血管内皮生长因子受体酪氨酸激酶抑制剂致肿瘤患者发生严重胃肠道事件风险的网状meta分析

Risk of severe gastrointestinal events in patients with cancer caused by vascular endothelial growth factor receptor tyrosine kinase inhibitors:a network meta‑analysis

目的系统评价血管内皮生长因子受体酪氨酸激酶抑制剂(VEGFR-TKI)致肿瘤患者发生严重胃肠道事件风险。方法检索国内外有关数据库(截至2020年12月),收集VEGFR-TKI治疗肿瘤的随机对照研究,以应用1种VEGFR-TKI者为试验组,以应用安慰剂或另1种VEGFR-TKI者为对照组,结局指标包含严重胃肠道事件发生率。采用Jadad评分量表评价纳入研究的质量,采用Review Manager 5.3软件对严重胃肠道事件发生风险进行直接meta分析;采用Stata13.0软件和基于频率学框架的混合线性模型对发生风险最高的严重胃肠道事件进行网状meta分析,结果用相对危险度(RR)及其95%置信区间(CI)表示。结果共38项研究纳入分析,均为高质量研究(Jadad评分4~7分);共包括15217例患者,试验组9130例,对照组6087例。meta分析结果显示,VEGFR-TKI组严重腹泻、严重厌食和严重恶心发生风险均明显高于对照组,差异均有统计学意义[6.8%(602/8894)比0.7%(49/6584),RR=6.62(95%CI:5.00~8.76),P<0.001;2.5%(201/7937)比0.7%(41/5831),RR=2.14(95%CI:1.40~3.25),P<0.001;1.5%(92/6343)比0.4%(21/4870),RR=1.95(95%CI:1.23~3.12),P=0.005],以严重腹泻的发生风险最高;而严重呕吐和严重腹痛发生风险与对照组比较差异无统计学意义[1.4%(79/5788)比0.7%(32/4428),RR=1.49(95%CI:0.90~2.47),P=0.120;1.7%(82/4766)比1.1%(40/3628),RR=1.35(95%CI:0.84~2.16),P=0.210]。对严重腹泻事件的网状meta分析结果显示,不同品种VEGFR-TKI致严重腹泻发生风险相对大小为阿昔替尼>安罗替尼>卡博替尼≈凡德他尼≈舒尼替尼≈仑伐替尼≈索拉非尼≈帕唑帕尼>瑞戈非尼>呋喹替尼>阿帕替尼。结论肿瘤患者应用VEGFR-TKI可增加严重腹泻的发生风险,尤以阿昔替尼风险较大,值得临床关注和警惕。

Objective To systematically evaluate the risk of severe gastrointestinal events in patients with cancer caused by vascular endothelial growth factor receptor tyrosine kinase inhibitors(VEGFR⁃TKI).Methods Randomized controlled trials of VEGFR⁃TKI in the treatment of tumors were collected by searching relevant databases at home and abroad(up to March 2,2019).The patients who were treated with a VEGFR⁃TKI were enrolled into the trial group,and those who received placebo or another VEGFR⁃TKI were enrolled into the control group.The outcomes included the incidence of serious gastrointestinal events.The Jadad scoring method was used to assess the quality of included studies.The Review Manager 5.3 software was used for direct meta⁃analysis on the risk of severe gastrointestinal events.Stata 13.0 software and linear mixed model based on frequency framework were used for network meta⁃analysis on severe gastrointestinal events at the highest risk.The results were expressed by relative risk(RR)and its 95%confidence interval(CI).Results A total of 38 studies were included in the analysis,all of which were high⁃quality studies(Jadad score 4⁃7),comprising a total of 15217 patients(9130 in the trial group and 6087 in the control group).The results of direct meta⁃analysis showed that the risks of severe diarrhea,severe anorexia,and severe nausea in the trial group were higher than those in the control group respectively,and the differences were statistically significant[6.8%(602/8894)vs.0.7%(49/6584),RR=6.62(95%CI:5.00-8.76),P<0.001;2.5%(201/7937)vs.0.7%(41/5831),RR=2.14(95%CI:1.40-3.25),P<0.001;1.5%(92/6343)vs.0.4%(21/4870),RR=1.95(95%CI:1.23-3.12),P=0.005];the risk of severe diarrhea was the highest[6.8%(602/8894)].There was no significant difference in the risk of severe vomiting and severe abdominal pain compared with the control group[1.4%(79/5788)vs.0.7%(32/4428),RR=1.49(95%CI:0.90-2.47),P=0.120;1.7%(82/4766)vs.1.1%(40/3628),RR=1.35(95%CI:0.84-2.16),P=0.210].The results of network meta⁃analysis on risk of severe diarrhea events showed that the relative risks of severe diarrhea caused by varieties of VEGFR⁃TKI were axitinib>anlotinib>cabozantinib≈vandetanib≈sunitinib≈lenvatinib≈sorafenib≈pazopanib>regorafenib>fruquintinib>apatinib in the order.Conclusion The application of VEGFR⁃TKIs,especially axitinib,can increase the risk of severe diarrhea in patients with tumors,which deserves clinical attention and vigilance.