GRAPHICAL ABSTRACT

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of cancer-related deaths worldwide.¹ According to the updated Barcelona Clinic Liver Cancer (BCLC) staging system, liver resection (LR) is recommended for BCLC stage 0 and BCLC stage A single HCC in patients with preserved liver function.² For multinodular HCC of BCLC stage A (Milan criteria), the BCLC staging system recommends liver transplantation (LT) over LR when feasible, primarily because of a high risk of recurrence.

However, LT may not always be feasible owing to factors such as donor unavailability, patient operability, and medical constraints in real-world cases. Therefore, clinicians generally choose alternative treatments, including LR, ablation, and transarterial chemoembolization (TACE).^2-4 Nonetheless, the choice of alternative treatment demonstrating better outcomes for multinodular BCLC stage A HCC is controversial. Given that LR is generally considered for curative purposes and TACE is considered a palliative treatment, LR may be a better treatment option for multinodular HCC. However, the high risk of recurrence and morbidities from LR also should be considered when choosing LR for these patients.^5,6 A few studies have compared overall survival (OS) and recurrence-free survival (RFS) between LR and TACE in patients with multinodular BCLC stage A HCC.^7,8 In a large nationwide cohort study conducted by the Liver Cancer Study Group of Japan, LR was predominantly performed on selected patients with multinodular BCLC stage A HCC and these patients exhibited better survival outcomes compared to those who underwent TACE.⁸ However, this study encompassed patients with various tumor characteristics, including macrovascular invasion and HCC beyond the Milan criteria. Moreover, the patients included in this study were enrolled between 2000 and 2007, almost 2 decades ago.

Therefore, we compared the survival and recurrence outcomes of LR and TACE in patients with multinodular BCLC stage A HCC (within the Milan criteria) using recent long-term follow-up data. Moreover, we evaluated the risk of liver-related morbidity and post-hepatectomy liver failure to assess LR safety.

METHODS

Study population and variables

This was a historical cohort study of patients with treatmentnaïve multinodular HCC within the Milan criteria between 2013 and 2022 at Asan Medical Center, Seoul, Republic of Korea. A total of 483 patients were analyzed retrospectively (Fig. 1). Patients who met all the following criteria were included 1) age ≥18 years, 2) diagnosed with HCC within the Milan criteria, 3) two or three tumors, 4) preserved or moderately preserved liver function corresponding to Child-Pugh (CP) class A or B7, and 5) underwent LR or TACE as a primary treatment. Patients who met any of the following criteria were excluded 1) LT, radiofrequency ablation (RFA), LR with RFA, best supportive care, or other primary treatments, 2) HCC beyond the Milan criteria or with extrahepatic metastasis at baseline, 3) severely impaired liver function, classified as CP class B8 or above to minimize the impact of deteriorated liver function on survival outcomes, 4) concurrent non-HCC malignancies, and 5) missing variables or insufficient data. Data on patient characteristics and outcomes were obtained from the electronic medical records of Asan Medical Center. HCC was radiologically or histologically diagnosed according to international guidelines.^3,4 The clinical information of the study population, including demographics, liver disease etiologies, and laboratory data, was evaluated at diagnosis. Furthermore, we initially assessed tumor characteristics, such as the number and size of the tumors, presence of macrovascular invasion, and invasion of the bile duct at the time of diagnosis, using dynamic computed tomography (CT) or multiphasic magnetic resonance imaging (MRI) for a baseline study. If a patient underwent LR as the initial treatment for HCC, the type of resection was also investigated. After TACE or LR, the clinical status of all patients was assessed using physical examination and laboratory findings during hospitalization. Patients who underwent LR were evaluated for postoperative complications, such as bleeding, wound complications, and infection, using laboratory findings and CT.

Subsequently, patients in the TACE group underwent an initial disease evaluation using CT 4-6 weeks after TACE initiation. If complete remission (CR) was not achieved and incomplete lipiodol deposition or residual HCC was identified, additional TACE was considered. Patients were followed up every 1-3 months for disease evaluation using laboratory findings and imaging, such as CT or MRI. Patients who underwent LR were monitored at regular intervals, every 1-3 months, for postoperative disease evaluation.

