Page 620 - Read Online

Ichida et al. Hepatoma Res 2020;6:54 I http://dx.doi.org/10.20517/2394-5079.2020.59 Page 5 of 11

Validation of the 5-5-500 criteria and the Japanese DEC
The relationship of the Milan criteria, the 5-5-500 criteria, and the Japanese DEC is presented in the
Venn diagram [Supplementary Figure 1]. The number of patients and patients with recurrence meeting
each indication criteria was summarized in Supplementary Table 1. The recurrence rate was the lowest in
patients meeting the 5-5-500 criteria (6.5%) followed by the Milan criteria (6.9%) and then the Japanese
DEC (8.2%). All criteria achieved the target of a recurrence rate below 10%. When focusing on each
area of the Venn diagram, the recurrence rate was the highest (42.9%) in patients within the Milan but
beyond the 5-5-500 criteria and in patients beyond the Japanese DEC. Meanwhile, the recurrence rate in
patients within the 5-5-500 but beyond the Milan criteria was lower (20%) than these patients. As for the
comparison of the number of patients, the number of patients included in the 5-5-500 criteria was larger
than that included in the conventional Milan criteria by eight (6.1% increase). In the Japanese DEC, 15
additional patients were included (11.5% increase). The overall survival and recurrence rate curves in
patients meeting each indication criteria are presented in Figure 1. The 5-year overall survival and the
5-year recurrence rate of all the patients, patients meeting the Japanese DEC, 5-5-500 criteria, and Milan
criteria was 76.9%, 77.9%, 79.0%, and 76.2%, and 10.9%, 9.2%, 7.4%, and 7.6%, respectively. There was no
significant difference both in the 5-year recurrence and 5-year survival rates amongst each criterion.

Usefulness of biomarkers in predicting the recurrence of HCC
The results of the ROC curve analysis for biomarkers is presented in Figure 2. Among the five biomarkers,
the area under the curve (AUC) value of AFP was the highest (0.852). The sensitivity of AFP was also the
highest (86.7%). Meanwhile, the false-positive rate (1-specificity) of AFP-L3 was the lowest (8.3%). Patient
recurrence rate curves stratified by each biomarker using the cutoff value obtained from the ROC curve
analysis are presented in Supplementary Figure 2. Though recurrence rate curves were well stratified with
AFP, AFP-L3, and DCP (P < 0.0001), significant results were not obtained with NLR and PLR (P = 0.076
and = 0.263 respectively).

Factors associated with HCC recurrence
Risk factors associated with HCC recurrence were evaluated with univariate and multivariate analyses.
Univariate analysis revealed that beyond the Milan, 5-5-500, and Japanese DEC were all significant
predictors [Table 2]. Among these three criteria, the hazard ratio and P value beyond the 5-5-500 criteria
was the highest (7.99) and the smallest (0.0005), respectively. Except for factors associated with these three
criteria, the high AFP value ≥ 60 ng/mL, high AFP-L3 value (≥ 35%), high DCP value (≥ 130 mAU/mL),
and large tumor size (≥ 2.0 cm) were all identified as significant predictors by univariate analysis. Among
the five biomarkers evaluated, the hazard ratio and P value of a high AFP value was the highest (11.50) and
the smallest (< 0.0001), respectively. Multivariate analysis revealed that high AFP and DCP values were the
independent significant predictors.

DISCUSSION
The results of the present study suggest that the 5-5-500 criteria and the Japanese DEC are appropriate and
acceptable since the 5-year recurrence rate in patients meeting these criteria were both below 10% in our
cohort. Compared with the conventional Milan criteria, the 5-5-500 criteria and the Japanese DEC could
increase the number of eligible LDLT candidates by 6.1% and 11.4%, respectively. As for the usefulness of
biomarkers in predicting the recurrence of HCC, AFP seems to be the most reliable. Though there were
some missing data, AFP-L3 also seems promising.

In Japan, the national insurance system had restricted LDLT to those falling within the Milan criteria until
recently, although some centers have been performing LDLT in private practice with a center-oriented
expanded criteria that has achieved a 5-year patient survival over 80% and a 5-year recurrence rate of
10% [27,28] . Consequently, a few patients had given up the chance for LDLT because of financial reasons,