| Research backgroundLiver cancer,mostly hepatocellular carcinoma(HCC),ranks fourth in cancer incidence and second mortality in China.China has a large burden of patients with chronic hepatitis B.In China,84%of HCC patients were caused by chronic hepatitis B virus(HBV)infection.HBV infection and The increased HBV-DNA level is closely related to the occurrence and recurrence of HCC.Partial hepatectomy,liver transplantation and local ablation/solidification can achieve the goal of curative treatment.But the shortage of donor organs and the long waiting time limit the application of liver transplantation in the treatment of HCC.Therefore,partial hepatectomy is still the first choice for the treatment of resectable HCC.However,the 5-year recurrence rate of hepatectomy is as high as 50-70%,which makes the long-term survival rate of patients with HCC unsatisfactory.Early recurrence after liver resection for HCC is one of the important factors leading to poor prognosis.Reducing the recurrence rate is the key to improve the efficacy of HCC.Therefore,in order to prevent and monitor the early recurrence of patients with HCC,it has become a hot spot to study the risk factors and prediction model of early recurrence of HCC.A large number of previous studies have reported the risk factors of early recurrence,including microvascular invasion(MVI),tumor capsule loss,tumor diameter,HBV/HCV infection,the level of HBV-DNA,PIVKA-II,alpha fetoprotein(AFP),anatomical hepatectomy,intraoperative hemorrhage and blood transfusion,etc,but there were some different conclusions of different studies.In recent years,real world research(RWR)has attracted the attention of medical researchers.In the real world,patients' choice of diagnosis and treatment depends entirely on their condition and wishes,it is a non random,open,non placebo,non blind trial,which is closer to the real medical environment,and the results are relatively real and reliable.In the real world,the risk factors of early recurrence of HCC patients with different conditions and backgrounds,at the same time,for the patients with recurrence after curative resection,how to choose an effective treatment to improve the survival time of patients has always been a problem for clinicians.Therefore,from the perspective of the real world,explore the risk factors of early recurrence and postoperative death of patients with hepatitis B-related HCC in China,establish a prediction model of early recurrence after curative resection of hepatitis B-related HCC,so as to carry out strict monitoring and early intervention for the high-risk recurrence and death population,and select appropriate intervention measures for the recurrence of HCC,so as to improve the efficacy of HCC patients.Part one:Analysis of risk factors of early recurrence of hepatitis B-related HCC after curative hepatectomyObjectiveIn the current retrospective cohort study,we are to explore the risk factors associated wilth postoperative early tumor recurrence in patients with hepatitis B-related HCC after curative resection based on real world data.We would identify patients with high-risk of early recurrence and provide intensive monitor and follow-up for these patients so as to improve the survival rate in patients with hepatitis B-related HCC after hepatectomy.Patients and methods1.Through the database of China Liver Cancer Clinical Study(CLCS)and the Hospital Information System,we collected 3958 patients who were treated for HCC in First Affiliated Hospital of University of Science and Technology of China(Anhui Provincial Hospital)between January 1,2012 and August 31,2018.Of them,465 patients with hepatitis B-related HCC who underwent curative resection were included in this study according to the purpose and requirements of this study.We collected the clinical information including:(1)The basic information of patients:name,hospital number,gender,age,drinking history,smoking history.(2)Preoperative serum tumor markers,serological examination and classification of liver function:hepatitis B core antibody(anti-HBc),hepatitis B surface antigen(HBsAg),preoperative serum AFP,HBV-DNA,serum alanine aminotransferase(ALT),serum albumin(ALB),serum total bilirubin(TB),prothrombin time(PT),platelet(PLT),the ratio of neutrophil to lymphocyte(NLR),the ratio of platelet to lymphocyte(PLR),the ratio of serum albumin to globulin(AGR),Child-Pugh classification.(3)Operation related data:surgical approaches,the type of hepatectomy,operation duration,intraoperative bleeding,perioperative blood transfusion,ascites.(4)Postoperative pathological examination and liver cancer stage:tumor size,tumor number,liver cirrhosis,microvessel invasion(MVI),tumor capsule,Edmondson grade,Chinese Liver Cancer(CNLC)(2017 version)stage,Barcelona Clinic Liver Cancer(BCLC)(2018 version)stage.