Research ArticleClinical Studies

The Japanese 5-5-500 Rule Predicts Prognosis of Hepatocellular Carcinoma After Hepatic Resection

TERUYUKI TAKISHIMA, KOICHIRO HARUKI, TOMOHIKO TANIAI, KENEI FURUKAWA, TAKASHI HORIUCHI, SHINJI ONDA, MITSURU YANAGAKI, YOSHIHIRO SHIRAI, RYOGA HAMURA and TORU IKEGAMI
Anticancer Research April 2023, 43 (4) 1623-1629; DOI: https://doi.org/10.21873/anticanres.16312

Abstract

Background: The 5-5-500 rule has been proposed to increase the candidates of liver transplantation for patients with hepatocellular carcinoma with reasonable recurrence rates. However, the clinical significance of the 5-5-500 rule in patients who underwent hepatic resection for hepatocellular carcinoma has not been fully investigated. Patients and Methods: The study comprised 206 patients who had undergone primary hepatic resection for hepatocellular carcinoma between 2008 and 2018. We retrospectively investigated prognostic significance of the 5-5-500 rule and disease-free, as well as overall, survival and further prognostic stratification using inflammatory-based biomarkers. Results: 132 patients (64%) were classified within the 5-5-500 rule, while 74 patients (36%) were classified outside the 5-5-500 rule. Among the patients outside the 5-5-500 rule, 62 patients had tumors greater than 5 cm, and 23 patients showed serum AFP levels greater than 500 ng/ml. In the multivariate analysis, being female (p<0.01), HBs-Ag positive (p<0.01), having an ICGR15 ≥15% (p=0.03), and being outside the 5-5-500 rule (p=0.01) were independent and significant predictors of disease-free survival, while being HBs-Ag positive (p=0.04), having poor tumor differentiation (p=0.03), and residing outside the 5-5-500 rule (p=0.01) were independent and negative predictors of overall survival. Elevated CRP-to-albumin ratio was associated with poor overall survival in the patients outside the 5-5-500 rule, but not in patients within the 5-5-500 rule (p=0.17). Conclusion: The 5-5-500 rule can be a prognostic factor in patients with hepatocellular carcinoma after hepatic resection. CRP-to-albumin ratio might be useful to stratify the outcomes in patients outside the 5-5-500 rule.

Key Words:

Hepatocellular carcinoma (HCC) is the seventh for cancer incident and second cause of cancer-related death worldwide (1). Despite advances in surgical techniques and perioperative management, the recurrence rate of HCC after curative hepatic resection remains high. Although hepatic resection may have a prognostic advantage over other treatment options (2), the guidelines recommended transarterial chemoembolization or systemic chemotherapy for advanced HCC classified as Barcelona Clinic Liver Cancer (BCLC) B or outside Milan criteria (3). Surgical resection may contribute to improved survival for advanced HCCs, however, there has been limited evidence on hepatic resection for these tumors (4, 5). Therefore, the assessment of prognostic factors in advanced HCCs after liver resection is critically important in clinical decision-making.

The 5-5-500 rule has been proposed as new expanded criteria of liver transplantation for HCC (6). The criteria include not only number and size of the tumors but also alpha-fetoprotein (AFP), i.e., tumor size being ≤5 cm in diameter, tumor number ≤5 and serum alpha-fetoprotein (AFP) ≤500 ng/ml. Thus, the 5-5-500 rule may reflect molecular biological characteristics of the tumors. However, the prognostic value of the 5-5-500 rule for hepatic resection has not been well-investigated (7). Evidence suggests that the systematic inflammatory response, including neutrophil-to-lymphocyte ratio (NLR) (8), platelet-to-lymphocyte ratio (PLR) (9), lymphocyte-to-monocyte ratio (LMR) (10), and C-reactive protein-to-albumin ratio (CAR) (11) have been associated with survival in patients with HCC. Therefore, in this study, we investigated the prognostic value of the 5-5-500 rule in patients with HCC after hepatic resection. We further stratified HCCs outside the 5-5-500 rule, focusing on systemic inflammatory response, which can be a potential biomarker to stratify advanced HCCs.

