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Hiyama et al. Hepatoma Res 2021;7:44 https://dx.doi.org/10.20517/2394-5079.2021.21 Page 5 of 12

was defined as no evidence of disease on imaging and a normal AFP level. Event-free survival (EFS) and OS
were the endpoints of this study. EFS was defined between the date of registration and the earliest date of
the first occurrence of progression or relapse, death, or the latest contact. OS was defined the time between
the date of registration and the date of death or the last contact.

Statistical analysis
Student t-test or Chi-square test was used to compare characteristics or values between groups, as
appropriate. Survival curves were analyzed by the Kaplan-Meier method for evaluation of the five-year OS
and EFS rates and the log-rank test was used to compare these curves. Cox’s regression method was used for
the multifactor analysis. Statistical significance was defined as P < 0.05.

RESULTS
Of the 361 HB patients from JPLT-2, 4 died before surgery and 14 had unresectable tumors following
preoperative CTx. In the remaining 343 patients (95.0%), primary tumor resection including total
hepatectomy followed by LT (n = 17) was performed. Among them, there were 6 cases of macroscopically
incomplete resection (1.7%). Histological examination of the resected margin of resected tumor specimens
in the remaining cases revealed that 25 cases (6.9%) were marginal positive [Table 1 and Figure 2].

Consequently, complete resection was achieved in 312 (86.4%), which was a significantly higher resection
rate than that in the previous JPLT-1 trial (71.6%) [Figure 3]. The resection rate was 90.4% (n = 263) in the
patients with non-metastatic disease (n = 291) and 73.8% (n = 62) in those with PRETEXT IV tumors
(n = 84); these rates were also significantly higher than those in JPLT-1 (81.3% and 40.0%, respectively).

The five-year EFS and OS rates were 76.0% and 87.7% in the patients who underwent complete resection
(microMNR) of their primary tumor (n = 312), respectively, compared with 60.3% and 83.1% in those who
underwent incomplete resection (n = 31), including microMPR (n = 25) [Table 1 and Figure 4]. Among the
patients without distant metastasis (n = 290), the five-year EFS and OS rates were 81.8% and 90.8% in those
with complete resection (n = 263), respectively, compared with 68.2% and 90.9% in those with microMPR (n
= 22). The EFS rates were significantly higher (P = 0.031 and P = 0.022, respectively) in the patients with
complete resection vs. microMPR. Events occurred in 72 and 11 cases in patients with complete resection
and microMPR, respectively, and a significantly higher rate of intrahepatic local recurrence was found in
the latter cases [32 (10.2%) vs. 9 (36.0%), chi-square = 12.11, P < 0.01], whereas the OS rate did not differ
significantly (P = 0.135) between the two groups. In the patients who underwent complete resection
(microMNR) of their primary tumor without LT, the five-year EFS and OS rates were 76.3% and 88.2% in
total (n =295) and 81.9% and 92.0% in those without distant metastasis, respectively. The EFS rate was also
significantly higher (P = 0.027 and P = 0.015, respectively) in the patients with complete resection vs.
microMPR. Except for the cases with macroscopic positive margin, regression analysis using a multivariable
Cox proportional hazards model revealed that age of more than 8 years, distant metastasis, and microMPR
were independent predictors of shorter EFS, but PRETEXT classification including co-factors except for
metastasis was not significantly correlated with EFS [Table 2]. An extended hepatectomy was performed in
122 (39.0%) of 337 cases who underwent resection of primary tumor. MicroMPR cases included 15 of 122
cases with extended hepatectomy and 10 of the remaining cases. A significantly higher rate of microMPR
occurred in extended hepatectomy cases [15 (12.3%) vs. 10 (4.7%), chi-square = 6.60, P = 0.012].

Among 11 patients with a tumor with microMPR who had recurrence, 7 patients had a tumor with local
recurrence, 2 had lung metastasis, and 2 had both. Among them, 2 cases underwent surgical approaches
consisting of LT (n = 1) and lung metastasectomy (n = 1), but they both died of disease. Six were alive after