Ethical approval was obtained from the Institutional Review Board (IRB) of Asan Medical Center (IRB No. 2019-0932), and the requirement for informed consent was waived owing to the retrospective nature of the study. Moreover, we followed the guidelines for reporting observational epidemiological studies (Supplementary Table 1).

Definitions of LR, post-hepatectomy biochemical dysfunction and liver-related morbidity, and technical methods of TACE

Among the 483 patients, 107 (22.2%) underwent LR as the primary treatment for HCC. We used the Brisbane 2000 Terminology of Liver Anatomy and Resections to classify the type of LR.⁹ A major hepatectomy was defined as the resection of three or more contiguous or non-contiguous liver segments. At our center, LRs are performed by highly experienced hepatobiliary surgeons with >10 years of expertise in hepatobiliary surgery and liver transplantation. Anatomical resection is the preferred approach over non-anatomical resection when deemed suitable, with the extent of hepatectomy tailored to the estimated remnant liver volume and functional hepatic reserve. Post-hepatectomy biochemical dysfunction (PHBD) was defined as increased international normalized ratio >1.5 or hyperbilirubinemia (total bilirubin >2.9 mg/dL) on or after postoperative day ≥5.¹⁰ Surgery-related complications other than PHBD were defined according to the Clavien-Dindo classification.¹¹

Additionally, the 90-day mortality after index surgery was also investigated. The TACE procedure was performed in our hospital as previously described.¹² After selective catheterization of the feeding artery using a microcatheter, either 50 mg of adriamycin or cisplatin (2 mg/kg body weight) was infused into the feeding artery, followed by an infusion of an emulsion of iodized oil and embolization with gelfoam slurry.

Definition of recurrence

The first recurrence after treatment initiation was evaluated. In the LR group, recurrence was defined as radiological detection of tumors after LR, regardless of the location. According to the modified response evaluation criteria in solid tumors (mRECIST), the first recurrence after TACE was defined as viable tumor detection after achieving CR.¹³ mRECIST measures the size of target lesions enhanced in the arterial phase and washed out in the venous phase. Based on mRECIST, CR was defined as the disappearance of any intratumoral arterial enhancement in all target lesions. If residual tumors were observed in the disease evaluation and no new lesions developed after TACE, we considered them to be in non-CR. Therefore, this case was excluded from the assessment of RFS risk for comparative purposes.

Study outcomes

The primary outcome of this study was the OS. OS was defined as the duration from the date of LR or TACE to death from any cause, LT, or the last follow-up date, whichever occurred first. We also analyzed the RFS and compared the two treatments. RFS after LR was defined as the duration from LR to recurrence, whereas RFS after TACE was defined as the duration from the achievement of a complete response after TACE to recurrence. OS in the study cohort and RFS in patients who underwent LR and TACE and achieved complete response were analyzed. For patients who underwent LR, postoperative adverse outcomes, which included any liver-related morbidity after LR, including PHBD, ascites, bleeding, wound infection, bile leakage, fluid collection, and 90-day mortality, were also evaluated.

Subgroup analysis based on the number of tumors at baseline

To investigate the possible association between the number of tumors and survival outcomes, we performed a sensitivity analysis based on the number of tumors. The entire patient population was stratified into two subgroups based on the number of tumors at baseline: a subgroup with two tumors and a subgroup with three tumors at baseline. OS and RFS were evaluated and compared between the two treatments in each subgroup.

Statistical analysis

Regarding baseline characteristics, data were summarized as mean values±standard deviation for continuous variables and numbers with percentages for categorical variables. The t-test or Mann-Whitney U test was used for continuous variables and the chi-square or Fisher’s exact test for categorical variables, as appropriate. OS and RFS rates were estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to identify predictive factors for OS and RFS. We also used propensity score (PS) matching analysis to minimize potential confounding between the two treatment groups in the entire cohort and within subgroups based on number of tumors. Missing values ranging from 2.3% (diabetes) to 0.2% (total cholesterol and alkaline phosphatase) of the baseline laboratory data were imputed using linear interpolation in the MICE package. A 1:2 nearest neighbor matching scheme with a caliper size of 0.2 was used for PS matching. None of the standardized differences between baseline covariates in the matches exceeded 0.2. Statistical analyses were performed using the R software (http://cran.r-project.org/). Statistical significance was set at P<0.05.

