切换至 "中华医学电子期刊资源库"

中华乳腺病杂志(电子版) ›› 2019, Vol. 13 ›› Issue (02) : 98 -106. doi: 10.3877/cma.j.issn.1674-0807.2019.02.007

所属专题: 文献

论著

来那替尼治疗乳腺癌引起肝毒性和胃肠道不良反应风险的Meta分析
邓茜1, 李柏群1,(), 黄道秋1, 方伟1, 胡彦君1   
  1. 1. 404000 万州,重庆三峡中心医院药学部
  • 收稿日期:2018-05-04 出版日期:2019-04-01
  • 通信作者: 李柏群

Risk of hepatic toxicity and gastrointestinal adverse events in breast cancer patients treated with neratinib: a meta-analysis

Qian Deng1, Boqun Li1,(), Daoqiu Huang1, Wei Fang1, Yanjun Hu1   

  1. 1. Department of Pharmacy, Chongqing Three Gorges Central Hospital, Wanzhou 404000, China
  • Received:2018-05-04 Published:2019-04-01
  • Corresponding author: Boqun Li
  • About author:
    Corresponding author: Li Boqun, Email:
引用本文:

邓茜, 李柏群, 黄道秋, 方伟, 胡彦君. 来那替尼治疗乳腺癌引起肝毒性和胃肠道不良反应风险的Meta分析[J/OL]. 中华乳腺病杂志(电子版), 2019, 13(02): 98-106.

Qian Deng, Boqun Li, Daoqiu Huang, Wei Fang, Yanjun Hu. Risk of hepatic toxicity and gastrointestinal adverse events in breast cancer patients treated with neratinib: a meta-analysis[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2019, 13(02): 98-106.

目的

研究来那替尼治疗乳腺癌引起肝毒性和胃肠道不良反应风险。

方法

检索Cochrane、PubMed、Web of Science、中国知网、维普及万方等相关数据库,检索时间为从建库以来至2018年3月1日,收集关于来那替尼治疗乳腺癌且描述了肝毒性[丙氨酸氨基转移酶(ALT)或天门冬氨酸氨基转移酶(AST)升高]和胃肠道不良反应(包括腹泻、呕吐或恶心)等不良事件的随机对照临床研究。不良反应按严重程度分为1~5级,其中所有级别包括1~5级;严重级别包括3级及以上。由2名研究人员独立完成文献筛选、数据提取,运用Cochrane手册推荐的风险评价工具对文献质量进行评价。采用相对危险度(relative risk, RR)和95%置信区间(confidence interval, CI)作为效应量;采用Q检验分析数据的异质性,并根据异质性结果选择固定效应模型或随机效应模型。

结果

本研究共纳入4项RCT研究,共3 745例患者。其中2项研究为来那替尼单用,另外2项研究为来那替尼联用紫杉醇。来那替尼组的所有级别ALT与AST升高发生率与对照组比较,差异无统计学意义(ALT:RR=1.37,95%CI:0.50~3.76,P=0.54; AST: RR=1.19,95%CI:0.36~3.92,P=0.78),但严重级别的ALT升高发生率来那替尼组高于对照组(RR=3.63,95%CI:1.58~8.36,P<0.01),来那替尼组的严重级别AST升高发生率与对照组比较,差异无统计学意义(RR=2.08,95%CI:0.80~5.43,P=0.13)。关于胃肠道不良反应,所有级别与严重级别的腹泻发生率在来那替尼组均高于对照组(所有级别:RR=2.06,95%CI:1.38~3.08,P<0.01;严重级别:RR=8.77, 95%CI:2.91~26.40,P<0.01);所有级别与严重级别的呕吐发生率在来那替尼组均高于对照组(所有级别:RR=2.13,95%CI:1.43~3.18, P<0.01;严重级别:RR=6.22,95%CI:3.16~12.27, P<0.01)。所有级别和严重级别的恶心发生率,来那替尼组与对照组比较,差异无统计学意义(所有级别:RR=1.28, 95%CI:0.81~2.04,P=0.29;严重级别:RR=3.10, 95%CI: 0.87~11.00,P=0.08)。

结论

来那替尼用于治疗乳腺癌后,严重级别的ALT升高、腹泻和呕吐的发生率增加,AST升高和恶心的发生率没有明显变化,因此,需要密切监测患者的肝功能和胃肠道功能。

Objective

To investigate the risk of hepatic toxicity and gastrointestinal events in breast cancer patients treated with neratinib.

