New Score Model Predicting Tumor Recurrence Of Patients With HBV-related HCC After Curative Hepatectomy

Background and objectiveHepatocellular carcinoma (HCC) is the fifth most common malignant tumors in the world with high malignant degree, low survival rate and overall poor prognosis. According to the statistics, there is an estimated one million new cases of HCC annually and an estimated six hundred and ninety thousand deaths throughout the world. One-, three-, and five-year survival rates of patients with HCC are 66.1%, 39.7% and 32.5% respectively, and of early-phase-patients, they are 93.5%,70.1%, and 59.1%.There are many risk factors for HCC. The most common causes of HCC in China are infection of HBV or HCV and cirrhosis led by various risk factors.As research of HCC continues, people learn more about the mechanisms of the genesis and development of HCC. Improvement of clinical diagnosis and treatment and development of surgical techniques let HCC patients receive more effective treatments and prolong their survival than before. But mortality of HCC patients is still high, especially the patients of hepatitis B virus related hepatocellular carcinoma (HBV-related HCC), which is caused by chronic HBV infection. High incidence and recurrence rate after surgical resection of HBV-related HCC make it difficult for clinical HCC treatment.There are many chronic hepatitis B patients in China, and the number of HBV-related HCC patients accounts for most of the number of HCC patients. Surgery is still one of the treaments which can be used to cure HBV-related HCC. But the tumor recurrence rate of HBV-related HCC after operation is high, and some tumors grow back early after curative hepatectomy. Therefore, building a Prediction score model for HBV-related HCC might have important implications for choices of treatments before and after operation. Through a retrospective analysis on clinical data and prognosis of 180 HBV-related HCC patients with curative hepatectomy, this research aims to build a scoring system to predict the tumor recurrence of patients with HBV-related HCC after curative hepatectomy and provide basis for choices of treatments.Method1. Clinical data of 180 patients with HBV-related HCC who underwent curative hepatectomy in Department of Hepatobiliary Surgery, Nanfang Hospital affiliated to Southern Medical University from January 2009 to July 2011 were collected. Of the patients,157 cases were male and 23 cases were female with age ranging from 23 to 76 years old and a median age of 49 years old. These are inclusion criteria of the research. (1) The preoperative correct diagnosis was HBV-related HCC. The patients should have HBV infections before and their HBsAg should be positive. The tumor characteristics of patients should be in conformity with HBV-related HCC in at least two kinds of screenage assist examination before operations, or just in conformity with HBV-related HCC in one kind of creenage assist examination with the AFP of patients are higher than 400μg/L. (2) All of the patients received curative hepatectomy. It means that no tumor metastases were found in all of the preoperative examinations, and the tumor should be resected completely with no tumor lesions and portal vein tumor thrombus left. There must be no tumour cells fround in the resection margins of surgical specimens in postoperative pathologic examination. (3) The postoperative pathologic examination suggests HCC. (4) The postoperative Child-Pugh class of patients should be A or B. (5) All of the patients diden’t receive radiofrequency ablation, TACE, chemotherapy, and radiation before operations. (5) All of the patients had no systemic infections before operations. The clinical data of patients include age, gender, cirrhosis, tumor diameter, tumor number, tumor location, ascites, portal vein tumor thrombus(PVTT), blood routine examination and blood biochemistry results of peripheral blood collected in 1 week before operation were gathered. The results of blood routine examination include neutrophil, lymphocyte and blood platelet(PLT) count and the blood biochemistry include levels of alphafetoprotein(AFP), HBV-DNA, serum aspartate transaminase(AST), alanine aminotransferase(ALT), albumin(ALB), total bilirubin (TBIL), direct bilirubin(DBIL) and prothrombin time(PT). All patients were followed up after hepatectomy, and their tumor recurrence and survival were recorded.2. Neutrophil to lymphocyte ratio(NLR) and total tumor volume(TTV) were calculated according to the clinical data. The formula of tumor volume is 4/3×3.14×r3 (r is the maximum radius of tumor). TTV is the sum of all tumor volumes which can be measured. The cut-off values of all continuous variables were defined respectively by using receiver operating characteristic(ROC) curves plotting. Common clinical and laboratory cut-off values were used when the variable