxetin combined with trifirlin. For the 5 year OS, tamoxifen combined with amoxifen, cestalin, or trripririn can benefit the patients. Therefore, it is suggested that tamoxifen combined with any combination of GnRH alpha drugs. GnRH alpha ovarian suppression therapy is recommended. For a course of treatment, 5 years of treatment does not benefit for the benefit of increased survival for 3 years. The treatment for 3 years is better than the treatment of 2 years. Therefore, GnRH alpha ovarian suppression is recommended for 3 years. The number of studies on premenopausal aromatase inhibitors combined with ovarian suppression requires more clinical trials to support and support the existing clinical evidence.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.9

【相似文献】