全脑放疗联合替莫唑胺治疗非小细胞肺癌脑转移的Meta分析

System review of concomitant or adjuvant temozolomide with whole brain radiotherapy for patients with brain metastasis from non-small cell lung cancer

目的系统评价全脑放疗联合替莫唑胺(whole brain radiation therapy+Temozolomide,WBRT+TMZ)治疗非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移的疗效、患者生存情况及不良反应。方法利用Meta分析方法对国内外从建库到2016年5月发表的有关WBRT+TMZ与单纯WBRT治疗NSCLC脑转移的文献进行汇总定量分析。由两名研究者独立提取有效数据。使用的Cochrane风险偏倚评估工具对文献进行质量分析及评价。使用RevMan 5.3对各效应量进行统计分析。结果共纳入文献6篇(427例患者)。Meta分析结果显示:采用WBRT+TMZ模式治疗的客观缓解率(62.6%)明显优于单纯WBRT治疗模式(46.0%),相对危险度(risk ratio,RR)为1.41[95%CI(1.17,1.71),P=0.0004]。但WBRT+TMZ治疗模式使血液毒性反应及胃肠道副反应的发生率增加,其中WBRT+TMZ组血液毒性反应发生率是单纯WBRT组的2.29倍,RR为2.14[95%CI(1.12,4.06),P=0.02];胃肠道副反应发生率是单纯WBRT组的1.9倍,RR=1.84[95%CI(0.98,3.47),P=0.06]。两种治疗模式的总生存时间与无进展生存期比较,差异均无统计学意义,危险比分别为1.09[95%CI,(0.80,1.48),P>0.05],1.15[95%CI,(0.73,1.80),P>0.05],表明WBRT+TMZ治疗模式并未增加患者远期生存获益。结论对于NSCLC脑转移的治疗,WBRT+TMZ与单纯WBRT相比,改善了客观反应率,但增加了患者Ⅲ/Ⅳ期血液毒性反应,而胃肠道不良反应未明显增加,联合治疗方案未能将近期的局控获益转化为远期的生存获益。因此,对于WBRT+TMZ治疗NSCLC脑转移的疗效和安全性,还需要进一步的大规模、高质量、前瞻性的临床研究进行验证。

Objective To evaluate the effectiveness and safety of concomitant or adjuvant TMZ with WBRT in the management of non-small cell lung cancer patients with brain metastases. Methods All of the randomized controlled trials comparing whole brain radiotherapy plus temozolomide with whole brain radiotherapy alone were searched from the following databases： PubMed, EMBASE, Cochrane Library, CNKI, WANFANG, and Chinese Biomedical Literature Database. Search result was screened according to the inclusive and exclusive criteria. The date extraction and quality assessment of eligible RCTs were conducted by two reviewers independently according to Cochrane reviewer＇s handbook 5.1. and the Cochrane collaboration＇ s tool for assessing risk of bias. The RevMan 5.3 software was used for metaanalysis. Results 6 eligible RCTs involving 427 patients were included. 2 trials indicated the method of random sequence generation, and 1 study was an open label, multicentric RCTs. All other trials did not mention the method of randomization, allocation concealment and blinding. Meta-analysis showed that TMZ plus WBRT made a potential benefit for patients with brain metastasis from NSCLC. The objective response rate of WBRT＋TMZ group was superior to that of WBRT group （62.6% vs 46.0%）, and the difference between two groups was significantly different （P = 0. 0004）. The RR and 95M CI were 1.41 （1.17, 1.71）. Regretfully, the combined therapeutic model did not make any difference in over survival and progress-flee survival. The P value, HR and 95%CI were 0.60, 1.09 （0.80, 1.48） and 0.59, 1.15（0.73, 1.80）, respectively. The incidence of Ill/IVgrade hematological toxicity of TMZ＋ WBRT group was much higher than that of WBRT group （P=0.02, RR=2.14, CI[1.12,4. 06]）. The gastrointestinal symptoms in WBRT＋TMZ group were also higher than that in WBRT group, but there was no statistical difference between two groups （P=0.06, RR= 1.84, CI[0.98, 3.47]）. Three trials reported symptom of headache, and the incidence was observed frequently in the combined group than in the control group. However, the difference Between two groups with no significant statistical meaning （P=0.66, RR= 1.13, CI[0.67, 1.89]）. Conclusion Existing evidence suggested that the combined therapeutic model of TMZ plus WBRT improved the objective response rate, but no survival benefit achieved for the patients with brain metastasis from NSCLC. Meanwhile, the Ⅲ/IVgrade hematological toxicity and gastrointestinal symptom rate were increased. In view of the defect, such as small scale and low quality of the included studies, this conclusion need to be further proved with more high-quality, large-scale, and double-blind RCTs.