(5)Follow up information:the status of tumor recurrence,recurrence time.2.We Compared the clinicopathological characteristics between patients with early recurrence and those without early recurrence.3.Kaplan Meier curve was used to analyze the clinicopathological factors associated with early recurrence in patients with hepatitis B-related HCC after curative resection.Subgroup analysis was performed in male and female patients.The multivariate Cox hazard model was used to analyze the independent risk factors that were related to early recurrence in patients with hepatitis B-related HCC after curative resection.Result1.The following factors were associated with early recurrence after curative resection for hepatitis B-related HCC:NLR,PLR,AGR,blood loss,tumor size,tumor encapsulation,MVI,anatomical resection,Edmondson grade,HBV-DNA,perioperative blood transfusion,CNLC stages and BCLC stages(P<0.05).The following factors were associated with post-operative death:NLR,PLR,AGR,blood loss,tumor size,MVI,TB,Edmondson grades,Child-Pugh classification,CNLC stages and BCLC stages(P<0.05).2.The Kaplan Meier curve was used to analyze 465 patients with hepatitis B-related HCC after curative resection.One hundred and eighty one patients were diagnosed with early recurrence.The 1-year and 2-year recurrence-free survival rates were 69.4%and 60.6%,respectively.In the subgroup analysis of male and female patients,156 cases of early recurrence occurred in men and 25 cases in women.The 1-year recurrence-free survival rates of men and women was 67.9%and 76.9%,respectively.Log-rank test showed that there was no statistical significance in the 2-year recurrence free survival curve of men and women.3.Multivariate Cox proportional hazard model analysis showed that MVI,tumor diameter>5cm and ALB<35 g/L were independent risk factors for early recurrence of hepatitis B-related HCC.Conclusion1.There are some statistical differences in some basic characteristics between patients with early recurrence and those non early recurrence after curative hepatectomy.2.MVI,tumor diameter>5 cm,and ALB<35 g/L were independent risk factors for early recurrence in patients with hepatitis B-related HCC(P<0.05).Part two:Construction and validation of early recurrence prediction model after curative resection of hepatitis B-related HCCObjectiveBuild a prediction model for early recurrence.With this model,we would predict the possibility of recurrence accurately.Patients and methods1.Based on the results of the part one of this study,with these independent risk factors,a prediction model was established to predict early recurrence,and early recurrence prediction nomogram was drew.The prediction model was internally verified with ROC curves.2.Through the database of the Hospital Information System of Taizhou hospital in Zhejiang Province,9858 discharged patients with operation records in hepatobiliary and pancreatic surgery department from January 1,2012 to August 31,2018 were collected.A total of 175 patients with hepatitis B-related HCC who underwent curative resection were screened according to the purpose and requirements of the study.Through the database of the Hospital Information System of Taizhou Enze hospital in Zhejiang Province,2806 discharged patients with operation records in hepatobiliary and pancreatic surgery department from January 1,2015 to August 31,2018 were collected.According to the research purpose and requirements,45 patients with hepatitis B-related HCC were selected for radical resection.This data of clinical cases were collected as the external validation data of the prediction model of early recurrence after curative hepatectomy.ResultMultivariate Cox proportional hazard model analysis showed that MVI,tumor diameter>5cm and ALB<35 g/L were independent risk factors for early recurrence of hepatitis B-related HCC.According to the results of multivariate Cox proportional hazard model,an early recurrence risk-prediction model was fitted as H(T)=h(t)=hOexp(0.60X 1+0.50X2+0.48X3),and the nomogram of early recurrence prediction model was drawn.The AUC of the prediction model is 0.638(95%CI:0.588?0.687),and the AUC of the external validation is 0.656(95%CI:0.579?0.732).The calibration curve shows that the prediction probability of the prediction model is close to the actual observation probability and has strong consistency.ConclusionMVI,tumor diameter>5 cm,and ALB<35 g/L were independent risk factors for early recurrence in patients with hepatitis B-related HCC(P<0.05).A prediction model based on these 3 factors can predict the recurrence of HCC patients aftercurative operation which was validated in an independent cohort,the predicitionmodel has a good discrimination and calibration,therefore,the prediction modelcould be extended to other cohort of HCC patients.Part three:Risk factors of death and survival analysis of different treatmentmeasures after curative resection of hepatitis B-related HCCObjectiveIn the current retrospective cohort study,we are to explore the risk factors associated wilth postoperative death in patients with hepatitis B-related HCC after curative resection based on real world data,Also,we