Patients and Methods

Patient selection. Between August 2008 and November 2018, among the patients with HCC that underwent hepatic resection at the Department of Surgery, The Jikei University Hospital, 206 patients with available data on tumor size, number of tumors, and serum alfa-fetoprotein (AFP) were included in this study. We performed a retrospective review of a prospectively maintained patient database. This study was approved by the Ethics Committee of the Jikei University School of Medicine (#27-177).

Treatment and follow-up. Generally, the extent and type of hepatic resection was decided by preoperative tumor staging, retention rate of indocyanine green at 15 min (ICGR15) before surgery, and hepatic reserve, as described by Miyagawa et al. (12). The nomenclature of the segments and types of operations follow the Brisbane 2000 terminology (13). The type of resection was either anatomical resection or non-anatomical partial resection (14). The Tumor-Nodes-Metastasis (TNM) classification was based on the tumor pathology and the General Rules for the Clinical and Pathological Study of Primary Liver Cancer by the Liver Cancer Study Group of Japan (15). The recurrence of HCC was detected by ultrasonography, computed tomography, and magnetic resonance imaging with or without increase in the serum level of AFP and protein induced by vitamin K absence or antagonist-II. For recurrent HCC in the liver, repeated hepatic resection, local ablation therapy, or transarterial chemoembolization was performed based on hepatic functional reserve evaluated mainly by ICGR15. Extrahepatic recurrence was mainly treated with systemic chemotherapy.

Definition of the 5-5-500 rule. The 5-5-500 rule was defined by macroscopic and pathological findings with serum AFP level. Patients were classified into within the 5-5-500 rule if tumor size was ≤5 cm in diameter, tumor number was ≤5, and serum AFP level ≤500 ng/ml, while patients who exceeded any criteria were classified into outside the 5-5-500 rule (6).

Assessment of systematic inflammatory response. Systemic inflammatory response was assessed by inflammation-based biomarkers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and C-reactive protein (CRP) to albumin ratio (CAR). NLR was calculated by dividing absolute neutrophil count with absolute lymphocyte count (8). PLR was calculated by dividing absolute platelet count with absolute lymphocyte count (9). LMR was calculated by dividing absolute lymphocyte count with absolute monocyte count (10). CAR was calculated by dividing serum CRP level (mg/l) with serum albumin level (g/l) (11).

Statistical analyses. Data are expressed as median, interquartile range, or ratio. Univariate analysis was performed using the Mann-Whitney U-test, Chi-square test, or Fisher’s exact test, as appropriate. The optimal cut-off values of the inflammation-based biomarkers were determined by ROC analysis. The Kaplan-Meier method was used to estimate cumulative survival probabilities, and the differences between groups were compared using the log-rank test.

We used the two-sided α level of 0.05. Our primary analyses were assessment of the survival association of the 5-5-500 rule with disease-free and overall survival. All other tests, including assessment of risk estimates, represented secondary analyses. All analyses were conducted using the EZR statistics version 1.54 (Jichi Medical University, Saitama, Japan) (16).

We evaluated the prognostic significance of the 5-5-500 rule in patients with HCC. Univariate Cox proportional-hazards regression models were used to estimate the hazard ratios for disease-free and overall survival. We evaluated the following variables, including age (≥65 vs. <65), sex (female vs. male), hepatitis B virus antigen (positive vs. negative), hepatitis C virus antibody (positive vs. negative), preoperative ICGR15 (≥15 vs. <15%), Child-Pugh grade (B vs. A), serum AFP level (≥500 vs. <500 ng/ml), tumor differentiation (poor vs. well/moderate), tumor T factor (pT3 or T4 vs. T2 or T1), type of resection (anatomical vs. partial), duration of operation (≥360 vs. <360 min), intraoperative blood loss (≥1,000 vs. <1,000 g), NLR (≥1.5 vs. <1.5), PLR (≥142 vs. <142), LMR (≤3.8 vs. >3.8), CAR (≥0.03 vs. <0.03), 5-5-500 rule (outside vs. within). Multivariate analysis was performed, incorporating all variables with p<0.05 on univariate analysis.

As secondary analyses, we investigated the prognostic association of inflammation-based markers with disease-free and overall survival in subgroups of patients with HCC outside and within the 5-5-500 rule.