differences of ROC curves were not statistically significant. Transformed all continuous variables into dichotomous variables according to corresponding cut-off values. Kaplan-Meier method were used in univariate survival analysis, and survival curves were compared between groups by using log-rank method. Put P<0.05 into multivariate analysis and use Cox proportional-hazards regression model in multivariate analysis. At last, filter out the independent risk factors for tumor recurrence of patients with HBV-related HCC after curative hepatectomy.3. Established a preoperative prediction score model with the independent risk factors. Weighted sum method was used for the model establishment. Scoring methods were got by calculating corresponding weight for each independent risk factor and then all 180 patients were marked by the scoring methods. Calculated the overall 1-3 year disease free survival rates and survival rates of the patients in different score. The patients whose 3 year disease free survival rates are higher than 50% were combined to group A. Similarly, the 3 year disease free survival rates of group B were between 10% and 50% and group C were lower than 10%. Disease free survival rates and survival rates were compared between groups by using Kaplan-Meier method, and in the end, the preoperative prediction score model was obtained.4. The ability of score model to predict tumor recurrence is evaluated by comparing with TNM system, BCLC staging system, OKUDA system and CLIP scoring system in ROC curves.Results1. After calculating TTV and NLR, ROC analyses showed statistics significance at difference of NLR, TTV, ALT, AST, PLT and DBIL (P<0.05), and their cut-off values were defined respectively by using Youden index(TTV= 183.59cm3 NLR=2.21、PLT=204.5G/L、ALT=23.1U/L、AST=50.55U/L、DBIL=4.75μmol/L). The differences of age, ALB, PT and TBIL in ROC analyses had no statistics significance (P>0.05). Common clinical and laboratory cut-off values were used to define their cut-off values(age=50、ALB=35g/L、PT=13S、TBIL=34.2μmol/L).2. After transforming all continuous variables into dichotomous variables, univariate survival analysis showed that multiple tumors, PVTT, AFP>400μg/L, HBV-DNA≥1000cps/ml, TTV> 183.59cm3, NLR>2.21, PLT> 204.5G/L, ALT> 23.1U/L, AST> 50.55U/L, ALB<35g/L, DBIL> 4.75umol/L, Child-Pugh B were significantly related to tumor recurrence(P< 0.05), while age, gender, cirrhosis, ascites, PT, TBIL were not(P>0.05). Multivariate analysis by cox proportional-hazards regression model showed that that PVTT, AFP>400μg/L, HBV-DNA>1000cps/ml, TTV> 183.59cm3, NLR>2.21, PLT> 204.5G/L, AST> 50.55U/L were independent risk factors for tumor recurrence of HBV-related HCC patients after curative hepatectomy(P<0.05).3. By weighted sum method, the weights of PVTT, AFP, NLR, PLT, AST were 3,1,1,1,1, respectively. Marked the 180 patients and calculated their overall 1-3 year disease free survival rates and survival rates. The patients whose score were 0 and 1 were combined to group A(the 3 year disease free survival rates were 86.96% and 52.94% respectively). Those whose score were 2 and 3 were combined to group B(the 3 year disease free survival rates were 13.3% and 15.38% respectively), and the rest were combined to group C(the 3 year disease free survival rates were 6.67%,0%, 0%,0% respectively). After the combination, the 3 year disease free survival rate of group A was 63.51%, group B was 14.08% and group C was 2.86%. The disease free survival rates and survival rates between groups were significantly different(P< 0.05).4. Area under the ROC curve(AUC) of the prediction score model in predicting tumor recurrence which occured in 1 year after curative hepatectomy was 0.783, TNM system was 0.701, BCLC staging system was 0.741, OKUDA system was 0.611 and CLIP scoring system was 0.730(P<0.05). AUC of the prediction score model in predicting tumor recurrence which occured in 3 year after curative hepatectomy was 0.814, TNM system was 0.769, BCLC staging system was 0.756, OKUDA system was 0.638 and CLIP scoring system was 0.740(P<0.05).ConclusionsIn conclusions, for HBV-related HCC patients, multiple tumors, PVTT, AFP>400μg/L, HBV-DNA>1000cps/ml, TTV> 183.59cm3, NLR> 2.21, PLT> 204.5G/L, ALT> 23.1U/L, AST> 50.55U/L, ALB≤35g/L, DBIL> 4.75μmol/L, Child-Pugh B are significantly related to tumor recurrence after curative hepatectomy(P< 0.05). Multiple tumors, PVTT, AFP>400μg/L, HBV-DNA≥1000cps/ml, TTV> 183.59cm3, NLR> 2.21, PLT> 204.5G/L, AST> 50.55U/L are independent risk factors for tumor recurrence after curative hepatectomy(P< 0.05). The new prediction score model which is constituted by PVTT, AFP, TTV, NLR, PLT, AST can predict tumor recurrence of HBV-related HCC patients after curative hepatectomy, and its predicting effect is better than those of TNM system, BCLC staging system, OKUDA system and CLIP scoring system.