RESULTS

Baseline characteristics of the study population

The median age of the study population was 68 years, and 85.1% were men. Among the 483 patients, 107 (22.2%) and 376 (77.8%) underwent LR and TACE, respectively, as primary treatments for HCC (Table 1). Chronic hepatitis B was the most common etiology in both groups. Compared with patients in the TACE group, those in the LR group had a significantly lower rate of CP class B7 and significantly higher platelet and serum albumin levels. The LR group had a significantly higher proportion of patients with two tumors than the TACE group.

LR

Of the 107 patients in the LR group, 30 (28.0%) underwent major resection and 77 (72.0%) underwent minor resection. The most common type of major and minor resection were hemihepatectomy and right anterior sectionectomy, respectively.

OS

During a median follow-up of 5.3 years, the OS rates after treatment in the entire cohort at 1, 3, 5, 7, and 10 years were 97.5%, 85.7%, 73.6%, 68.6%, and 60.8%, respectively. Among the 483 included patients, 140 (29.0%) died during the follow-up period and the median OS was not reached.

The OS rates after LR at 1, 3, 5, 7, and 10 years were 100.0%, 97.1%, 90.7%, 85.5%, and 75.8%, respectively. In the TACE group, the OS rates at 1, 3, 5, 7, and 10 years were 96.7%, 82.4%, 68.5%, 63.4%, and 56.4%, respectively (Fig. 2A). The median OS of the LR and TACE groups were also not reached during the follow-up.

Recurrence and subsequent treatment after recurrence

During the follow-up period, 76 patients (71.0%) in the LR group experienced recurrence. Among the 376 patients in the TACE group, 237 (63.0%) achieved a CR of the target tumor lesions after TACE. Among them, 190 (80.2%) experienced recurrence after achieving CR (Supplementary Table 2). In the LR group, 75 patients (98.7%) and one patient (1.3%) showed intrahepatic and extrahepatic recurrence (peritoneal seeding), respectively. In the TACE group, the recurrence pattern was mostly intrahepatic (98.4%) and no cases of isolated extrahepatic recurrence were observed. One patient (0.5%) exhibited both intrahepatic and extrahepatic recurrences, whereas two patients (1.1%) died of liver-related causes rather than recurrences.

The RFS rates after LR at 1, 3, 5, 7, and 10 years were 82.0%, 54.0%, 37.8%, 28.3%, and 19.5%, respectively. In the TACE group, the RFS rates at 1, 3, 5, 7, and 10 years were 59.7%, 18.1%, 7.9%, 5.5%, and 4.8%, respectively. The median RFS of the LR group was significantly longer than that of the TACE group (3.4 vs. 1.2 years, P<0.001) (Fig. 3A).

As the treatment for recurrence, TACE was performed in 56 (73.7%) and 132 (69.5%) patients in the LR and TACE groups, respectively (Supplementary Table 2). Local ablation treatments such as RFA and percutaneous ethanol injection therapy were administered to 15 (19.7%) and 34 (16.5%) patients in the LR and TACE groups, respectively.

Predictive factors for OS and RFS

In multivariate analysis, patients in the TACE group had significantly worse survival outcomes than those in the resection group (adjusted hazard ratio [aHR], 1.81; 95% confidence interval [CI], 1.08-3.04; P=0.03) (Table 2). Old age (aHR, 1.06), increased total bilirubin levels (aHR, 1.27), and chronic hepatitis C (aHR, 2.12) were associated with poor survival outcomes. Increasing size of the largest tumor (aHR, 1.43) was also significantly associated with worse survival in the multivariate analysis.

