Efficacy And Safety Of PD-1/PD-L1 Inhibitors Versus Chemotherapy In Second-line Treatment Of Advanced Esophageal Cancer:A Meta-Analysis Of Randomized Controlled Trials

Objective:PD-1/PD-L1 inhibitors have shown significant efficacy in a variety of advanced solid tumors,but the efficacy and safety of PD-1/PD-L1 inhibitors in second-line treatment of advanced esophageal cancer should be further determined compared with traditional chemotherapy.we systematically evaluated the efficacy and safety of PD-1/PD-L1 inhibitors versus chemotherapy in the second-line treatment of advanced esophageal cancer through a meta-analysis based on RCT studies,hoping to provide some reference for clinical decision-making.Methods:Pub Med,The Cochrane Library,Embase,CNKI,Wanfang and CQVIP were searched up to December 2020,after screening the literatures and extracting the data according to the inclusion and exclusion criteria,compared the differences in the efficacy and adverse reactions between PD-1/PD-L1 inhibitors single drug and chemotherapy,the HR（hazard ratio）or RR（relative risk）and 95%CI（confidence intervals）were calculated and analyzed using Review Manager 5.3 software.Result:A total of 1495 patients with second-line treatment for advanced esophageal cancer from three randomized controlled trials were included in the meta-analysis.As to the efficacy,in comparison with chemotherapy,PD-1/PD-L1 inhibitors reduce mortality[HR=0.80,95%CI（0.72,0.90）,P<0.0001],improved 12-month survival[RR=1.40,95%CI（1.20,1.63）,P<0.0001]and 18-month survival[RR=1.57,95%CI（1.25,1.96）,P<0.0001],prolonged median overall survival[HR=0.80,95%CI（0.72,0.90）,P=0.0001],improved 18-month PFS（progression-free survival）rate[RR=3.12,95%CI（1.65,5.89）,P=0.0005].However,there was no significant difference in objective response rate,disease control rate,median progression-free survival,6-month and 12-month PFS rate between PD-1/PD-L1 inhibitors and chemotherapy（P>0.05）.Subgroup analysis suggested that PD-1/PD-L1 inhibitors were more effective in men,younger than 65 years of age,Asian,PD-L1 expression≥1%and esophageal squamous cell carcinoma subtypes（HR<1,P<0.05）,but there was no significant positive relationship between its efficacy and PD-L1 expression level[HR_PD-L1≥1%=0.64,95%CI（0.51,0.80）,P<0.0001,HR_PD-L1≥5%=0.65,95%CI（0.48,0.87）,P=0.004、HR_PD-L1≥10%=0.66,95%CI（0.47,0.92）,P=0.02].In terms of safety,there was no significant difference in TRAE（treatment-related adverse events）between PD-1/PD-L1 inhibitors and chemotherapy[RR=0.82,95%CI（0.59,1.13）,P=0.22],the incidence of hypothyroidism was higher than that of chemotherapy group[RR=16.98,95%CI（6.25,46.17）,P<0.00001],however,the incidence of grade≥3TRAE was lower than that of chemotherapy[RR=0.40,95%CI（0.29,0.54）,P<0.00001],there was no significant difference in the incidence of treatment-related death between the two groups[RR=1.35,95%CI（0.60,3.01）,P=0.47].Conclusion:Single drug treatment with PD-1/PD-L1 inhibitors can achieve long-term clinical benefit for patients with advanced esophageal cancer for second-line treatment,with less incidence of serious adverse reactions and good safety.PD-1/PD-L1 inhibitors were more effective in men,younger than 65 years of age,Asian,PD-L1 expression≥1%and esophageal squamous cell carcinoma subtypes,but there was no significant positive relationship between its efficacy and PD-L1 expression level.