| Objective:It has been proved that targeted therapy has good efficacy in EGFR positive patients with advanced non-small cell lung cancer(NSCLC).This paper aims to compare the efficacy and safety of different targeting drugs in first-line treatment of EGFR-positive non-small-cell lung cancer,and provide a theoretical basis for the selection of different schemes in clinic.Methods:A preliminary analysis was made on the selection status of first-line treatment EGFR advanced non-small cell lung cancer in a third class hospital.PubMed,EMBASE and Cochrane databases were searchd to identify randomized controlled trials(RCTs)that EGFR-TKIs as first-line treatment for patients with EGFR-positive non-small-cell lung cancer.The outcomes included progress-free survival(PFS),overall Survival(OS),objective remission rate(ORR)and the incidence of diarrhea,rash,and stomatitis.The bias of the studies was assessed as described in the Cochrane Handbook.Network meta-analysis and traditional meta-analysis were carried out by gemtc package and meta package of R.3.6.1 software,respectively.We calculated the hazard ratio(HR)with 95% confidence intervals(CIs)for survival related time-event data(such as PFS and OS)and the odds ratios(ORs)with 95%CI for binary variables(such as ORR and incidence of adverse reactions).All data were pooled using a random-effects model.Node split method was used to evaluate the consistency of direct comparison and indirect comparison.Funnel plots were used to detect publication bias.Results:97.1% of EGFR positive patients with advanced NSCLC use first generation EGFR-TKIs.Seventeen RCTs involving 3262 patients were included in this analysis.Randomization was carried out in all studies.Five studies did randomisation with a computer-generated system,and three studies used dynamic hierarchical allocation.Other studies did not report specific methods for random sequences generation.All studies based on intention-to-treat(ITT)analysis and did not perform blinding.All outcomes had good convergence degree of the model and consistency.In terms of PFS,gefitinib [HR = 0.49,95% CI(0.35,0.68)],erlotinib [HR = 0.27,95% CI(0.17,0.42)],afatinib [HR = 0.39,95% CI(0.25,0.61)],dacomitinib [HR = 0.29,95% CI(0.13,0.64)],oxetinib[HR = 0.22,95% CI(0.10,0.49)],gefitinib + chemotherapy[HR = 0.25,95% CI(0.1,0.55)],and erlotinib + bevacizumab [HR = 0.17,95% CI(0.089,0.32)]were superior to chemotherapy.And erlotinib [HR = 0.55,95% CI(0.31,0.95)],oxetinib [HR = 0.46,95% CI(0.23,0.93)],erlotinib + bevacizumab [HR = 0.35,95% CI(0.17,0.71)] shoued a longer PFS than gefitinib.In all interventions,patients received erlotinib + bevacizumab had the longest PFS,and patients received chemotherapy had the shortest PFS.In terms of OS,gfitinib + chemotherapy has a better advantage than chemotherapy [HR = 0.43,95% CI(0.27,0.70)],gfitinib[HR = 0.45,95% CI(0.29,0.70)],erlotinib [HR = 0.43,95% CI(0.2,0.75)],afatinib[HR = 0.49,95% CI(0.30,0.81)],oxiotinib [HR = 0.56,95% CI(0.33,0.97)],and erlotinib + bevacizumab [HR = 0.46,95% CI(0.23,0.88)].Of all the interventions,erlotini + bevacizumab had the shortest OS.In terms of ORR,gfitinib[OR = 3.70,95% CI(2.30,5.70)],erlotinib [OR = 5.60,95% CI(3.00,11.00)],afatinib[OR = 5.70,95% CI(3.20,10.00)],dacomitinib[OR = 4.10,95% CI(1.50,13.00)],oxiotinib [OR = 4.40,95% CI(1.60,13.00)] and gefitinib + chemotherapy [OR = 6.30,95% CI(2.20,20.00)]were significantly superior to chemotherapy,and erlotini + bevacizumab also had a superiority than erlotini [OR = 6.60,95% CI(2.30,19.00)].Of all interventions,the first two were erlotinib + bevacizumab and gefitinib + chemotherapy,and the lowest was chemotherapy.In terms of diarrhea,gfitinib[OR = 5.10,95% CI(1.80,16.00)],erlotinib [OR = 9.00,95% CI(3.20,26.00)],afatinib [OR = 60.00,95% CI(21.00,190.00)],dacomitinib[OR = 28.00,95% CI(3.80,230.00)],gefitinib + chemotherapy[OR = 12.00,95% CI(1.60,94.00)]and erlotini + bevacizumab[OR = 11.00,95% CI(2.20,59.00)]showed a higher diarrhea incidence than chemotherapy.Afatinib also had a higher diarrhea incidence than gefitinib[OR = 12.00,95% CI(3.30,41.00)]and erlotinib(OR = 6.60,95% CI = 1.50-31.00).Of all the interventions,chemotherapy had the lowest diarrhea incidence,and the highest was afatinib.In terms of rash,gfitinib [OR = 18.00,95% CI(3.80,93.00)],erlotinib[OR = 23.00,95% CI(3.70,140.00)],afatinib [OR = 64.00,95% CI(10.00,420.00)],dacomitinib [OR = 33.00,95% CI(1.10,1100.00)],and gefitinib + chemotherapy[OR = 33.00,95% CI(1.10,1100.00)]lead to a higher rash incidence than chemotherapy.Of all the interventions,the lowest rash incidence was chemotherapy.The rash rates of erlotinib + bevacizumab,gefitinib + chemotherapy,dacomitinib and afatinib were higher.In terms of stomatitis,erlotinib[OR = 4.50,95% CI(1.10,23.00)],afatinib[OR = 15.00,95% CI(5.80,41.00)],dacomitinib [OR = 7.50,95% CI(1.10,49.00)],and erlotini + bevacizumab[OR = 7.00,95% CI(1.20,52.00)]brought a higher stomatitis incidence than chemotherapy.Afatinib also had a higher stomatitis incidence than gefitinib[OR = 7.20,95% CI(2.30,25.00)].Of all the interventions,the lowest stomatitis incidence was chemotherapy,and the highest was afatinib.Conclusion:EGFR positive patients with advanced non-small cell lung cancer,the first-line treatment protocol needs to be comprehensively evaluated according to the patient’s gene mutation type,ps score,and general situation.(1)In patients with classic mutations,oxiotinib may be first choice for first-line treatment,especially in patients with brain metastases.(2)If PS= 0~1,gefitinib + chemotherapy is preferred as a first-line treatment for patients whose economic conditions do not permit.(3)EGFR positive patients with rare mutations,afatinib is recommended as a first-line treatment regimen.(4)In terms of adverse reactions,oxiotinib had the lowest incidence of diarrhea and rash,and gefitinib had the lowest incidence of stomatitis.(5)Erlotinib + bevacizumab did not benefit overall survival,and further trials are needed to explore its beneficial population. |
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