Methods

The Cochrane, PubMed, Web of Science, CNKI, VIP and Wanfang databases were searched for randomized controlled trials in breast cancer patients treated with neratinib from the earliest data available to March 1, 2018. The enrolled studies described hepatic toxicity such as elevated alanine aminotransferase(ALT) or elevated aspartate aminotransferase(AST) or gastrointestinal events induding diarrhea, vomiting and nausea. All adverse events were divided into 5 grades(1-5). The adverse events at all levels included all 5 grades and high-level adverse events refered to the events at grade 3 and above. Two researchers independently completed literature retrieval and data extraction, and evaluated the quality of the included studies using the recommended bias tools of the Cochrane handbook. The relative risk (RR) and 95% confidence interval (CI) were used as effect quantities and Q test was used to analyze the heterogeneity of the data. A fixed effect model or a random effect model was chosen according to the results of the heterogeneity.

Results

Four studies were included, among which neratinib monotherapy was used in two studies and neratinib combined with paclitaxel in other two studies. The results showed that there was no significant difference in the incidence of ALT and AST increase at all levels between neratinib group and control group (ALT: RR=1.37, 95%CI: 0.50-3.76, P=0.54; AST: RR=1.19, 95%CI: 0.36-3.92, P=0.78). The incidence of high-level elevation of ALT was significantly higher in neratinib group than in control group (RR=3.63, 95%CI: 1.58-8.36, P<0.01), while no significant difference was found in the incidence of high-level elevation of AST (RR=2.08, 95%CI: 0.80-5.43, P=0.13). As to gastrointestinal events, the incidences of nausea at all levels and high level were significantly higher in neratinib group than in control group(at all levels: RR=2.06, 95%CI: 1.38-3.08, P<0.01; high-level: RR=8.77, 95%CI: 2.91-26.40, P<0.01); the incidences of vomiting at all levels and high level were significantly higher in neratinib group than in control group(at all levels: RR=2.13, 95%CI: 1.43-3.18, P<0.01; high-level: RR=6.22, 95%CI: 3.16-12.27, P<0.01). The incidence of nausea at all levels and high level presented no significant difference between neratinib group and control group (at all levels: RR=1.28, 95%CI: 0.81-2.04, P=0.29; high-level: RR=3.10, 95%CI: 0.87-11.00, P=0.08).

Conclusions

The application of neratinib in breast cancer patients will increase the incidences of high-level ALT increase, diarrhea and vomiting, but no significant changes are observed in AST increase and nausea. Therefore, the liver function and gastrointestinal function should be closely monitored if neratinib is used against breast cancer.

图1 来那替尼治疗乳腺癌引起胃肠道不良反应和肝毒性相关研究的筛选流程图
表1 纳入4篇文献的基本情况
表2 Cochrane偏倚风险评估工具对4篇纳入文献的质量评价结果
图2 乳腺癌患者与来那替尼治疗相关的所有级别(a)和严重级别(b)丙氨酸氨基转移酶升高发生率的森林图及异质性分析
图3 乳腺癌患者与来那替尼治疗相关的所有级别(a)和严重级别(b)天门冬氨酸氨基转移酶升高的不良反应发生率的森林图及异质性分析
图4 乳腺癌患者与来那替尼治疗相关的所有级别(a)和严重级别(b)腹泻发生率的森林图及异质性分析
图5 乳腺癌患者与来那替尼治疗相关的所有级别(a)和严重级别(b)恶心不良反应的发生率的森林图及异质性分析
图6 乳腺癌患者与来那替尼治疗相关的所有级别(a)和严重级别(b)呕吐发生率的森林图及异质性分析
[1]
Zuo TT, Zheng RS, Zeng HM, et al. Female breast cancer incidence and mortality in China, 2013[J].Thorac Cancer, 2017, 8(3):214-218.
[2]
Jelovac D, Wolff AC. The adjuvant treatment of HER2-positive breast cancer[J].Curr Treat Options Oncol, 2012, 13(2):230-239.
[3]
Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2-and HER3-mutant cancers[J].Nature, 2018, 554(7691):189-194.
[4]
Echavarria I, Lopez-Tarruella S, Marquez-Rodas I, et al. Neratinib for the treatment of HER2-positive early stage breast cancer[J].Expert Rev Anticancer Ther, 2017, 17(8):669-679.
[5]
National Cancer Institute. Common terminology criteria for adverse events v.4.0 (CTCAE) [EB/OL].[2018-05-01].

URL    
[6]
Higgins J, Green S. Cochrane handbook for systematic reviews of interventions[EB/OL]. [2018-05-01].

