GRAPHICAL ABSTRACT

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related mortality worldwide. The disease is more common in men, and the global burden is expected to rise due to aging populations and persistent risk factors.¹ In the United States, there are racial and ethnic disparities among patients affected by HCC, with black patients experiencing worse outcomes compared to Hispanic, Asian, and white patients.² Therefore, the American Association for the Study of Liver Diseases (AASLD) recommends HCC surveillance using a combination of liver ultrasound and the biomarker alpha-fetoprotein (AFP) to enhance early detection of tumors. Treatment options include surgical, locoregional, and systemic therapies, determined by factors such as tumor burden, extent of liver dysfunction, and patient performance status.³

Treatment options are determined by factors such as tumor burden, extent of liver dysfunction, and patient performance status, typically guided by the Barcelona Clinic Liver Cancer (BCLC)⁴ staging system. The management of multinodular early-stage HCC (BCLC-A), defined as having multiple nodules (≤3 nodules, each ≤3 cm) when liver transplantation is not feasible, remains a critical clinical debate. Notably, multinodular HCC BCLC-A constitutes a biologically heterogeneous group, with variability in tumor burden and liver function, which may influence treatment outcomes. The 2022 BCLC algorithm and 2024 AASLD guidelines prioritize percutaneous radiofrequency ablation (PRFA) or transarterial chemoembolization (TACE) for this specific subgroup. These recommendations emphasize nonsurgical therapies due to their lower invasiveness, feasibility of repeated application, and the goal of minimizing perioperative risk in patients with compromised liver function. Liver resection (LR) is typically indicated only for BCLC stage 0 and A single tumor in patients with preserved liver function.^3,4

However, this therapeutic hierarchy is increasingly challenged by emerging evidence and clinical practice. Several studies have suggested that LR may offer superior overall survival (OS) and disease-free survival (DFS) compared to PRFA and TACE for early-stage multinodular HCC, leading to a divergence in global guidance.^5-15 For example, the European Association for the Study of the Liver (EASL) 2025 guidelines suggest that LR may be a treatment option for patients with multinodular HCC, provided that minimally invasive liver surgery is feasible. This ongoing debate highlights a critical gap in current clinical recommendations.^16-20

To resolve this clinical question, meta-analyses are necessary to consolidate the fragmented data. However, a previous meta-analysis by Romano et al.²¹ had significant methodological limitations. First, they used binary data instead of hazard ratios (HRs) and did not properly account for censored patients, which could bias survival estimates. Additionally, the authors did not include recent studies.^10,11,13,15 These limitations should be considered when interpreting the results, as they may affect the validity and applicability of the conclusions to clinical practice. Other recently published meta-analyses did not specifically focus on multinodular (≤3 nodules, each ≤3 cm) HCC or did not compare LR with TACE.^22-24

Given these methodological and clinical considerations, the aim of this systematic review and meta-analysis is to rigorously evaluate the OS and DFS in patients with multinodular BCLC-A HCC who underwent LR, compared with those treated with radiofrequency ablation (RFA) or TACE.

MATERIALS AND METHODS

Search strategy

This systematic review and meta-analysis was conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines²⁵ and the Cochrane handbook for systematic reviews of interventions.²⁶ The study protocol was prospectively registered on the international prospective register of systematic reviews (PROSPERO) (CRD42024624055). A comprehensive literature search was performed in PubMed, Embase, and the Cochrane Library to identify studies published up to December 2024. The search strategy included the following keywords: (HCC OR hepatocellular carcinoma) AND (multiple OR multinodular) AND (liver resection OR hepatectomy) AND (RFA OR ablation OR TACE OR transarterial chemoembolization). Additional synonymous terms were also used to ensure comprehensive retrieval. Two independent reviewers (MFFV and LBC) screened the articles in a double-blind process using Rayyan Software (Rayyan, Cambridge, MA, USA). Discrepancies between the reviewers were resolved by consulting a third reviewer (AAB).

Eligibility criteria and outcomes

The inclusion criteria were: 1) patients with BCLC-A multinodular HCC (≤3 tumors, ≤3 cm each), 2) studies comparing LR with RFA or TACE, 3) prospective and retrospective cohort studies. We recognize that RFA and TACE represent heterogeneous interventions; variations in technical application (e.g., electrode type, embolization selectivity) and treatment intent are potential sources of procedural heterogeneity that strict eligibility criteria cannot fully eliminate. Exclusion criteria were studies with designs other than cohort studies, meeting abstracts or studies lacking population data or clear population definitions, articles published in languages other than English; studies evaluating combined therapies or those not reporting any of the predefined outcomes of interest; studies lacking HRs or Kaplan-Meier curves to estimate the HR.

