多靶点酪氨酸激酶抑制剂联合化疗与单纯化疗比较治疗晚期非小细胞肺癌疗效和安全性的Meta分析

Efficacy and safety of tyrosine kinase inhibitors combined with chemotherapy versus chemotherapy in advanced non-small cell lung cancer: a meta-analysis

目的系统评价多靶点酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)联合化疗与单纯化疗比较治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床疗效和安全性。方法计算机检索The Cochrane Library、Pub Med和EMBase数据库,搜集TKIs联合化疗与单纯化疗比较治疗晚期NSCLC的随机对照试验(RCT),检索时限均为建库至2016年12月。由2位评价员独立筛选文献、提取数据和评价纳入研究的偏倚风险后,采用RevMan 5.3软件进行Meta分析。结果共纳入12个RCT,共6 559例患者。Meta分析结果显示:TKIs联合化疗组的中位无进展生存期(PFS)[HR=0.86,95%CI(0.81,0.91),P<0.001]和客观缓解率(ORR)[HR=1.43,95%CI(1.20,1.70),P<0.001]均高于单纯化疗组。但两组在中位生存时间(OS)[HR=0.91,95%CI(0.82,1.00),P=0.06]、疲劳发生率[RR=1.03,95%CI(0.97,1.11),P=0.33]、呼吸困难发生率[RR=1.01,95%CI(0.91,1.13),P=0.82]和咳嗽发生率[RR=1.01,95%CI(0.89,1.15),P=0.91]方面差异均无统计学意义。但TKIs联合化疗组的中性粒细胞减少发生率[RR=1.16,95%CI(1.05,1.28),P=0.003]、血小板减少发生率[RR=1.46,95%CI(1.23,1.73),P<0.001]、腹泻发生率[RR=2.09,95%CI(1.81,2.37),P<0.001]和高血压发生率[RR=2.91,95%CI(2.28,3.71),P<0.001]均高于单纯化疗组,而贫血发生率[RR=0.86,95%CI(0.75,0.98),P=0.03]低于单纯化疗组。结论与单纯化疗相比,TKIs联合化疗可延长患者中位无进展生存期和客观缓解率,可作为晚期NSCLC患者的一种治疗手段。受纳入研究的数量和质量限制,上述结论仍需开展更多高质量研究予以验证。

Objective To systematically review the efficacy and safety of tyrosine kinase inhibitors combined with chemotherapy versus chemotherapy in advanced non-small cell lung cancer（NSCLC）. Methods An electronically search was conducted in The Cochrane Library, PubMed and EMbase databases from inception to December 2016 to collect randomized controlled trials （RCTs） about tyrosine kinase inhibitors combined with chemotherapy versus chemotherapy for NSCLC. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed by using RevMan 5.3 software. Results A total of 12 RCTs involving 6 559 patients were finally included. The results of meta-analysis showed that： The median progression free survival （PFS） （HR=0.86, 95%CI 0.81 to 0.91, P〈0.001） and objective response rate （ORR） （HR=1.43, 95%CI 1.20 to 1.70, P〈0.001） of tyrosine kinase inhibitors combined with chemotherapy were significantly longer than those of the chemotherapy group. There were no significant differences between two groups in incidence of median overrall survival （OS） （HR=0.91, 95%CI 0.82 to 1.00, P=O.06）, fatigue （RR=1.03, 95%CI 0.97 to 1.11, P=0.33）, dyspnea （RR=1.01, 95%CI 0.91 to 1.13, P=0,82） and cough （RR=1.01, 95%CI 0.89 to 1.15, P=0.91）. However, the incidence of neutrocytopenia （RR=1.16, 95%CI 1.05 to 1.28,P=0.003）, thrombocytopenia （RR=1.46, 95%CI 1.23 to 1.73, P〈0.001）, diarrhea and hypertension （RR=2.91, 95%CI 2.28 to 3.71, P〈0.001） of tyrosine kinase inhibitors combined with chemotherapy group were significantly higher than those of the chemotherapy group. The tyrosine kinase inhibitors combined with chemotherapy group had lower rate of anemia （RR=0.86, 95%CI 0.75 to 0.98, P=0.03）. Conclusion Compared with chemotherapy alone, tyrosine kinase inhibitors combined with chemotherapy can improve the median PFS and ORR while it can be used as a treatment for advanced non-small cell lung cancer patients. Due to the limited quality and quantity of the included studies, more high quality studies are needed to verify above conclusion.