Characteristics of patients and recurrent patterns. A total of 891 patients who underwent curative liver resection for HCC were enrolled in this study. Male predominance (n=706, 79.2%) and high prevalence of viral hepatitis (n=713, 80.0%) were observed. The mean age was 57.0 ± 13.1 with a range from 11.1 to 89.4 years. The majority (n=656, 73.6%) of the patients had single tumor. Near half of the patients (n=411, 46.1%) had cirrhosis, but most of them (n=880, 98.8%) were classified into Child-Pugh class A (supplement table 1). After a median follow-up of 83.4 months, 589 (66.1%) patients developed recurrent HCC and 362 (40.6%) of them had early tumor recurrence. Among these 362 patients with early tumor recurrence, 276 (31.0%) patients had tumor recurrence beyond the Milan criteria and 86 (9.6%) patients’ tumors were within the Milan criteria. The other 227 (25.5%) patients had late recurrence. 181 (23.3%) patients’ tumors were inside the Milan criteria and 46 (5.2%) patients’ tumors were outside Milan criteria (Fig. 1).
Survival in HCC patients according to recurrent patterns. After a median follow-up of 83.4 months, 413 patients (46.4%) died. The cumulative overall survival rates for all enrolled patients were 67.7% and 51.8% at 5 and 10 years, respectively. When the patients with tumor recurrence were stratified into 4 groups according to recurrent patterns, cumulative overall survival rates at 5 and 10 years were 89.5% and 83.6% for the patients without tumor recurrence, 87.7% and 56.8% for LR-MI group, 74.0 and 40.6% for LR-MO group, 68.4% and 51.6% for ER-MI group, and 29.4 and 15.5% for ER-MO group, respectively. ER-MO group had an inferior outcome to other recurrent patterns (Fig. 2, P < 0.001). The long-term survival between ER-MI and LR-MI was comparable. Therefore, ER-MO had the worst outcome and seemed different in natures from other recurrent patterns.
Clinical characteristics according to different recurrent patterns. According to 4 recurrent patterns, the clinicopathological features of the patients with tumor recurrence were presented in table 1. For patients in ER-MO and ER-MI groups, there were no significant difference between age, gender, hepatitis status, hematology/biochemistry data, indocyanine green 15-minute retention test (ICG R15) and serum bilirubin. But, the patients in ER-MO group were highly associated with large tumors, multiple tumors, and micro-vascular invasion (P<0.05) and also had the tendency toward high serum AFP level and absence of tumor capsule. When the patients in ER-MO group were compared to LR-MI group patients who had a better outcomes, the patients in ER-MO group had higher population with high level of AFP and worse tumor characteristics including large-sized tumors, multiple tumors, poor histological differentiation, and microvascular invasion (Table 1).
Development of ER-MO prediction model. The ER-MO group had the worst survival, compared to other groups. In this study, we tried to identify the risk factors of ER-MO and establish a predicting model of ER-MO prior to liver resection. The results of univariate and multivariate logistic regression analyses of prognostic factors for EM-MO were shown in table 2. In univariate analysis, seven pre-operative and three peri-/post-operative risk factors were identified including large tumor size, non-single tumor, hypoalbuminemia, high AFP level, high neutrophil-to-lymphocyte ratio (NLR), high ICG R15, history of tumor rupture, high intraoperative blood loss, presence of micro-vascular invasion and high histology grade. In the further multivariate analysis focusing only on pre-operative factors, large tumor size (for 3-5cm, HR = 1.90; for > 5cm, HR = 3.39), non-single tumor (HR = 1.76), high AFP (HR = 5.56), high NLR (HR = 1.60) and high ICG R15 (HR = 1.58) were the independent predictors of ER-MO. The relative points were transformed from multiplying the coefficients (β) by five and then run into integer to construct a scoring system. Different score allocations were given 2 points for AFP > 800ng/dL, 2 points for ICG R15 >10%, 2 points for preoperative NLR > 2.5, 4 points for multiple tumors, 3 points for tumor size between 3 to 5 centimeters and 5 points for tumor size > 5 centimeters. Full score is 15 points. As expected, there was no patient situated in a sum score of 1, 12, and 14 by possible permutation, and we also did not have any patient with a full score of 15. To simplify the calculation, we grouped every two score and got 8 groups in sequence (0, 2, 3-4, 5-6, 7-8, 9-10, 11, 13). By comparing the Kaplan-Meier survival curves for the 8 groups, the risk of ER-MO was re-stratified into 4 classes with no survival difference between intra-class groups. Class I, II, III and IV were corresponded to score 0, 2-6, 7-10 and ≥11, respectively (Table 3). Subsequently, this scoring system was used for analyses. The ER-MO event at 24 months after surgery was 12.5% for class I, 22.5% for class II, 45.4% for class III and 66.3% for class IV, respectively (Fig. 3a, P< 0.05 between any two groups). Our scoring model also deliberate long-term overall survival difference between each class. The median survival was 104.4, 88.8, 35.2 and 16.9 months for class I to IV, respectively. The 5- and 10-year overall survival were 86.7% and 58.6% for class I, 69.1% and 44.7% for class II, 43.8% and 31.6% for class III, and 27.2% and 19.6% for class IV, respectively (Fig. 3b, P< 0.05 between any two groups). The ROC curve of our scoring system to predict ER-MO had an AUC of 0.712 (95% CI: 0.675-0.749) with a best cut-off at 6. (supplement fig. 1)
Treatments for recurrent HCC. The principle of treatments for recurrent HCC is the same as primary diseases by considering disease extension, liver function and ECOG-Performance Status (PS). In the present study, TACE accounted for the most common treatment (369/589 patients, 62.6%) for recurrent HCC. Among the patients with tumor recurrence, 114 (19.4%) patients had curative treatments, including 80 re-hepatectomyies, 14 RFA and 20 liver transplantation. For the 80 patients received re-hepatectomy, 15 patients were in ER-MO group, 24 patients in ER-MI group, and 41 patients in LR-MO/LR-MI groups. For the 20 patients (9 in ER-MO group and 11 in other groups) undergoing liver transplantation, 15 (75.0%) of them had TACE for disease-control or down-staging prior to salvage liver transplantation. The median waiting time between recurrence and liver transplantation were 15.2 months for all transplant recipients, but 30.0 months for the 9 patients in ER-MO group, who were able to have liver transplantation after successful down-staging of tumors. Six of 9 (66.7%) patients in ER-MO group achieved long-term post-transplant disease-free survival and 3 died of HCC recurrence after liver transplantation. Therefore, for the patients in ER-MO group, the curative chance was only 8.7% (24 in 276 patients) including 15 patients having re-hepatectomies and 9 patients having liver transplantation after successful down-staging of recurrent HCC.