Outcomes and data extraction

Data were extracted on baseline patient characteristics and intervention details. The primary outcomes assessed were OS and DFS, reported using HR. For studies that did not directly report HRs, data were extracted from Kaplan-Meier curves using the WebPlotDigitizer tool (https://automeris.io). To mitigate subjective error and ensure data robustness, this extraction was performed independently by two reviewers to verify inter-observer reliability before calculating the HR using the formula described by Tierney et al.²⁸ Whenever available, data adjusted for baseline differences (e.g., propensity score matching) were prioritized. Two independent reviewers (DCMSV and AAB) collected data using a predefined online spreadsheet, with disagreements resolved by a third reviewer (LBC).

Statistical analysis

Statistical analyses were conducted using Review Manager 5.4 (Cochrane Collaboration, London, UK). Pooled analyses of survival outcomes were performed using HR with 95% confidence intervals (CI). Heterogeneity was assessed using the Chi-square test and I² statistics, with I²<25% indicating low heterogeneity. A fixed-effects model was used for low heterogeneity outcomes, while a random-effects model was applied when heterogeneity was high. The Hartung-Knapp-Sidik-Jonkman method was used when Tau2>0, while Wald-Type method was used when Tau2=0 and a small number of articles (<3). For studies with adjusted data, these estimates were used to account for baseline differences, reducing selection bias and improving effect size accuracy. Sensitivity analysis was performed for the outcomes with moderate and high heterogeneity (I²>30%) and the leave-one-out method was applied.

Quality assessment

The quality of the included observational studies was assessed using the Newcastle-Ottawa scale (NOS). The quality of randomized controlled trials (RCTs) was assessed using the Cochrane Risk of Bias tool (RoB-2; Cochrane Collaboration). We explicitly acknowledge the potential selection bias inherent to comparisons between surgical and non-surgical treatments. Patients selected for resection generally possess superior physiological reserve and performance status compared to those allocated to locoregional therapies. Quality assessments were performed independently by two reviewers (BCMRA and AAB), with discrepancies resolved by a third reviewer (MFFV).

RESULTS

Study selection and baseline characteristics

The systematic search identified 11,458 studies across three databases. After removing duplicates (n=3,968), the remaining studies were screened based on title and abstract. Of these, 19 studies were sought for retrieval. A total of 15 studies were included in the final analysis (Fig. 1).

The included studies comprised two randomized controlled trials and 13 cohort studies, with a total of 2,869 patients. Among them, 1,316 (45,8%) underwent LR. Of the 15 articles, four studies included only LR and TACE groups,^6-8,11 nine studies included only LR and RFA,^{5,9,12,13,15,34-37} and two studies compared all three treatment groups (Table 1).^10,14

Most of the included articles did not specifically focus on the population of interest, limiting the availability of certain baseline characteristics (Table 1). Therefore, this meta-analysis considered only studies that included patients with multinodular BCLC-A HCC to analyze baseline characteristics (Supplementary Table 1). Only Min et al.³⁴ did not provide most of the baseline data, once this meta-analysis only used propensity score-matching (PSM) results. Among these 1,493 patients included for this analysis, 1,181 (79%) were male and at least 1,136 had viral cause.

Liver resection×RFA

The endpoint of OS was reported in nine studies, encompassing a total of 1,211 patients. LR was found to be significantly superior to RFA (HR, 1.38; 95% CI, 1.03-1.84; P=0.01; I²=26%) (Fig. 2).

A similar result was observed for DFS, which was analyzed in eight studies involving 704 patients. In this outcome, LR also demonstrated statistically significant superiority over RFA (HR, 2.16; 95% CI, 1.26-3.70; P=0.001; I²=71%) (Fig. 3).

A sensitivity analysis was conducted to assess the high heterogeneity in the DFS outcome using the leave-one-out method. This analysis involved excluding studies that reported data using Kaplan-Meier curves without providing the numbers at risk.^12,36 As a result, heterogeneity was eliminated (HR, 1.6; 95% CI, 1.28-2.05; P<0.0001; I²=0%), suggesting that such data may not be entirely reliable. Nevertheless, the statistical significance of the difference remained (Supplementary Fig. 1).

Liver resection×TACE

The endpoint of OS was reported in six studies, incorporating a total of 1,877 patients. LR was found to be significantly superior to TACE (HR, 2.11; 95% CI, 1.37-3.25; P<0.0001; I²=48%) (Fig. 4).

A comparable result was noted for DFS, which was analyzed in two studies covering 330 patients. In this outcome, LR also demonstrated statistically significant superiority over TACE (HR, 2.77; 95% CI, 1.04-7.36; P=0.04; I²=87%) (Fig. 5).

It was not possible to perform the sensitivity analysis for DFS because only two studies were analyzed, leading to a limited sample size and reduced statistical power, which may have contributed to the observed heterogeneity. The moderate heterogeneity of OS was tested using the same methodological approach as the sensitivity analyses for LR vs. RFA, and heterogeneity was eliminated (HR, 1.86; 95% CI, 1.54-2.23; P<0.00001; I²=0%). However, there was no compromise in statistical significance (Supplementary Fig. 2).

