Development Of A Prognostic Model And Exploration Of Predictors Of Sorafenib-related Survival Benefits In Patients With Unresectable Hepatocellular Carcinoma

BackgroundTranscatheter arterial chemoembolization(TACE)was recommended as the standard therapy for patients with intermediate-advanced-stage hepatocellular carcinoma(HCC).Regrettably,the median overall survival(OS)for these patients varies widely and ranges from 13 to 43 months,at the same time,patients with poor local control after receiving TACE had a significant decrease in OS,so satisfactory therapeutic results cannot be achieved.Sorafenib has been proven to improve the survival of patients with advanced HCC significantly.However,sorafenib-related adverse events and resistance diminish its survival benefits.A similar situation also occurred when patients received regorafenib.Previous studies found that serum VEGF levels increased in HCC patients after the TACE procedure.In addition,elevations in circulating VEGF were related to poor prognosis in patients with HCC.On the basis of the above facts,researchers envisaged that the anti angiogenic effect of sorafenib may prevent tumor proliferation induced by increased serum VEGF.Unfortunately,the therapeutic superiority of combination therapy over TACE alone remains controversial.Some studies have suggested that the combination therapy of TACE-Sorafenib significantly prolongs the OS of patients with HCC compared with TACE alone.Yet two trials demonstrated that the TACE plus sorafenib treatment only improved time to progression(TTP)and progression-free survival(PFS).Interestingly,the SPACE study revealed that TACE plus sorafenib failed to improve OS and TTP significantly compared to TACE alone.We summarize that,in addition to differences in population distribution and duration of sorafenib treatment,the more important reason for these inconsistencies is that the need to confirm an available biomarker that can predict the therapeutic effects of sorafenib remains unmet.A previous randomized controlled trial(RCT)of sorafenib versus placebo explored the prognostic value of serum VEGF and its predictive value for the sorafenib benefits in patients with advanced HCC and found that VEGF can independently influence the prognosis of HCC patients but failed to predict the survival benefits from sorafenib.Another RCT study revealed that magnitude improvements in OS in response to sorafenib were observed in patients with hepatitis C virus,with low neutrophil-to-lymphocyte ratio(NLR),or without extrahepatic spread(EHS).To our knowledge,there is no study that has previously described the role of VEGF in predicting the sorafenib-related survival benefits in HCC patients after receiving TACE.In addition,it can be concluded that the survival benefit for advanced HCC patients is highly heterogeneous whether receiving TACE or TACE-Sorafenib.Therefore,accurately estimating the survival of HCC patients receiving these two treatment modalities remains a challenge.An ideal prognostic model requires an individualized and accurate prediction of the patient’s probability of survival for some time to come.However,the current risk scores and models widely applied in clinical work,such as Barcelona Clinical Liver Cancer(BCLC)stage B,hepatoma arterial embolization prognostic(HAP)score,and"four-and-seven" criteria,which are used for risk stratification in HCC patients but unable to provide detailed information on individualized estimation of survival.At present,few studies have integrated two treatment modalities(TACE and TACE-Sorafenib)to establish a prognostic model to estimate the survival of patients with advanced HCC.PurposeOn the basis of the above backgrounds,we performed this retrospective study to accomplish the following two purposes.Firstly,reassess the survival difference between combination therapy and TACE alone according to our data;explore the prognostic value and the predictive value of the efficacy of sorafenib of VEGF and other clinical characteristics in HCC patients treated with TACE;estimate the association between baseline VEGF concentrations and the risk of death in patients with unresectable HCC.Secondly,integrate VEGF and other clinical characteristics to develop a clinical prognostic model for OS prediction and verify the model internally;compare the final model with the CNLC stage,AJCC stage,BCLC stage,and the model without "VEGF";stratify the patients by age using the established prognostic model.Research Contents:Ⅰ.Exploration of Predictors of Sorafenib-related Survival Benefits in patients with Hepatocellular CarcinomaPurpose:We aimed to explore the relationship between VEGF and the prognosis,as well as the mortality risk of HCC patients who received TACE,and whether it and other variables could be considered as potential biomarkers for predicting the survival benefits from sorafenib.Methods:A total of 230 consecutive newly diagnosed patients with unresectable HCC treated with either TACE or TACE-sorafenib were collected retrospectively.Cox regression analyses were performed to evaluate the prognostic value of VEGF.Furthermore,restricted cubic splines were fitted to assess the nonlinear associations between VEGF and OS,and the threshold effect analysis was subsequently performed.Lastly,the potential factors for predicting the survival benefits from sorafenib after the TACE procedure were identified using the Cox proportional hazard model with an interaction term.Results:VEGF was recognized as an independent prognostic factor for OS in the TACE alone cohort(HR=3.237,p=0.013).A nonlinear relationship was observed between VEGF and OS in HCC patients with TACE administration after adjustment for confounders(p for nonlinearity=0.030);the mortality risk increased with increasing the baseline VEGF before the inflection point(189.79pg/mL),and the HR for death was 1.008.There was no significant interaction between the VEGF levels and treatment modality(p for interaction=0.233),and further studies are needed to identify its predictive value on the efficacy of sorafenib.Patients with tumor size>7 cm or total bilirubin ≤17.3μmol/L derived significant sorafenib-related benefits in OS when compared to those with tumor size ≤7 cm or total bilirubin>17.3μmol/L(pfor interaction=0.004 and 0.031,respectively).Conclusion:Within a certain concentration range,elevated baseline VEGF meant an increased risk of death in HCC patients treated with TACE.Significant improvements in OS associated with sorafenib were observed in patients with higher tumor size and lower total bilirubin after TACE treatment.Ⅱ.Development of a Prognostic Model in Patients with Unresectable Hepatocellular CarcinomaPurpose:High serum vascular endothelial growth factor(VEGF)levels have been identified as an independent risk factor for hepatocellular carcinoma(HCC).We aimed to construct a VEGF-included prognostic model to accurately perform individualized predictions of survival probability for patients with unresectable HCC.Methods:From October 2018 to March 2021,182 consecutive newly diagnosed patients with unresectable HCC were retrospectively enrolled in Xijing hospital.Baseline serum VEGF-A and other characteristics were collected for all patients.Univariate Cox regression analysis and LASSO regression model were applied to develop the prognostic model,enhanced bootstrap method with 100 replicates was performed to validate its discrimination and calibration.We compared the final model with China Liver Cancer(CNLC)stage,American Joint Committee on Cancer(AJCC)stage,Barcelona Clinic Liver Cancer(BCLC)stage,and the model without the "VEGF".Finally,the established model was stratified by age.Results:The VEGF-associated prognostic model we established has high accuracy with a Harrell’s C-index of 0.7892 after correction for optimistic estimates.The area under the curve(AUC)of the time-dependent receiver operating characteristic(ROC)curves at 6-month,1-year,and 2-year after correction were 0.843,0.860,0.833,respectively,and the calibration of the model was 0.1153,0.1514,and 0.1711,respectively.The final model showed significant improvement in predicting OS when compared to the other models according to Harrell’s C-index,The AUC of the time-dependent ROC,area under the decision curve analysis(AUDC),integrated discrimination improvement(IDI),and continuous net reclassification index(NRI).Conclusion:The VEGF-associated prognostic model may help to predict the survival probabilities of HCC patients with favorable performance and discrimination.However,further validation is required since we only verified this model using internal but not external data.