Demographic characteristics of the patients
As shown in Table 1, the patients in the cohort were predominantly male with a mean age of 69.1 years. Chronic hepatitis B was the most common underlying liver disease, followed by chronic hepatitis C and alcoholic liver disease. All the patients were within Child-Turcotte-Pugh (CTP) grade A at enrollment, but about half of them were classified as the albumin-bilirubin (ALBI) grade 2/3. 27 (15.6%) patients had trace or small esophageal varices, but no one had gastric varices. The median ARFI velocity value for LS was 2.06 m/s (interquartile range IQR, 1.40–3.03), and the median ARFI velocity value for SS was 3.08 m/s (IQR, 2.57–3.51). The cutoff value for LS that provided greatest specificity and sensitivity for predicting mortality was 1.5 m/s, with AUROC of 0.63 (95% CI 0.56–0.70; p = 0.014). Patients with ARFI velocity value > 1.5 m/s for LS had a higher risk of mortality (HR 4.756; 95% CI 1.462–15.467; p = 0.010).
When divided by the optimal cut-off value of 1.5 m/s for LS, 126 patients were classified as having significant liver fibrosis, and the other 47 patients were not. Patients with LS > 1.5 m/s had significantly greater serum levels of alpha-fetoprotein (AFP), prothrombin time, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, blood neutrophil counts as well as greater AST to platelet ratio index (APRI) and ALBI grade, but lower platelet counts and serum albumin level compared with their counterpart (Table 2). However, the rates of viral etiology, anti-viral treatment, and alcoholism were comparable between these two groups of patients. Besides, higher ARFI velocity values for SS were also found in patients with significant LS; and there was a modest positive association between LS and SS measured by ARFI velocity (R2 = 0.215, p < 0.001, Fig. 1). In addition, more hepatic decompensated events, especially formation of ascites, and death developed in patients with significant LS during the follow-up period.
After propensity score 1:1 matched by number of tumors, viral hepatitis status, serum levels of AFP and total bilirubin which would have impacts on adverse tumor events, patients with significant LS still had greater levels of prothrombin time, ALT,AST, APRI, white blood cell counts, but lower serum albumin and platelet counts. Hepatic decompensated events did not develop more in patients with significant LS; but more patients died in this group.
OS in patients with HCC post-RFA
During the median follow-up period of 27.7 months (IQR, 13.3–44.6), 38 (22.0%) patient deaths occurred. No patients underwent liver transplantation during the follow-up period. The cumulative 1, 2, and 5-year OS rates were 93.8%, 80.3%, and 71.4%, respectively. Stratified by the status of LS, the cumulative 1, 2, and 5-year OS rates were 97.6%, 94.0%, and 89.5% in patients with ARFI ≤ 1.5 m/s, while they were 92.3%, 74.4%, and 65.0% in those with ARFI > 1.5 m/s, respectively (p = 0.004, Fig. 2A). On the other hand, the best cutoff value for SS was 3.0 m/s, with AUROC of 0.61 (95% CI 0.53–0.68; p = 0.047). However, the OS rates were not significantly different when stratified by SS status (p = 0.167, Fig. 2B). After propensity score matching, a significant better OS was still observed in patients with ARFI ≤ 1.5 m/s for LS. Nevertheless, no significant difference of OS could be divided by the status of SS (Fig. 2C,D).
By the multivariate analysis which included dimensional ARFI velocity value for LS, anti-viral treatment was the only predictor of survival benefit (model 1). After including dichotomous value of LS into analysis (model 2), both anti-viral treatment (hazard ratio [HR]: 0.396, p = 0.015) and LS > 1.5 m/s (HR: 4.105, p = 0.028) were independent predictors to OS in patients with HCC after RFA (Table 3). However, SS was not significantly associated with OS even among patients with esophageal varices or thrombocytopenia < 100 K/cumm at baseline (Supplementary Table).
RFS in patients with HCC post RFA
During the follow-up period, 80 (46.2%) patients developed tumor recurrence. The cumulative recurrence-free survival (RFS) rates at 1, 2, and 5 years were 73.2%, 54.1%, and 23.6%, respectively. As shown in Fig. 3A, patients with an ARFI velocity value > 1.5 m/s for LS at baseline had significantly shorter RFS compared to those with LS ≤ 1.5 m/s (22.3 vs. 54.9 months, p = 0.017). The cumulative RFS rates at 1, 2, and 5 years were 81.5%, 70.4%, and 35.6% in patients with LS ≤ 1.5 m/s, while they were 70.1%, 47.9%, and 15.0% and in those with ARFI > 1.5 m/s, respectively. However, the RFS rates were comparable according to ARFI values for SS (p = 0.342, Fig. 3B).
In the model analyzed competing risk of death, patients with LS > 1.5 m/s still had significantly shorter RFS compared with their counterparts (19.6 vs. 54.9 months, p = 0.006). Moreover, significant difference of RFS was also observed according to LS after propensity score matching in the competing risk model (18.0 vs. 54.9 months, p = 0.005) (Fig. 3C–F).
By including dimensional LS value into multivariate analysis in the competing risk model, a higher baseline AFP level was the only predictor to RFS after RFA (model 1). After including dichotomous value of LS into analysis (model 2), a higher baseline AFP level (subdistribution hazard ration [SHR]: 1.701, p = 0.040) and significant LS > 1.5 m/s (SHR: 2.000, p = 0.027) could independently predict HCC recurrence after RFA (Table 4). Nevertheless, SS was not significantly associated with RFS even among patients with clinically significant portal hypertension (Supplementary Table).
Development of hepatic decompensation in patients with HCC post RFA
During the follow-up period, 56 patients developed hepatic decompensation, in which 55 patients had ascites, 7 had variceal bleeding, and 17 developed hepatic encephalopathy. The cutoff value for LS to predict hepatic decompensation was 2.0 m/s, with AUROC of 0.65 (95% CI 0.56–0.72; p = 0.003). Patients with LS > 2.0 m/s had a higher risk of decompensation (OR 2.969; 95% CI 1.509–5.841; p = 0.002). Besides, the best cutoff value of SS for hepatic decompensation was 2.7 m/s, with AUROC of 0.66 (95% CI 0.58–0.74; p = 0.001). Higher SS > 2.7 m/s was associated with a significantly higher risk of hepatic decompensation (OR 4.870; 95% CI 2.033–11.663; p < 0.001).
In the multivariate analysis that including dimensional ARFI values of LS and SS (model 1), antiviral treatment, serum levels of creatinine and ALT, and ARFI velocity value for SS were independent predictors to hepatic decompensation. In the model 2 which included dichotomous ARFI values, anti-viral treatment, serum creatinine > 1.5 mg/dL, and SS > 2.7 m/s independently predict hepatic decompensation (Table 5).