Quality assessment

The risk of bias across the five domains assessed for RCTs (selection, performance, detection, attrition, and reporting biases) using the RoB-2 tool was low and showed concordance between the two authors (AAB and BCMRA).³³ For observational studies assessed with the NOS tool, only Guo et al.⁷ was classified as moderate quality, while all other studies were classified as high quality.^7,32

DISCUSSION

This meta-analysis evaluated the optimal treatment for early-stage multinodular HCC (BCLC-A) by comparing LR with RFA and TACE. The main findings were: 1) LR was associated with significantly improved OS compared to RFA and TACE, and 2) LR demonstrated superior DFS over both treatments, with low heterogeneity in the final analyses.

The EASL (2018) guidelines recommend TACE or RFA over LR for multinodular BCLC-A HCC when transplantation is not feasible, mainly due to concerns about high recurrence rates.³⁸ However, the EASL 2025 did not specifically address this topic, but it states that multifocal tumors affecting multiple segments require bridging or downstaging therapies to assess tumor stability over time before surgical resection is considered, with weak recommendation.¹⁸ In contrast, the Asia-Pacific guidelines (2017) already suggested evaluating LR for all patients with HCC and compensated cirrhosis without metastasis.¹⁹ Several studies have demonstrated the superiority of LR over RFA and TACE, challenging the traditional preference for non-surgical approaches in multinodular BCLC-A HCC.^9-11,14,15

Despite the observed superiority of LR, recurrence remains a concern. Yang et al.¹¹ reported a 71% recurrence rate, but importantly, most cases were intrahepatic and effectively managed with locoregional treatments such as TACE and RFA. These data indicate that recurrence alone should not preclude LR, given the availability of effective salvage therapies.

Furthermore, factors influencing local control must be considered when comparing LR and RFA in multinodular BCLC-A HCC. RFA is an established curative therapy for small HCC nodules, but its success is highly conditional on tumor location. Tumors in perihilar, perivascular, or subcapsular regions are associated with poorer outcomes due to the heat-sink effect or technical difficulty in achieving safety margins. This introduces a critical resectability confounder in the included studies: patients with tumors in unfavorable locations for ablation are often directed to LR, which enables definitive anatomical excision regardless of these constraints. The greater likelihood of achieving complete local disease clearance, reflected in the DFS advantage observed in our meta-analysis, likely contributes to the superior survival outcomes associated with LR. Therefore, the observed benefit of LR may partially reflect its ability to overcome the technical failures inherent to RFA in anatomically challenging cases.¹⁷

However, it is important to acknowledge that not all patients are candidates for LR. It requires a comprehensive, multi-dimensional assessment beyond the BCLC classification, including tumor burden, degree of liver dysfunction, and performance status (PS).^3,4,16-18

Although LR achieves superior oncologic outcomes, a balanced presentation must recognize the procedure’s inherent risks. Multiple high-quality cohort studies and guideline reports have shown that LR carries a higher peri-operative morbidity and mortality than locoregional therapies. In contemporary series, major postoperative complications (Clavien-Dindo grade III-IV) occur in roughly 15-25% of patients undergoing LR for early-stage HCC, and 30-day mortality ranges between 1-3%, particularly among patients with cirrhosis.^39-41 In contrast, RFA and TACE typically have 30-day mortalities below 1% and markedly lower rates of life-threatening complications.⁴² These data underscore that, despite long-term survival advantages, LR exposes patients to greater short-term harm.

LR also entails a substantially longer recovery period. Surgical resection requires general anesthesia, abdominal incision, parenchymal transection and routine drain placement, which translate into median hospital stays of 5-7 days and convalescence periods of 4-6 weeks in most series.⁴³ In contrast, RFA is performed percutaneously or laparoscopically, often with overnight observation, and TACE can be completed as an ambulatory procedure; most patients resume normal activities within days.⁴⁴ The prolonged convalescence after LR may delay subsequent systemic or locoregional therapies and reduce quality of life in the early postoperative period, factors that must be weighed when selecting therapy.

