Clinical Study Of Combination Therapy With Radiofrequency Ablation And Apatinib For Recurrent Small Hepatocellular Carcinoma

background: Primary hepatic cancer is a common malignant tumor in China.The incidence and mortality of PHC in malignant tumor rank fourth and third,respectively.Hepatocellular carcinoma(HCC)accounts for 85% to 90%.At present,the clinical treatment of HCC is diversified,but the ultimate bottleneck of treatment is relapse and metastasis.Although surgical resection remains the preferred treatment for recurrent small HCC,hepatectomy is limited due to poor tolerance,different degrees of cirrhosis,hepatic insufficiency,liver reserve function inadequatcy and multiple tumors.Radiofrequency ablation(RFA)has become a radical treatment for small HCC because of its advantages of minimally invasive,safe,simple and easy to repeat the treating procedure.The clinical effect of RFA is similar to hepatectomy.However,there are still some shortcomings in RFA,among which are incompletely ablation and heat-sink effect.In addition,studies have found that incomplete RFA may stimulate the high expression of vascular endothelial growth factor(VEGF),causing an increase in tumor microvessel density,and leading to rapid growth of liver cancer cells and even early recurrence and metastasis of liver cancer.Most scholars have proposed to reduce the blood flow of liver cancer by non-invasive or invasive means to improve the efficacy of RFA,and have been verified in animal experiments.Apatinib is an anti-angiogenic drug that can improve the prognosis of patients with HCC.Compared with sorafenib,apatinib has the advantages of high bioavailability,short half-life,more controllable adverse reactions,and the cost is more acceptable.According to the different mechanisms of RFA and Apatinib in the treatment of HCC,it is feasible to combine the two regimens and treat HCC by local and global approaches.Therefore,we hypothesized that combining RFA with apatinib may increase ablation efficacy.Objective: To explore the difference of clinical efficacy and safety of RFA combined with apatinib versus RFA alone in the treatment of recurrent small HCC.Methods: A total of 50 recurrent small HCC patients were enrolled in The Second People's Hospital of Neijiang from October 2015 to December 2017,dividing into two groups according to different treatment methods: RFA combined with apatinib group(group A,n=25)and RFA alone group(group B,n=25).Relevant data were obtained from clinical records of patients.The end of the follow-up was December 2018.The clinical data of gender,age,Netiology,size of tumor,location of tumor,number of tumor,Child-Pugh classification,AFP level and BCLC stage were collected and compared between the two groups.Disease control rate(DCR),Progression free survival(PFS),recurrence time of tumors and adverse reactions after treatment were compared between the two groups.Linical factors which may influence patients' PFS were investigated by univariate analysis.Cox's proportional hazards model was used to analyze variables associated with survival.Log-Rank test was used to investigate the relationship between the adverse reactions of apatinib and PFS.SPSS17.0 statistical software is used to Statistical analysis.P<0.05 is considered to be statistically significant.Result: 1.No significant difference of sex,gender,etiology,location of tumor,size of tumor,number of tumor,Child-Pugh classification,AFP level and BCLC stage between the two groups of patients were found(all P>0.05).The two groups of patients had comparability.2.The evaluation after treatment,group A: DCR accounted for 56.00%(14/25),group B: DCR accounted for 28.00%(7/25),and the difference was statistically significant(56.00% vs.28.00%,P<0.05).3.The median progression-free survival(mPFS)of group A was 23.50 months(95% CI: 21.27-25.73 months),and of group B was 15.50 months(95% CI: 9.79-21.21 months),and the difference was statistically significant(P<0.05).4.In the two groups,29 patients had recurrence and metastasis of HCC,group A accounted for 11 cases,6 cases underwent RFA again,and group B accounted for 18 cases,10 cases underwent RFA again.Group A had fewer the frequency of re-RFA and longer the average interval of re-RFA.The average recurrence time of tumor in group A was 18.73±3.97 months,while that in group B was 18.73±3.97 months,and the difference was statistically significant(P<0.05).5.Univariate analysis found that location of tumor(P=0.017),antiviral therapy(P=0.039),and oral Apafitini(P=0.013)affected the prognosis of patients with PFS.Cox's proportional hazards model analysis showed that location of tumor and oral Apatinib were independent-prognosis factors for PFS.6.In group B,The mPFS was 25 months of patients with secondary hypertension(95% CI: 23.83-25.93 months),21.50 months of patients without secondary hypertension(95% CI: 18.00-25.00 months),with significant difference(P<0.05);The mPFS was 25 months in patients with secondary proteinuria(95% CI: 23.95-26.17 months),and 21.50 months in patients without secondary proteinuria(95% CI: 18.04-24.96 months),with significant difference(P<0.05).The mPFS of patients with secondary hand-foot syndrome was 23.50 months(95%CI: 21.67-25.13 months)and that of patients without secondary hand-foot syndrome was 22 months(95%CI: 13.08-30.92 months).There is no significant(P>0.05).7.The main adverse reactions of RFA,such as fever,pleural effusion,pain in operation area and abnormal liver function were observed,all of which were mild complications,and no severe complications occurred.No statistically significant was manifested between the two groups(all P>0.05).The main adverse reactions of apatinib were hypertension,proteinuria,hand-foot syndrome.Severe adverse reactions(grade 3/4)occurred in 4 cases,including 2 cases with grade 3/4 hypertension and 2 cases with grade 3/4 hand-foot syndrome.All patients continued to take orally at the original dose or reduced dose,and no serious adverse reactions occurred after that.Conclusion: 1.RFA combined with apatinib has more advantages in the treatment of recurrent small HCC,which can significantly prolong PFS and recurrence time of tumor,and most adverse reactions can be tolerated.2.The independent-prognosis factors with PFS of recurrent small HCC relates to location of tumor and apatinib administration.In addition,Secondary hypertension and proteinuria may bring potential survival benefits with recurrent small HCC after treatment with apatinib.