Results

Patient characteristics according to the 5-5-500 rule. In Table I, patient characteristics are shown as median, interquartile range, ratio, or numbers. Among 206 patients, 132 patients (64%) were classified within the 5-5-500 rule, whereas 74 patients (36%) were classified outside the 5-5-500 rule. In the patients outside the 5-5-500 rule, there was less HCV-Ab positivity, anatomical resection than those in the patients within the 5-5-500 rule (p<0.01). Serum AFP, T factor, duration of operation, intraoperative blood loss, and all of the inflammation-based biomarkers were greater in the patients outside the 5-5-500 rule (p<0.01).

View this table:
Table I.

Patient characteristics according to the 5-5-500 rule.

Univariate and multivariate analysis for disease-free survival in patients with hepatocellular carcinoma after hepatic resection. In univariate analysis, being female (p=0.01), HBs-Ag positive (p<0.01), ICGR15 ≥15% (p=0.04), intraoperative blood loss ≥1000g (p=0.03), CAR ≥0.03 (p<0.01), and outside the 5-5-500 rule (p<0.01) were significant predictors of disease-free survival (Table II). In multivariate analysis, being female (p<0.01), HBs-Ag positive (p<0.01), ICGR15 ≥15% (p=0.03), and outside the 5-5-500 rule (p=0.01, Figure 1A) were independent and significant predictors of disease-free survival.

View this table:
Table II.

Univariate and multivariate analysis for disease-free survival in patients with hepatocellular carcinoma after hepatic resection.

Figure 1.
Figure 1.

Kaplan-Meier curves of disease-free survival (A) and overall survival (B) after hepatic resection for HCC. The 5-5-500 rule was associated with worse disease-free survival (p<0.01) and overall survival (p=0.019).

Univariate and multivariate analysis for overall survival in patients with hepatocellular carcinoma after hepatic resection. In univariate analysis, being HBs-Ag positive (p=0.03), Child-Pugh grade B (p=0.04), poor tumor differentiation (p<0.01), and outside the 5-5-500 rule (p=0.02) were significant predictors of overall survival (Table III). In the multivariate analysis, HBs-Ag positive (p=0.04), poor tumor differentiation (p=0.03), and outside the 5-5-500 rule (p=0.01, Figure 1B) were independent and negative predictors of overall survival.

View this table:
Table III.

Univariate and multivariate analysis for overall survival in patients with hepatocellular carcinoma after hepatic resection.

Prognostic association of inflammation-based biomarkers with disease-free and overall survival in patients with HCC according to the 5-5-500 rule. Using the log-rank test, NLR, PLR, and LMR were not associated with disease-free and overall survival in the patients outside or within the 5-5-500 rule (p>0.09). CAR was associated with higher overall mortality in patients with HCC outside the 5-5-500 rule (p=0.01), but there was no significant association of CAR with overall mortality in patients with HCC within the 5-5-500 rule (p=0.17) (Figure 2).

Figure 2.
Figure 2.

Kaplan-Meier curves of disease-free survival and overall survival after hepatic resection for HCC according to the 5-5-500 rule. In patients within the 5-5-500 rule, CAR was not associated with disease-free survival (p=0.17) (A) and overall survival (p=0.27) (B). In patients outside the 5-5-500 rule, CAR had a tendency towards worse disease-free survival (p=0.13) (C), and it was associated with overall survival (p=0.01) (D).

Discussion

This study demonstrated that the 5-5-500 rule was a significant predictor of poor disease-free survival and overall survival in patients who underwent hepatic resection for HCC. Moreover, systemic inflammatory response, represented by CAR, can stratify the patients with HCC outside the 5-5-500 rule. Our findings suggest the benefit of the 5-5-500 rule as a prognostic indicator in surgical patients of HCC, and the possibility of further stratification using the systemic inflammatory response that can reflect the molecular characteristics of HCC.

