抗VEGF与抗EGFR靶向药物联合化疗一线治疗转移结直肠癌Meta分析

First-line treatments of anti-EGFR and anti-EGFR targeted drugs combined with chemotherapy in metastaticcolorectal cancer:Meta-analysis and systematic review of RCTs

目的 NCCN指南推荐抗VEGF或抗EGFR作为伴RAS野生型的转移结直肠癌(metastatic colorectal cancer,mCRC)一线治疗的标准方案,但抗VEGF与抗EGFR在转移结直肠癌预后的差异性罕见系统评价参考。本研究拟通过系统评价分析抗VEGF与抗EGFR靶向药物联合化疗对转移结直肠癌疗效的影响。方法计算机检索Cochrane、Pubmed、Web of science、Embase、ASCO、ESMO、Clinical Trials和中国生物医学文献数据库等,同时追溯参考文献。收集抗VEGF联合化疗对比抗EGFR联合化疗治疗mCRC头对头的随机对照试验(Randomized controlled trial,RCT),根据Cochrane系统评价手册5.3质量评价标准,采用Stata 12.0和Revman 5.3进行Meta分析。结果共纳入3篇临床随机对照试验,共2 014例研究对象。Meta分析结果显示,一线给予抗EGFR或抗VEGF联合化疗的mCRC患者,无论KRAS野生型(HR=1.03,95%CI为0.93~1.13)或RAS野生型(HR=0.92,95%CI为0.71~1.18)的无进展生存期(pogression free survival,PFS)均差异无统计学意义,P<0.05。一线给予抗EGFR联合化疗方案的总生存期(overall survival,OS)KRAS野生型(HR=0.82,95%CI为0.72~0.93)和RAS野生型患者(HR=0.79,95%CI为0.67~0.93)均优于抗VEGF联合化疗,P<0.05。mCRC伴KRAS野生型患者,接受抗EGFR联合化疗客观缓解率(objective response rate,ORR)显著提高,RR=0.84,95%CI为0.76~0.94;这种优势对于所有的RAS野生型患者更加明显,RR=0.80,95%CI为0.68~0.93。无论使用抗EGFR或抗VEGF联合化疗,左半结直肠癌患者相比右半结肠癌患者有生存获益PFS(HR=0.64,95%CI为0.45~0.91)及OS(HR=0.53,95%CI为0.36~0.76)。结论 mCRC伴KRAS或RAS野生型患者的一线治疗,抗EGFR单克隆抗体可能是替代抗VEGF治疗作为晚期mCRC的初始治疗的最佳治疗方案。而对于肿瘤的位置而言,无论接受何种靶向药物治疗,左半结肠肿瘤相比右半结肠肿瘤的患者都具有更好的生存优势。

OBJECTIVE NCCN guidelines recommend that anti-VEGF or anti-EGFR as a standard regimen for first-line treatment of metastatic colorectal cancer （mCRC） with RAS wild-type, but there is no systematic review to eval uate the prognosis difference between anti-VEGF and anti-EGFR in metastatic colorectal cancer. The effect of anti-EGFR and anti EGFR targeted drug combined with chemotherapy on metastatic colorectal cancer was analyzed. METHODS Cochrane, Pubmed, Web of Science, Embase, clinical trial database were retrieved by computer, and the reference were retrospectively reviewed. Head-to-head randomized controlled trials （RCTs） of anti-VEGF combined with chemotherapy versus anti-EGFR combined with chemotherapy in the treatment of metastatic colorectal cancer （mCRC） were collected. Quality Evaluation Criteria was performed according to the Cochrane System Evaluation Manual 5. 3. Stata 12. 0 Software and Revman 5.3 were used for meta analysis. RESULTS Three randomized controlled trials involving 2014 participants,rectaanalysis showed that mCRC patients who received either anti-VEGF or anti-EGFR combined with chemotherapy, regard less of KRAS wild type （HR =1.03,95%CI：0.93-1.13） or RAS wild type （HR=0.91,95%CI：0.74-1. 13）,PFS were not statistically significant. OS in patients receiving first-line anti-EGFR treatment was prolonged compared with patients receiving anti-VEGF therapy （KRAS wild-type HR= 0. 82,95%CI： 0. 72 - 0. 93, RAS wild-type HR= 0. 79, 95 %CI：0. 67-0. 93）. KRAS wild-type mCRC patients receiving anti-EGFR chemotherapy compared to anti-VEGF combined with chemotherapy had a more significant increase in ORR （RR= 0. 84,95% CI：0.76-0. 94）, This effect was even stronger for all RAS wild-type patients （RR=0.80,95 % CI： 0.68-0. 93）. Regardless of the use of anti-EGFR or anti- VEGF combined with chemotherapy,left colorectal cancer patients were significantly better than those with right-sided coloneancer（PFS,HR=0.64,95%CI：0.45-0.91,OS, HR=0.53,95%CI：0.36-0. 76）. CONCLUSIONS As the firstline treatments for mCRC with KRAS or RAS wild-type, anti-EGFR monoclonal antibody may be a substitute for anti- VEGF treatment as the best initial treatment. For the tumor location, regardless of what kind of targeted drug treatment, left colon cancer patients have better survival advantage than the right colon cancer.