When analyzing the 344 patients who underwent LR or achieved CR after TACE, TACE was associated with a lower RFS (aHR, 2.41; 95% CI, 1.78-3.25; P<0.001) in the multivariate analysis (Supplementary Table 3). Additionally, tumor size of the largest tumor was significantly associated with lower RFS (aHR, 1.44) in the multivariate analysis. Furthermore, three tumors (aHR, 1.27) showed a trend toward a lower RFS than two tumors, although the result was not statistically significance.

Development of PHBD and liver-related morbidity after resection

Among the 107 patients in the LR group, ascites developed in 69 patients (64.5%) and was the most common perioperative morbidity. PHBD developed in 11 patients (10.2%) (four and seven who underwent major and minor resections, respectively). Table 3 presents the details of the morbidity after LR. Surgery-related morbidities occurred in 15 patients (13.9%) . The most common surgery-related morbidity was pleural effusion, followed by wound complications, bile leakage, and fluid collection. Among patients who developed postoperative pleural effusion, 5.6% required percutaneous drainage during their hospital stay. Most patients with wound infections required wound repair (n=3, 2.8%). All patients who experienced bile leakage underwent endoscopic intervention. None of the patients experienced life-threatening complications to the extent that necessitated intensive care management, corresponding to grade 4 of the Clavien-Dindo classification of surgical complications. Moreover, none of the patients died within 1 year after LR.

PS matching analysis

To minimize potential confounding factors, we generated a PS-matched cohort in a 1:2 ratio. Finally, 97 patients in the LR group were matched with 171 patients in the TACE group. Baseline characteristics in this PS-matched cohort between the two groups did not significantly differ, showing a standardized mean difference of <0.2 in all matched variables (Table 1).

In the PS-matched cohort, the TACE group showed significantly worse OS than the LR group (P=0.008) (Fig. 2B). OS rates in the LR group at 1, 3, 5, 7, and 10 years were 100.0%, 96.8%, 89.7%, 85.4%, and 74.5%, respectively, whereas the OS rates of the TACE group at 1, 3, 5, 7, and 10 years were 98.2%, 91.4%, 74.1%, 67.5%, and 59.9%, respectively.

The TACE group demonstrated a significantly poorer RFS outcome than the LR group (P<0.001) (Fig. 3B). The RFS of the LR group at 1, 3, 5, 7, and 10 years were 80.1%, 53.8%, 35.9%, 27.0%, and 24.8%, respectively. In the TACE group, RFS at 1, 3, 5, 7, and 10 years were 60.7%, 19.3%, 8.8%, 5.9%, and 5.9%, respectively.

Subgroup analysis according to the number of tumor

Among 349 patients with two tumors, 87 and 262 underwent LR and TACE, respectively. Patients who underwent LR in this subgroup showed a significantly longer OS than those in the TACE group (P<0.001) (Fig. 4A). Regarding recurrence, the LR group was significantly associated with better RFS than the TACE group (P<0.001) (Fig. 4B).

Of the 134 patients with three tumors, 20 and 114 underwent LR and TACE, respectively. The OS of the LR group was better than that of the TACE group (P=0.11) (Fig. 4C). The LR group had a significantly better RFS than the TACE group (P<0.001) (Fig. 4D).

When conducting PS-matched analysis with 1:2 ratio for OS evaluation in each subgroup, in the subgroup with two tumors, 70 patients from the LR group were matched with 118 patients from the TACE group. In the subgroup with three tumors, 12 patients from the LR group were matched with 22 patients from the TACE group. However, when performing PS-matching for RFS evaluation, in the subgroup with two tumors, 65 patients from the LR group were matched with 90 patients from the TACE group. In the subgroup with three tumors, 12 patients from the LR group were matched with 17 patients from the TACE group (Supplementary Tables 4, 5).

After PS-matched analysis in each subgroup, the subgroup with two tumors showed that the LR group had longer OS and RFS rates than the TACE group (Supplementary Fig. 1A, B). However, no significant differences were observed in OS between the two treatment groups, whereas the LR group showed better RFS than the TACE group in the subgroup with three tumors (Supplementary Fig. 1C, D).

