Clinical Study On The Application Of PD-1 Antibody In Postoperative Adjuvant Therapy For Resectable Primary Liver Cancer

Background and Objective:Primary liver cancer is currently the fourth common malignant tumor and the second cause of tumor death in China,of which hepatocellular carcinoma accounts for about 90%of cases,which has seriously threatened the life and health of the Chinese people.Although surgical resection is the preferred treatment for resectable liver cancer in China,the recurrence rate is still high in 5 years after surgery,which has seriously restricted the treatment effect of liver cancer.In the comprehensive treatment mode of liver cancer based on surgery,immunotherapy represented by programmed death-1(PD-1)has increasingly enriched the treatment methods of liver cancer,and is likely to improve the prognosis of patients.However,the monotherapy regimen of immunotherapy has not met expectations,and the idea of postoperative adjuvant therapy or combined anatomic liver resection is gradually supported by increasing research evidence.This study aims to explore the efficacy of PD-1 antibody in postoperative adjuvant maintenance therapy for resectable primary liver cancer,hoping to provide a basis for the treatment plan of patients with hepatocellular carcinoma.Methods:The clinical data and survival data of patients with hepatocellular carcinoma who underwent radical surgical resection or combined with adjuvant postoperative PD-1antibody therapy in our hospital from August 2020 to March 2023 were retrospectively collected.A total of 156 patients were enrolled based on the inclusion and ranking criteria,including 108 males and 48 females,with a mean age of 54.7±9.8 years.Those who met the indications for radical surgery after evaluation all underwent anatomical/non-anatomical liver resection in our hospital,and according to the different surgical methods and postoperative adjuvant therapy,the enrolled patients with hepatocellular carcinoma were divided into four groups:(1)36 people in the non-immune+non-anatomical group,and PD-1 monoclonal antibody adjuvant therapy was not received after non-anatomical hepatectomy;(2)41 people in the immune+non-anatomical group,PD-1 antibody adjuvant therapy after non-anatomical hepatectomy for 6 months;(3)There were 39 people in the anatomical+non-immune group,and PD-1 antibody adjuvant therapy was not performed after anatomic liver resection;(4)40 people in the immune+anatomical group,adjuvant treatment with PD-1 monoclonal antibody after anatomic hepatectomy for 6 months.Regular follow-up was conducted through outpatient or telephone,and the patient’s recurrence and survival were recorded in detail.SPSS 26.0 statistical software was used to analyze the data,univariate log-rank and multivariate Cox regression to analyze patient-related risk factors,Kaplan-Meier method to calculate recurrence-free survival and overall survival,t-test compared with the number of peripheral blood T lymphocyte subsets(%)before and after immunotherapy,χ~2test to compare and analyze anatomical/non-anatomical liver resection perioperative adverse event differences,all statistical tests were double-sided.P<0.05 was considered statistically significant,with 95%confidence in the confidence intervals.Results:1.There were no significant statistical differences in the comparison of baseline data,such as gender,age,Child-Pugh grade,CNLC stage,preoperative AST,preoperative AFP,HBs Ag,microvascular invasion,tumor number,tumor diameter,liver cirrhosis,intraoperative blood loss volume in four different treatment groups(P>0.05).2.Patients before surgery had met the indications for radical surgery,and the postoperative pathology was confirmed to be R0 resection with wide incision margin.Within 1 month after surgery,no residual tumor lesions were confirmed by imaging.During the perioperative period,there were 6 cases of abdominal hemorrhage,42 cases of pleural effusion,14 cases of biliary leakage,20 cases of pneumonia,6 cases of impaired renal function,12 cases of transferring to ICU,8 cases of lower extremity venous thrombosis,and4 cases of poor incision healing.These patients were discharged from hospital after conservative management and did not die perioperatively.Compared with non-anatomic liver resection,the incidence of adverse events such as abdominal bleeding,pleural effusion,pneumonia,and renal impairment was lower(P<0.05).3.The median tumor-free survival time in the non-immune+non-anatomical group was 8.0 months(95%CI:1.27-14.73 months).The median tumor-free survival in the immune+non-anatomical group was 28.0 months(95%CI:16.78 to 39.22 months).The median tumor-free survival in the anatomical+non-immune group was 26.0 months(95%CI:19.51 to 32.49 months).The immune+anatomical group did not achieve median tumor-free survival during the follow-up period.The median tumor-free survival time of the above four groups was statistically significant(χ~2=31.899,P<0.001).4.The enrolled patients were all early and did not reach the median overall survival time during the follow-up period.The overall comparison of total survival time of the above four groups was statistically significant(χ~2=15.75,P=0.001).5.Univariate Log-rank and multivariate Cox regression model analysis showed that the higher risk of postoperative recurrence was associated with AFP≥40ng/ml(HR=3.46,1.94-6.16,P<0.001),tumor diameter≥5cm(HR=2.34,1.33-4.11,P=0.003),and multiple tumors(HR=3.18,1.75-5.80,P<0.001),combined with microvascular invasion(HR=2.16,1.19-3.92,P=0.011),and different treatment groups.The risk of death was related to AFP≥40ng/ml(HR=7.03,2.12-23.33,P=0.001),multiple tumors(HR=10.26,2.76-38.08,P=0.001),combined with microvascular invasion(HR=3.81,1.17-12.45,P=0.027),and whether or not immuno+anatomical regimens were used(HR=0.15,0.03-0.75,P=0.021).6.There was no significant difference in CD4+(%),CD8+(%)and CD4+/CD8+between the groups before postoperative PD-1 antibody adjuvant maintenance therapy.After 6 months of PD-1 treatment,CD4+(t=18.842,P<0.05)and CD4+/CD8+(t=16.627,P<0.05)levels were higher than those in the non-immunotherapy group,and CD8+levels were lower than those in the non-immunotherapy group(t=14.536,P<0.05).Conclusion:1.Patients with resectable primary liver cancer can be treated with PD-1 antibody adjuvant maintenance therapy for 6 months after surgery,which can increase the level of helper T lymphocytes,reduce the level of suppressor T lymphocytes,and enhance cellular immune surveillance and anti-tumor function.2.Anatomical liver resection method with wide incision margin can be adopted in patients with resectable primary liver cancer,which can improve safety.3.Postoperative use of PD-1 antibody adjuvant maintenance therapy,anatomical liver resection with wide margins or a combination of the two can prolong the tumor-free survival time and overall survival time after surgery.4.Preoperative AFP,multiple tumor nodules,MVI and different treatment regimens are independent risk factors affecting the tumor-free survival and overall survival time of patients with hepatocellular carcinoma.