| Objective :Cholangiocarcinoma(CCA)is a malignant tumor of the biliary system derived from the epithelial cells of the bile duct,which is divided into intrahepatic and extrahepatic cholangiocarcinoma.Due to its high degree of malignancy and poor prognosis,it is prone to lymph node metastasis and nerve and vascular infiltration,so the five-year survival of patients is low and the therapeutic effect is poor.The main treatment for cholangiocarcinoma is radical surgical resection.However,due to the hidden disease in the early stage,most patients cannot receive surgical treatment and can only receive drug treatment,but the effect is poor.Apatinib,as an antiangiogenic drug developed independently in China,has become an important drug therapy for a variety of malignant tumors,which can inhibit the production of blood vessels and the proliferation of tumor cells.Apatinib is an anti-angiogenic drug developed by our country,and its efficacy has been validated in gastric cancer,small cell lung cancer and other malignant tumors.Immune Checkpoint Inhibitors(ICIs),as a kind of immune therapy,has been successfully applied in the treatment of a variety of malignant tumors,and has achieved satisfactory therapeutic effect,becoming an important means of anti-tumor therapy.However,in the treatment of bile duct cancer is still in the stage of clinical research and exploration.Therefore,we evaluated the efficacy and safety of Apatinib combined with immune checkpoint inhibitors in the second-line treatment of advanced cholangiocarcinoma,analyzed the expression of related immune factors in the bile duct tumor microenvironment and the correlation between Apatinib and immunotherapy for advanced cholangiocarcinoma,and provided new ideas for the second-line treatment of patients with advanced cholangiocarcinoma..Methods:The study selected 40 patients with cholangiocarcinoma diagnosed by the Department of Oncology and Hepatobiliary Surgery of the Second Affiliated Hospital of Nanchang University from June 2018 to June 2022,who received second-line treatment after progression or intolerance of first-line treatment.They were divided into two groups according to different treatment plans.The first group was combined treatment with Apatinib combined with ICIs.The other group was chemotherapy group,with 20 cases in each group.The medical history,general laboratory Tumors,and clinicopathological data of the two groups were collected,The objective response rate,disease control rate,median progression-free survival and median survival of the two groups were evaluated comprehensively.The incidence of adverse drug reactions in the two groups was analyzed.In addition,the expression of CD3,CD4,CD8,NK cells and related tumor markers in peripheral blood of patients’ tumors were detected,and the correlation with the therapeutic effect of Apatinib and immunotherapy on advanced cholangiocarcinoma was analyzed.Gene Sequencing of tumor tissue in 15 patients in the combination treatment group was performed through Next Generation Sequencing(NGS),and the results were evaluated and analyzed by gene sequencing..Results:1.There were no statistically significant differences in the characteristics of baseline clinical data such as gender,age,ECGO score,metastatic site,surgical resection history and first-line treatment between the two groups,which were comparable(p>0.05).2.According to the study results and RECIST 1.1 standard evaluation,no patients achieved Complete remission(CR)and 5 achieved Partial response(PR)rates in the combined group.There were 14 patients with Stable disease(SD)and one patient with Progressive disease(PD).Objective response rate(ORR)was 15.00%,and Disease control rate(DCR)was 95.00%.In the chemotherapy group,0 patients achieved CR,0 patients achieved PR,15 patients with SD,5 patients with PD,ORR was 0.00%,DCR was 75%.median Progression-free survival(m PFS)and median Overall survival(m OS)were 4.20 months and 7.10 months respectively in the combination group.median Progression-free survival(m PFS)was 3.90 months and median Overall survival(m OS)was 6.80 months in the chemotherapy alone group.The m PFS and m OS of the two groups were significantly different(P<0.05).3.In terms of adverse reactions,a total of 16 patients in the combined treatment group experienced adverse reactions after treatment,including 11 cases of thrombocytopenia(55.00%),11 cases of leukopenia(55.00%),10 cases of secondary hypertension(50.00%)and 9 cases of fatigue(45.00%).There were 6 cases of hand-foot syndrome(30.00%),5 cases of proteinuria(25.00%),5 cases of anorexia(25.00%),4 cases of oral mucositis(20.00%),4 cases of anemia(20.00%),2 cases of rash(10.00%),in addition,3 cases of abnormal liver function(15.00%),and 3 cases of grade 3-4 adverse reactions.Including 1 case of secondary hypertension(5.00%)and 1 case of leukopenia(5.00%).9 cases of thrombocytopenia(45.00%)and 9 cases of leukopenia(45.00%)occurred in chemotherapy alone group.There were 7 cases of secondary hypertension(35.00%),6 cases of fatigue(30.00%),5 cases of anorexia(25.00%),5 cases of oral mucitis(25.00%),4 cases of hand-foot syndrome(20.00%),4 cases of albuminuria(20.00%),2 cases of anemia(10.00%),1 case of rash(5.00%).There was no significant difference between the two groups in the incidence of total adverse reactions and the incidence of grade 1-2 adverse reactions(P> 0.05),and the incidence of grade 3-4 adverse reactions was 10.00% in combined treatment group and 45.00% in chemotherapy group,which was significantly higher in chemotherapy group than in combined group(P<0.05).4.Compared with before treatment,the levels of CD3+,CD4+,CD8+ and NK cells in peripheral blood of patients in the combined treatment group were significantly increased after treatment,while the levels of tumor markers were significantly decreased(P<0.05),and the levels of immune factors and tumor markers in the combined treatment group were significantly better than those in the control group(P<0.05).5.The mutation rate of TP53 was 33.33%,that of ARIDIA was 26.27%,and that of BAPI,IDHI and FGFR2 were all 20.00%.The mutation rates of CDKN2 A,BRAF and ERBB2 were 13.33%.Kaplan-Meier curve assessment showed that patients with TP53,CDKN2 A and ERBB2 mutations had significantly shorter m PFS than wild-type patients,with statistical significance(P<0.05).Conclusion:1.The combination of Apatinib and ICIs in second-line treatment of advanced cholangiocarcinoma can significantly improve the efficacy and prolong the survival time of patients.2.The Apatinib combined with ICIs treatment group showed no significant difference in grade 1-2 adverse reactions compared with the chemotherapy group alone,while the incidence of grade 3-4 adverse reactions was significantly reduced,which was more beneficial to improve patients’ medication compliance,reduce patients’ economic burden,and improve patients’ quality of life.3.The levels of CD3+,CD4+,CD8+ and NK cells in peripheral blood,as well as CEA,CA199,CA125 and AFP in serum can be used as efficacy evaluation indexes of Apatinib combined with ICIs.4.Single factor analysis of gene test CDKN2 A,ERBB2 and TP53 mutations can shorten PFS in patients. |
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