Apatinib Plus Metronomic S-1 Versus S-1 Plus Oxaliplatin,or Sorafenib Alone In The First-line Treatment Of Advanced Primary Liver Cancer

Objective:To explore the efficacy and safety of apatinib plus metronomic S-1(AS)versus S-1 combined with oxaliplatin(SOX),or sorafenib alone(SOR)for patients with advanced primary Liver cancer(PLC)that was unresectable or unable to perform local treatment.Method:This retrospective study involved patients with advanced PLC,who were treated with SOX regimen(oxaliplatin[130 mg/m~2]on day 1 and S-1[40-60mg/day]on day 1–14,every 3 weeks),sorafenib(400mg twice daily,continuous medication),or apatinib(250mg twice daily,continuous medication)combined with metronomic S-1(20mg twice daily,continuous medication)in the first-line treatment.Objective effects of the three groups were evaluated according to the RECIST 1.1 standard,and adverse reactions were evaluated according to the CTCAE 5.0 standard.The progression-free survival,overall survival were analyzed by Kaplan-Meier analysis and compared by log-rank test on the SPSS 19.0,the COX regression model was used to analyze the independent influencing factors of patients with advanced PLC.Results:1.The baseline clinical characteristics of the three groups of patients were analyzed for differences among groups.There were no significant differences in age,gender,history of liver virus infection,history of alcoholism,Smoking history,AFP concentration,ECOG-PS score,Child-pugh classification,BCLC stage,and TNM stage among the groups.2.The mPFS of the apatinib combined with metronomic S-1 group was 6.8months(95%CI:3.8-9.8 months),and the mOS was 9.7 months(95%CI:7.5-11.9 months);The median progression-free survival(mPFS)of the sorafenib group was 4.3 months(95%CI:3.9-4.7 months),and the median overall survival time(mOS)was 10.2 months(95%CI:0.3-20.1months);The mPFS of the SOX group was 3.3 months(95%CI:2.2-4.4 months),and the mOS time was 8.0 months(95%CI:4.2-11.8 months).The mPFS of the AS group was longer than those of the sorafenib group and SOX group,and the differences were statistically significant(P=0.041,P=0.000);the mPFS of SOX group was shorter than the SOR group,but the difference was not statistically significant(P=0.129).There was no statistically difference among the three groups.Multivariate analysis using the COX model found that AFP concentration is an independent risk factor for OS in advanced primary liver cancer(HR=1.58,95%CI:1.03-2.42;P=0.036).We didn’t found independent risk factors affecting PFS in advanced PLC.3.143 patients’objective efficacy evaluations were compared.The ORR of AS group was higher than that of SOR group,the difference was not statistically significant(17%vs 7.9%,P=0.223);the DCR of AS group was higher than that of SOR group,the difference was statistically significant(91.2%vs 63.2%,P=0.004);The ORR and DCR of the AS group were higher than those of the SOX group,and the difference was statistically significant(17%vs 3.1%,P<0.001;91.2%vs 40.6%,P=0.013);the ORR of the SOX group was lower than that of the SOR group,and the difference was not statistically significant Significance(3.1%vs 7.9%,P=0.283),the DCR of SOX group was lower than that of SOR group,the difference was statistically significant(40.6%vs 63.2%,P=0.029).4.165 cases can be evaluated for safety.The total incidence of adverse events in the AS group was 67.2%.Common adverse reactions were nausea(38.1%),vomiting(30.2%),diarrhea(12.7%),leukopenia(12.7%),thrombocytopenia(14.3%),proteinuria(22.2%),hand-foot syndrome(31.7%),hypertension(42.9%);grade III/IV adverse reaction rate was 7.9%,mainly:proteinuria(6.3%),hand-foot syndrome(7.9%),high Blood pressure(7.9%).The total incidence of adverse events in the SOR group was 76.3%.Common adverse reactions were nausea(10.5%),vomiting(10.5%),diarrhea(50%),leukopenia(26.3%),hypertension(26.3%),hand-foot synthesis Sign(31.6%);the rate of grade III/IV adverse reactions was 13.2%,mainly:diarrhea(7.9%)and hypertension(2.6%).The total incidence of adverse events in the SOX group was 79.7%.Common adverse reactions were nausea(40.6%),vomiting(23.4%),leukopenia(53.1%),thrombocytopenia(28.1%),and peripheral neurotoxicity(7.8%);ⅢThe gradeⅣadverse reaction rate was 12.5%,mainly due to thrombocytopenia(9.4%)and leukopenia(9.4%).The total incidence of adverse events in the AS group was significantly lower than that in the SOR group(67.2%vs 76.3%,P=0.033).The AS group had a higher risk of nausea,vomiting,thrombocytopenia,proteinuria,and hypertension than the SOR group,but diarrhea occurred The risk of leukopenia is lower than that in the SOR group.Although the total incidence of adverse reactions in the SOX group was not significantly different from that in the SOR group and AS group(79.7%vs76.3%,P=0.436;79.7%vs 67.2%,P=0.099),its nausea and vomiting The incidence of leukopenia and thrombocytopenia were significantly higher than those of the other two groups,while the incidence of diarrhea,hand-foot syndrome,hypertension,and proteinuria were significantly lower than those of the other two groups.Conclusion:1.The AS regimen has a better objective effect than SOR regimen or SOX regimen in the first-line treatment of advanced primary liver cancer;2.The AS regimen has a longer mPFS than SOR regimen or SOX regimen in the first-line treatment of advanced primary liver cancer;3.There is no no significant difference in the OS among the AS regimen,SOR regimen and SOX regimen in the first-line treatment of advanced primary liver cancer;4.The total adverse reaction rate of the AS regimen was lower than those of SOR regimen and SOX regimen,but the differences in adverse reaction spectrum among the groups was significant.