Risk Stratification And Prognosis Evaluation Following Microwave Ablation In Patients With Early-stage Hepatocellular Carcinoma

Background:Hepatocellular carcinoma（HCC）is the 4^th leading cause of deaths among all malignancies.Early HCC accounts for 30%-65%of all HCC patients.Liver resection（LR）and local ablation are the main treatment modalities for early HCC.Microwave ablation（MWA）is a commonly used method for local ablation of early HCC.Though both LR and MWA are considered potentially curative treatment for early HCC.HCC recurrence occurs in up to 80%of early HCC patients after LR or MWA within 5years,which significantly affects the long-term survival of these patients.Controversial findings have been reported by studies as for the long-term survival benefit between LR and MWA in early HCC.The optimal candidates for MWA are yet to be determined.Few studies have investigated the recurrence patterns of HCC after MWA.Among patients with recurrent HCC,who will benefit from repeated HCC have not been clarified.In clinical practice,the model to stratify and predict long-term survival of early HCC patients after MWA needs to be established.Aims:1.To identify the optimal candidates for MWA treatment in early HCC patients by investigating the impact of initial treatments（LR or MWA）on HCC recurrence time,patterns,and long-term survival.2.To clarify the recurrence characteristics of early HCC after MWA by comparing the recurrence patterns and treatments between patients with early and late recurrence and post-recurrence survival（PRS）.3.To identify the optimal candidates of repeated MWA by comparing the outcomes of early HCC patients who received MWA as initial therapy and patients with recurrent HCC who underwent repeated MWA.4.To develop and validate a nomogram model to stratify risk and predict long-term survival in patients with early HCC after MWA.Methods:1.Retrospective study was performed in patients who developed recurrent HCC following LR or MWA for early HCC at our center.Using the Fisher exact probability test or Pearson’sχ2 tests,the recurrence patterns and treatment modalities were compared between recurrent HCC patients after LR or MWA before and after propensity score matching（PSM）.The overall survival（OS）and PRS between the two groups were compared before and after PSM using Kaplan-Meier（K-M）curves,and subgroup analysis was used to identify the proper population to treat with MWA.2.Patients with recurrent HCC were retrospectively reviewed.The patterns and treatment modalities of recurrence were compared between patients with early and late recurrence using the Fisher exact probability test or Pearson’sχ²tests.Log-rank test was used to compare the PRS in the two groups.The multivariable Cox model was then utilized to identify the prognostic factors associated with PRS,and the hazard ratio（HR）was calculated.3.Retrospective study was performed in patients who received repeated MWA for recurrent HCC and those received MWA as initial treatment for initial HCC.K-M curves were plotted before and after PSM to evaluate the OS and recurrence-free survival（RFS）of the two groups.Subgroup analysis was then carried out to identify the appropriate population of repeat MWA treatment.4.Demographical and clinical data of early HCC patients who received MWA at our center were collected.The variables associated with OS were identified using the multivariable Cox model and included to develop a nomogram model.The performance and discrimination abilities of the nomogram model were compared with that of other prognostic models using the area under time-dependent receiving operator characteristic curve（AUC）,concordance index（C-index）,and decision curve analysis.The ideal cut-off value for poor OS,which was determined using a“survival”software package,was used to stratify risk and evaluate the prognosis of HCC patients.Results:1.After PSM,no statistically significant differences were observed between LR and MWA groups in the recurrence pattern（size,number,stage,and vascular invasion）,and the percentage of patients undergoing radical treatment（77.3%vs 76.0%,P=0.847）for postoperative recurrent HCC.PRS（56.0 vs 45.0 months,P=0.150）were also comparable between the two groups.2.Subgroup analyses showed that MWA achieved comparable OS as LR in early-stage HCC in patients with age>60 y,neutrophil lymphocyte ratio（NLR）≤2.0 or Albumin-Bilirubin（ALBI）grade 1（all P value>0.05）.3.After MWA for early HCC,the majority of the recurrent tumors were intrahepatic-only recurrence（192/222,86.5%）,within the Milan criteria（166/222,74.8%）,and were candidates for potentially curative treatment（168/222,74.8%）.No significant differences in recurrence patterns and PRS（35.0 vs 33.0 months,P=0.523）were observed between patients with early and late recurrence.4.Multivariable Cox regression analyses suggested that multiple tumor number（HR,1.54;95%CI:1.03-2.30,P=0.038）,extra-hepatic recurrence（HR,2.14;95%CI:1.16-3.92,P=0.015）,vascular invasion（HR,2.37;95%CI:1.18-4.76,P=0.038）and higher ALBI grade（HR,2.18;95%CI:1.54-3.08,P<0.001）were independent risk factors of worse PRS,while curative treatment after recurrence（HR,0.59;95%CI:0.38-0.92,P=0.038）was associated with better PRS.5.For patients with solitary HCC≤3.0 cm,AFP≤200 ng/mL,ALBI grade 1,or ablative margins≥0.5 cm,no statistically significant differences were found in OS rates between the initial HCC and recurrent HCC groups.6.Multivariate Cox regression analyses suggested that AFP levels>400 ng/mL（HR,2.38;95%CI 1.41-4.01,P=0.001）,ALBI score（HR,1.50;95%CI:1.19-2.02,P=0.007）,ablative margins<0.5 cm（HR,4.14;95%CI:1.46-11.73,P=0.007）and platelet（PLT）counts<100×10⁹/L（HR,1.97;95%CI:1.23-3.20,P=0.006）were independent prognostic factors associated with OS,and then were included in the model development.7.The nomogram model demonstrated a significantly higher prediction performance when compared with other prediction models,including Barcelona Clinic Liver Cancer（BCLC）staging system,ALBI grade,platelet-albumin-bilirubin（PALBI）grade,and NLR,with a C-index of 0.64 and 0.69 in the training and validation cohorts,respectively.8.The nomogram model could predict individual survival of early HCC patients after MWA by using the optimal cut-off value to stratify into low-and high-risk groups with significantly different OS.Conclusions:1.Early HCC patients with age>60 y,NLR≤2.0,or ALBI grade 1 are optimal candidates of MWA treatment.2.No differences in recurrence patterns,post-recurrence treatments or PRS were found between HCC patients with early and late recurrence following MWA.3.In patients with solitary HCC≤3 cm,AFP≤200 ng/mL,ablative margins≥0.5 cm,or ALBI grade 1,MWA provided comparable long-term survival for initial HCC and recurrent HCC.Repeated MWA could be considered for these patients.4.The nomogram model based on AFP,PLT,ablative margins and ALBI score was a simple visualization model,which could stratify patients with early‐stage HCC after MWA and predict individualized long-term survival with favorable performance.