DISCUSSION

In the present study, the LR group demonstrated better OS and RFS than the TACE group for multinodular HCC within the Milan criteria. TACE, old age, and large tumor size were identified as crucial factors for predicting poor OS. Moreover, TACE and large tumor size were independent predictors of poor RFS. Nevertheless, the number of tumors was not associated with survival outcomes. The proportion of PHBD and surgery-related morbidities was relatively low, and no deaths were observed within 90 days or even within 1 year after LR.

The survival outcomes of the LR group in our study (OS at 5 years, 90.7%; RFS at 5 years, 37.8%) were even more favorable than those reported in a previous Japanese nationwide study within the Milan subgroup (OS at 5 years, 59.3%; RFS at 5 years, 34.5%).⁸ This difference might be attributed to the heterogeneity in the baseline characteristics of the study population between the two studies and the recency of our study. LR is not strongly recommended by the current guidelines for patients with multinodular BCLC stage A HCC owing to the high recurrence rate after treatment.²

As expected, the recurrence rate after curative LR was 71%. However, all recurrences after LR were mostly intrahepatic and were effectively managed with local treatments, such as TACE and ablation. Treatment of HCC does not end with first-line treatment unless LT is performed, and the remnant liver parenchyma is oncogenic owing to underlying liver disease. Therefore, regular and meticulous surveillance for recurrence is crucial to effectively manage intrahepatic recurrence even after curative LR, if LT is not feasible. In the TACE group, only 63.0% of the patients achieved CR after undergoing TACE. Among them, the recurrence rate was significantly higher than that in the LR group, despite adjusting for confounding covariates by PS matching. This also suggests the superiority of LR over TACE in terms of oncological outcomes in multinodular HCC within the Milan criteria.

The survival benefit of LR compared to locoregional treatment has been mostly reported in retrospective studies on BCLC stages A and B.^14,15 Since not all patients are suitable for LR in this setting, selecting eligible patients is crucial. In previous studies, the factors determining the feasibility of LR for multinodular HCC included preoperative alpha-fetoprotein level, presence of macrovascular invasion, and tumor size and number.^16,17 Preoperative alpha-fetoprotein was not associated with outcomes in our study, partly because we included relatively small tumors (median, 2.0 cm). Additionally, we did not include patients with macrovascular invasion, who belonged to BCLC stage C. However, the size of the largest tumor was associated with lower OS and RFS in the multivariate analysis, which was consistent with previous findings. This suggests that if a patient with multinodular HCC within the Milan criteria has the aforementioned favorable factors, LR can be suggested to achieve better oncological outcomes instead of TACE. In the subgroup analysis based on the number of tumors, the LR group demonstrated better OS and RFS than the TACE group, regardless of the number of tumors. Although there was no statistical significance in the comparison of OS in the subgroup with three tumors owing to the small sample size, the LR group tended to exhibit a longer OS than the TACE group. LR may be beneficial for patients with multinodular HCC within the Milan criteria, and may lead to better survival outcomes.

In this study, none of the patients in the LR group died within 1 year after LR, and post-hepatectomy liver failure, defined as PHBD, occurred in only 10.2% of the patients. These patients recovered well without any serious morbidities. Advanements in surgical techniques and postoperative care have been associated with better postoperative outcomes. Regarding patient selection from the perspective of liver function, total bilirubin and serum albumin levels were associated with worse OS but not RFS. This implies that liver function is essential for survival, although poor liver function may not directly affect recurrence. In summary, a meticulous patient selection process that considers the risk of HCC and liver function reserve may improve the indications for LR in patients with multinodular HCC within the Milan criteria.