URL    
[7]
Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer[J].N Engl J Med, 2016, 375(1):11-22.
[8]
Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2017, 18(12):1688-1700.
[9]
Martin M, Bonneterre J, Geyer CE Jr, et al. A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer[J].Eur J Cancer, 2013, 49(18):3763-3772.
[10]
Awada A, Colomer R, Inoue K, et al. Neratinib plus pclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial[J].JAMA Oncol, 2016, 2(12):1557-1564.
[11]
Abdel-Rahman O, Ahmed H, ElHalawani H. Risk of elevated transaminases in non-small cell lung cancer (NSCLC) patients treated with erlotinib, gefitinib and afatinib: a meta-analysis [J]. Expert Rev Respir Med, 2016, 10(2):223-234.
[12]
Abdel-Rahman O, ElHalawani H. Risk of oral and gastrointestinal mucosal injury in patients with solid tumors treated with ramucirumab: a systematic review and meta-analysis [J]. Expert Opin Drug Saf, 2015, 14(10):1495-1506.
[13]
Abdel-Rahman O, ElHalawani H, Fouad M. Risk of elevated transaminases in cancer patients treated with immune checkpoint inhibitors: a meta-analysis[J]. Expert Opin Drug Saf, 2015, 14(10):1507-1518.
[14]
Deeks ED. Neratinib: first global approval[J].Drugs, 2017, 77(15):1695-1704.
[1] 郝玥萦, 毛盈譞, 张羽, 汪佳旭, 韩林霖, 匡雯雯, 孟瑶, 杨秀华. 超声引导衰减参数成像评估肝脂肪变性及其对心血管疾病风险的预测价值[J/OL]. 中华医学超声杂志(电子版), 2024, 21(08): 770-777.
[2] 史学兵, 谢迎东, 谢霓, 徐超丽, 杨斌, 孙帼. 声辐射力弹性成像对不可切除肝细胞癌门静脉癌栓患者放射治疗效果的评价[J/OL]. 中华医学超声杂志(电子版), 2024, 21(08): 778-784.
[3] 李华志, 曹广, 刘殿刚, 张雅静. 不同入路下行肝切除术治疗原发性肝细胞癌的临床对比[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 52-55.
[4] 常小伟, 蔡瑜, 赵志勇, 张伟. 高强度聚焦超声消融术联合肝动脉化疗栓塞术治疗原发性肝细胞癌的效果及安全性分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 56-59.
[5] 高杰红, 黎平平, 齐婧, 代引海. ETFA和CD34在乳腺癌中的表达及与临床病理参数和预后的关系研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 64-67.
[6] 冯旺, 马振中, 汤林花. CT扫描三维重建在肝内胆管细胞癌腹腔镜肝切除术中的临床研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 104-107.
[7] 韩萌萌, 冯雪园, 马宁. 乳腺癌改良根治术后桡神经损伤1例[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 117-118.
[8] 叶劲松, 刘驳强, 柳胜君, 吴浩然. 腹腔镜肝Ⅶ+Ⅷ段背侧段切除[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(02): 315-315.
[9] 郭兵, 王万里, 何凯, 黄汉生. 腹腔镜下肝门部胆管癌根治术[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(01): 143-143.
[10] 李凯, 陈淋, 苏怀东, 向涵, 张伟. 超微创器械在改良单孔腹腔镜巨大肝囊肿开窗引流及胆囊切除中的应用[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(01): 144-144.
[11] 魏丽霞, 张安澜, 周宝勇, 李明. 腹腔镜下Ⅲb型肝门部胆管癌根治术[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(01): 145-145.
[12] 李浩, 陈棋帅, 费发珠, 张宁伟, 李元东, 王硕晨, 任宾. 慢性肝病肝纤维化无创诊断的研究进展[J/OL]. 中华临床医师杂志(电子版), 2024, 18(09): 863-867.
[13] 广东省护士协会介入护士分会, 广东省医师协会介入医师分会. 原发性肝癌低血糖患者护理规范管理专家共识[J/OL]. 中华临床医师杂志(电子版), 2024, 18(08): 709-714.
[14] 韦巧玲, 黄妍, 赵昌, 宋庆峰, 陈祖毅, 黄莹, 蒙嫦, 黄靖. 肝癌微波消融术后中重度疼痛风险预测列线图模型构建及验证[J/OL]. 中华临床医师杂志(电子版), 2024, 18(08): 715-721.
[15] 蔡晓雯, 李慧景, 丘婕, 杨翼帆, 吴素贤, 林玉彤, 何秋娜. 肝癌患者肝动脉化疗栓塞术后疼痛风险预测模型的构建及验证[J/OL]. 中华临床医师杂志(电子版), 2024, 18(08): 722-728.
阅读次数
全文


摘要