Clinicopathologic characteristics
According to the eligibility criteria, a total of 8119 patients diagnosed with HCC between 2004 and 2015 were identified from the SEER database. Of these, 2295 patients were in F0-4 group and 5824 patients were in F5-6 group (Figure 1). Patients with advanced fibrosis and cirrhosis were more frequently categorized as younger (61.76±9.54, p=0.000) and male (p=0.027) patients, in AJCC T1-T2 stage (p<0.0001), had no lymph node metastasis (p=0.0065), had no distant metastasis (p=0.0002), had positive AFP level (p<0.0001). In contrast, patients with none/ moderate fibrosis were more frequently classified as older and female patients, in AJCC stage T3-T4, with negative AFP level. Since the comparison of different degrees of liver fibrosis is subject to possible confounding induced by differences in baseline characteristics, we performed PSM to generate 1:1 pairs of patients. The matched groups consisted of 1660 F0-4 and 1563 F5-6 patients diagnosed with HCC (Figure 1). The covariates between the two groups were well-balanced and showed no significant differences at baseline (p>0.05 for all; Table 1 and figure 2A, 2B).
Increased fibrosis progression correlated with poor prognosis of HCC patients
In entire cohort of patients, the overall survival (OS) rate was significantly higher in patients of F0-4 group than those in F5-6 group (1-, 3-, 5-year cumulative OS rates were 65.8%, 44.5% and 33.9% vs 62.3%, 41.2% and 32.0%, respectively). Patients with advanced fibrosis/cirrhosis showed unfavorable prognosis (p=0.029) (figure 2C). The median overall survival (OS) time was longer in patients of F0-4 group than that of F5-6 group (27 versus 23 months) (Table 2). After one-to-one PSM, the 1-, 3-, 5-year cumulative OS rates were 70.6%, 49.6 and 37.6% in F0-4 group and 65.8%, 47.7% and 34. 7% in F5-6 group, respectively. The median OS time was again longer in patients of F0-4 group than that of F5-6 group (36 versus 28 months). Patients with advanced fibrosis/cirrhosis also showed unfavorable prognosis (p=0.028) (figure 2D). In univariate analysis of all matched patients, age (p=0.000), sex (p=0.008), primary tumor (p=0.000), lymph node metastasis (p=0.000), distant metastasis (p=0.000), vascular invasion (p=0.000), AFP level (p=0.000), fibrosis score (p=0.028) and tumor size (p=0.000) were closely associated with OS (Table 2). The multivariate Cox proportional hazards analysis for those factors showing significance by univariate analysis showed that advanced fibrosis/ cirrhosis (HR:1.131, 95%CI: 1.032-1.240, p=0.009), age more than 63 (HR: 1.365, p=0.000), AJCC stage T3-4 (HR: 1.810, p=0.000), distant metastasis (M1) (HR: 3.460, p=0.000), tumor size ≥1cm (HR: 2.536, p=0.000), minor vascular invasion (HR: 1.202, p=0.05), major vascular invasion (HR: 2.321, p=0.000) as well as elevated AFP level (HR: 1.511, p=0.000) were independent risk factors for increased mortality rate (Table 3).
Predictors of survival among advanced fibrosis/cirrhosis patients
Using multivariate analysis, predictors of survival among advanced fibrosis/cirrhosis patients were performed. As shown in Table 4, advanced fibrosis/cirrhosis patients whose age older than 63-year old demonstrated worse survival (HR: 1.480, 95%CI: 1.297-1.689, p=0.000). In advanced fibrosis/cirrhosis patients, AJCC stage T3-4 (HR: 1.900, 95%CI: 1.477~2.444, p=0.000), distant metastasis (M1) (HR: 3.270, 95%CI: 2.297-4.655, p=0.000), Tumor size ≥1cm (HR: 2.809, 95%CI: 2.152~3.668, p=0.000) and major vascular invasion (HR: 2.457, 95%CI: 1.819-3.319, p=0.000) were associated with worse survival. Negative AFP HCC patients demonstrated better survival than positive patients (HR: 0.702, 95%CI: 0.594~0.831, p=0.000).
Prognostic Nomogram construction and validation
The prognostic nomogram integrated all significant independent factors for survival in multivariate analyses (Figure 3A). The C-index for survival prediction was 0.749 (95%CI: 0.735~0.763). In addition, the calibration plot for the probability of survival at 1, 3 and 5 year presented an optimal agreement between the prediction by nomogram and actual observation (Figure 3B). Thirty percent of all cohort was randomly generated by R software to make internal validation. The C-index of internal validation of the nomogram was 0.761 (95%CI 0.736~0.786), calibration curves also showed good agreement between prediction and observation in 1-, 3- and 5-year OS (Figure 3C). These results indicated the nomogram that integrated fibrosis score with other factors of age, AJCC T stage, distant metastasis, tumor size, vascular invasion and AFP level was reliable for survival prediction of HCC patients.
Comparison between nomogram and single independent factors/ conventional staging systems
The larger of the C‐index represented a more accurate the predictive model. The C‐index of the prognostic nomogram was larger than the AJCC 7th edition, the AJCC TNM staging system, and single independent factors. For the nomogram of primary cohort, the C-index for survival prediction was 0.749 (95%CI: 0.735~0.763), which was higher than AJCC 7th edition (C-index 0.727), AJCC TNM stage (C-index 0.73), tumor size (C-index 0.506), vascular invasion (C-index 0.509), AFP (C-index 0.55), and age (C-index 0.536) (p<0.05). For internal validation of the nomogram, the C-index was 0.761 (95%CI 0.736~0.786), which was also higher than AJCC 7th edition (C-index 0.732), AJCC TNM stage (C-index 0.742), tumor size (C-index 0.502), vascular invasion (C-index 0.520), AFP (C-index 0.539), and age (C-index 0.534) (p<0.05). Taken together, these results suggest that the nomogram was useful and reliable predicting model for survival of patients with HCC relative to the AJCC 7th edition and AJCC TNM stage system.