This study has some limitations. First, this was a retrospective study, and biases, including selection and measurement bias, could not be completely avoided. Additionally, the inherent differences in baseline characteristics, particularly liver function, between the LR and TACE groups pose a challenge. For example, patients who undergo LR tend to have higher platelet counts than those who undergo TACE. Although a randomized trial would offer superior control over such biases, practical constraints preclude its implementation in our setting. Therefore, we used PS matching and multivariate analyses to address these limitations. Second, our center is a high-volume tertiary referral center. Therefore, our findings should be cautiously generalized to different centers with different environments in terms of surgical techniques and postoperative care. Third, we did not analyze the possible association between tumor location and outcomes. Our study was limited by the lack of data on tumor locations, which would have allowed us to differentiate between multicentric occurrence and intrahepatic metastasis. This distinction is crucial, as satellite nodules, which develop from intrahepatic metastasis, often portend a poorer prognosis than multicentric HCC. Future research should aim to incorporate tumor location data to inform tailored treatment strategies based on the underlying mechanisms of multiple tumors.

Additionally, as most patients in the present study underwent open LR, we did not compare the outcomes between laparoscopic and open LR. Fourth, we could not compare the survival outcomes between RFA, TACE, and surgery. Although the BCLC staging system recommends RFA for multinodular HCC within the Milan criteria as an alternative treatment for LT and LR, in clinical practice, its ability to treat the entire lesion is often limited, and the feasibility of RFA depends on the location of HCC.¹⁹ Therefore, in our cohort study, the number of patients who underwent RFA was limited, even when they satisfied the Milan criteria. Finally, comparing RFS between the LR and TACE groups presented challenges due to discrepancies in the definition of CR within each treatment group. CR was regarded as pathologic CR in the LR group, whereas in the TACE group, CR was equivalent to radiologic CR.²⁰ Therefore, CR evaluated by mRECIST could be overestimated depending on CT accuracy, the effect of lipiodol deposition on tumor necrosis, or the proficiency of radiologists.²¹

In conclusion, in real-world clinical practice, LR showed a superior long-term prognosis compared with TACE in patients with multinodular BCLC stage A HCC. Therefore, careful identification of suitable candidates for LR before choosing therapeutic options for these patients when LT is not feasible remains important. However, further prospective research is required to establish when LR should be given priority over TACE to make a clear decision regarding primary treatment for these patients.

Acknowledgments

Article information

Conflicts of Interest

Young-Suk Lim is an advisory board member of Bayer Healthcare and Gilead Sciences and receives investigator-sponsored research funding from both companies. Jonggi Choi has served as a speaker and an advisory committee member for Gilead Sciences. Otherwise, the authors have no conflicts of interest to disclose.

Ethics Statement

This study was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2019-0932). The need for informed consent was waived due to the retrospective nature of the evaluations.

Funding Statement

This study was supported by grants from the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (No. 2021R1G1A1009506) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI21C2448). The interpretation and reporting of the data were the sole responsibility of the authors. This study was supported by Korean Liver Cancer Association Research Award 2023.

Data Availability

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Author Contributions

Conceptualization: JY, WMC, DL, JHS, KMK, YSL, HCL, DBM, DHJ, JC

Data curation: JC, WMC, DL, JHS, KMK, YSL, HCL, DBM, DHJ

Formal analysis: JY, JC

Funding acquisition: JC

Investigation: JC

Methodology: JY, JC

Project administration: JC

Resources: JC

Supervision: JC

Visualization: JY, JC

Writing - original draft: JY, JC

Writing - review & editing: JY, JC

All authors read and approved the final version of the manuscript.

Supplementary Material

Figure 1.

Flowchart of patients. BCLC, Barcelona Clinic Liver Cancer; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.

Figure 2.

Overall survival according to the treatment. (A) Entire cohort. (B) Propensity score-matched cohort. TACE, transarterial chemoembolization.

Figure 3.

Recurrence-free survival according to the treatment. (A) Entire cohort. (B) Propensity score-matched cohort. TACE, transarterial chemoembolization.

Figure 4.

Outcomes based on subgroup analysis. (A) Overall survival in patients with two tumors according to the treatment. (B) Recurrence-free survival in patients with two tumors according to the treatment. (C) Overall survival in patients with three tumors according to the treatment. (D) Recurrence-free survival in patients with three tumors according to the treatment. TACE, transarterial chemoembolization.

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Figure & Data

References

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