According to the BCLC guideline, hepatic resection is recommended for patients with a performance status of 0, Child-Pugh grade A, single and with <2 cm of tumor, normal portal pressure, and serum bilirubin level <1.0 mg/dl (17). In Japan, hepatic resection is recommended for the patients with less than three tumors without distant metastasis. These criteria are mainly focused on tumor status, including number and size. Multiple and large tumors are likely to cause vascular invasion, which leads to a higher possibility of intrahepatic or other metastasis. A study indicated that a tumor number ≥4 and tumor size >5 cm were independent risk factors of prognosis of BCLC stage B HCC patients with R0 hepatic resection (18). A high serum AFP level (>400 ng/ml) has been reported as a poor prognostic factor in patients with hepatic resection for HCC, superior to tumor stage and size (19). Evidence suggests that AFP may be involved in the pathogenesis and accelerate tumor cell growth by suppressing the apoptotic pathway (20). There have been some reports that hepatic resection has been beneficial for non-early-stage HCC (4, 5). Given the recent development of molecular-targeted drugs and immune checkpoint inhibitors, the importance of molecular tumor characteristics is increasing. Therefore, tumor-related factors beyond tumor number and size should be considered for indication of hepatic resection in patients with advanced HCC.

Systemic inflammation has been associated with local tumor microenvironment (21). In cancer patients, inflammatory biomarkers including NLR, PLR, LMR, CRP and CAR have been associated with prognosis after resection (10, 22, 23). Increased serum CRP levels may stimulate the vascular endothelial growth factor (24) and impair anti-tumor immunity. Recent evidence suggests that CRP may suppress proliferation and effector function of CD4 and CD8 T cell (25, 26) and has been associated with the expression of PD-L1 (27). A study has also demonstrated that a postoperative peak of CRP can be associated with long-term outcomes in patients with HCC (28). Hypoalbuminemia can lead to immune dysfunction and malnutrition in patients with malignancies (29). These lines of evidence suggest that there has been a close relationship between systemic inflammation and tumor progression through modulation of the tumor immune microenvironment. Thus, inflammation-based biomarkers can be promising factors that can stratify prognosis in patients with advanced tumors. In the present study, CAR was associated with survival in patients with HCC outside the 5-5-500 rule.

However, we acknowledge certain limitations in this study. Firstly, this was a retrospective study, so potential confounders and selection bias could not be completely avoided. Secondly, this study was conducted in a single institution. Given our limited sample size, our findings need to be validated in larger studies. Thirdly, there have been many scoring systems for predicting survival in patients with HCC. Although we showed the prognostic significance of the 5-5-500 rule independently of potential confounders, scoring systems, such as BCLC (30), Milan criteria (31), CLIP score (32), and ALBI grade (33), need to be considered in future studies.

In conclusion, our study showed the prognostic significance of the 5-5-500 rule in patients with HCC after hepatic resection. Moreover, CAR might be useful to stratify the outcomes in patients outside the 5-5-500 rule, suggesting the utility of inflammation-based biomarkers in further stratification of prognosis in patients with HCC outside the 5-5-500 rule.

Acknowledgements

This work was supported by JSPS KAKENHI Grant Number JP21K08805 and by a research grant from Japanese Foundation for Multidisciplinary Treatment of Cancer.

Footnotes

  • Authors’ Contributions

    Takishima T and Haruki K developed the main concept and designed the study. Taniai T, Furukawa K, Horiuchi T, Onda S, Yanagaki M, Shirai Y and Hamura R were responsible for acquisition of clinicopathological data. Takishima T and Haruki K performed data analysis and interpretation. Takishima T, Haruki K, and Ikegami T drafted the manuscript. Taniai T, Furukawa K, Horiuchi T, Onda S, Yanagaki M, Shirai Y and Hamura R contributed to editing and critical revision for important intellectual content.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest.

  • Received July 9, 2022.
  • Revision received September 3, 2022.
  • Accepted September 5, 2022.

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The Japanese 5-5-500 Rule Predicts Prognosis of Hepatocellular Carcinoma After Hepatic Resection
TERUYUKI TAKISHIMA, KOICHIRO HARUKI, TOMOHIKO TANIAI, KENEI FURUKAWA, TAKASHI HORIUCHI, SHINJI ONDA, MITSURU YANAGAKI, YOSHIHIRO SHIRAI, RYOGA HAMURA, TORU IKEGAMI
Anticancer Research Apr 2023, 43 (4) 1623-1629; DOI: 10.21873/anticanres.16312
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