compare the survival time for patients receive different adjuvant therapies.With the using proper adjuvant therapies,we could improve the survival rate in patients with hepatitis B-related HCC after hepatectomy.Patients and methods1.In the same time,465 patients with hepatitis B-related HCC who underwent curative resection in the First Affiliated Hospital of Science and Technology of China(Anhui Provincial Hospital)were followed up for survival or death,cause of death,time of death and futher treatment measures after recurrence.2.We Compared the clinicopathological characteristics between patients with postoperative death and those without postoperative death,and the basic characteristics of the recurrent population treated and untreated.3.Kaplan Meier curve was used to analyze the survival of patients with hepatitis B-related HCC after curative resection,and the subgroup analysis of the survival between male and female patients.The multivariate Cox model was used to analyze the independent risk factors related to mortality in patients with hepatitis B-related HCC after curative resection.4.Kaplan Meier curve was used to analyze the survival of patients with recurrence after curative resection with different treatment measures,and subgroup analysis was carried out.The univariate and multivariate Cox model was used to analyze risk of death in patients receiving further treatment and untreated after recurrence.Result1.The following factors were associated with post-operative death:NLR,PLR,AGR,blood loss,tumor size,MVI,TB,Edmondson grades,Child-Pugh classification,CNLC stages and BCLC stages(P<0.05).2.There were 132 cases with death,the 1-,3-,and 5-year cumulative survival rates were 92,1%,78.0%and 64.0%,respectively.In the subgroup analysis,115 deaths occurred in men and 17 in women.The 1-year cumulative survival rate of men and women was 92.6%and 89.6%,the 3-year cumulative survival rate was 77.0%and 78.8%,and the 5-year cumulative survival rate was 62.6%and 70.2%,respectively.Log rank test showed that there was no significant difference in survival curve between men and women.In the subgroup analysis of early recurrence and non early recurrence population,31 cases in the non early recurrence group and 101 cases in the early recurrence group had death outcome events,with the 1-year cumulative survival rate of 99.6%and 79.6%,3-year cumulative survival rate of 96.5%and 46.7%,5-year cumulative survival rate of 85.3%and 25.4%,respectively.Log rank test showed that the difference of survival curve between the two groups was statistically significant.3.Multivariate Cox proportional hazard model analysis showed that MVI,Edmondson grades III/IV,BCLC stage B,and TB>20.5?mol/L were independent risk factors for postoperative mortality in patients with hepatitis B-related HCC.4.The Kaplan Meier curve was used to analyze 239 hepatitis B-related HCC patients with recurrent after curative resection,95 of whom did not receive further treatment and 144 received further treatment.The median survival time was 19 months and 75 months,respectively.The 1-year survival rate was 73.0%and 92.9%,the 3-year survival rate was 27.3%and 79.1%,and the 5-year cumulative survival rate was 9.0%and 58.0%,respectively.Log rank test showed that the difference of survival curve between the treatment group and the untreated group was statistically significant(P<0.001).The risk of death was reduced by 80%(HR:0.21,95%Cl:0.14-0.30)in the treated group compared with the recurrent untreated group.There were 75 cases,31 cases,13 cases and 4 cases in the non treatment group,TACE group,operation/radio frequency/solidification group and other treatment groups respectively,The median survival time was 19 months,61 months,Na and 47 months.The 1-year cumulative survival rate of the four groups was 73.0%,89.0%,97.7%and 100%respectively.The 3-year cumulative survival rate was 27.3%,75.0%,82.0%and 86.0%respectively.The 5-year cumulative survival rates were 9.0%,52.4%,65.0%and 26.7%respectively.5.Multivariate Cox proportional hazard model analysis showed that compared with those who did not receive post-recurrence treatment,the risk of death was reduced by 75%,85%and 78%,respectively,in those who received TACE,operation/radiofrequency/solidification and other treatments,respectively.Conclusion1.There are some clinicopathological factors associated with post-operative death.Post-recurrence treatments were also associated post-operative death.2.MVI,Edmondson grades ?/?,BCLC stage B and TB>20.5?mol/L were independent risk factors for postoperative death(P<0.05).The survival time of patients with early recurrence was shorter than that of patients without early recurrence(P<0.0001).3.Patients received post-recurrence treatment had a relatively lower risk of death.Patients who received operation/radiofrequency/solidification after tumor recurrence had a lowest risk of death and had a highest 5-year survival rate. |
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