A critical limitation of LR in cirrhotic patients is the irreversible loss of functional parenchyma. Hepatic resection removes a fixed volume of liver tissue, which decreases the future liver remnant and can precipitate post-hepatectomy liver failure (PHLF), especially in individuals with subclinical portal hypertension or indocyanine green retention rates exceeding 15%.^40,45 Both EASL and AASLD guidelines stress that the presence of clinically significant portal hypertension (hepatic venous pressure gradient ≥10 mmHg) or Child-Pugh B/C cirrhosis markedly increases the risk of PHLF and should generally preclude LR.^3,38,46 In comparison, RFA and TACE spare hepatic parenchyma and do not compromise the potential for future treatments or transplantation. Furthermore, resection may limit options for repeat interventions if the disease recurs in the remaining liver, whereas percutaneous or endovascular techniques can be repeated multiple times with minimal cumulative injury.⁴⁴

Taken together these considerations emphasize that LR should be reserved for carefully selected patients with preserved liver function (Child-Pugh A), absence of significant portal hypertension, favorable tumor location and adequate PS.^39-46 Treatment should occur in high volume centers within a multidisciplinary framework to optimize peri-operative care and minimize complications.⁴¹

Hepatic Reserve remains the most important prognostic factor, and the favorable survival results of resection are largely applicable to Child-Pugh A patients, and cautiously, to Child-Pugh B, with a low degree of portal hypertension. Additionally, the absence of clinically significant portal hypertension (CSPH) is essential, as its presence (defined by a hepatic venous pressure gradient ≥10 mmHg) is closely associated with an elevated risk of post-hepatectomy liver failure and decompensation.³

Concomitantly, the patient's PS is a mandatory and critical component of HCC staging. Curative treatments, including LR and RFA, are generally restricted to patients with a preserved functional status, typically defined as Eastern Cooperative Oncology Group (ECOG) PS 0-1.^3,4

Regarding institutional factors, the achievement of favorable survival outcomes following LR is critically dependent on the volume and experience of the center. Multidisciplinary care is deemed critical for HCC management. The presence of a dedicated multidisciplinary team (tumor board) is indispensable, as it facilitates an integrated and balanced assessment of tumor characteristics, liver function, and patient PS. This process ensures that LR is safely and reproducibly utilized as the priority treatment option only when implemented under these conditions of high specialization and collaborative assessment.^3,4,16-18

Nonetheless, it is pertinent to note that recent technological advancements in locoregional therapy may potentially narrow this treatment gap. Techniques such as microwave ablation (MWA), which is less susceptible to the heat-sink effect, and the integration of 3D stereotactic navigation systems for multi-needle placement, are enhancing the precision and efficacy of thermal injury in multinodular settings. Future studies incorporating these modern modalities are required to determine if they can achieve oncological parity with surgical resection in BCLC-A candidates.⁴⁷

Historically, OS was the endpoint that suggested RFA as non-inferior to LR in multinodular BCLC-A HCC.^12,13,34,35 Only studies with small sample sizes and older data showed LR to be superior to RFA.^5,9,15 However, a recent study by Vitale et al.¹⁰ provided strong evidence supporting the superiority of LR over RFA, reinforcing our findings. Our results further confirm this with low heterogeneity, strengthening the argument for re-evaluating treatment recommendations.

This is the second meta-analysis assessing OS and DFS in multinodular BCLC-A HCC comparing LR to RFA and TACE. A previous meta-analysis by Romano et al.²¹ found similar results, but there were notable methodological differences. Romano et al.²¹ relied on binary data at fixed time points (3- and 5-year OS/DFS), which does not fully capture the time-dependent nature of survival outcomes and may lead to biased estimates due to inadequate handling of censored patients. Additionally, their analysis reported moderate to high heterogeneity but did not conduct sensitivity analyses to explore its sources, limiting the robustness of their conclusions.

This meta-analysis has several strengths that enhance the reliability and clinical relevance of its findings. First, it is the most up-to-date and comprehensive analysis comparing LR, RFA, and TACE specifically in patients with multinodular BCLC-A HCC, addressing a critical gap in current guidelines. Unlike previous meta-analyses that relied on binary survival data, we used time-to-event analyses, extracting HR from Kaplan-Meier curves, which provide a more precise estimation of survival outcomes while properly accounting for censored patients. Additionally, we prioritized adjusted estimates, particularly those derived from PSM and multivariate adjustments, minimizing selection bias and improving the comparability between treatment groups. To further strengthen result reliability, sensitivity analyses, including a leave-one-out approach, were conducted to assess and mitigate heterogeneity. Finally, our findings are supported by low heterogeneity in key outcomes, reinforcing the robustness of the conclusions and providing strong evidence to reconsider the role of LR as a primary treatment option for multinodular BCLC-A HCC when liver transplantation is not feasible.

However, this study has some limitations that should be considered. Most included studies were retrospective, introducing an inherent risk of selection bias. Patients undergoing LR generally had better liver function (mostly Child-Pugh A), higher performance status, and surgically favorable tumor profiles, introducing a potential resectability bias. To address this, we prioritized studies using PSM or multivariable adjustment to balance baseline differences. Although BCLC-A typically includes Child-Pugh A patients, most LR, RFA, and TACE studies focused on those with preserved hepatic function (Child-Pugh A and B). Therefore, caution is warranted when applying these results to individuals with Child-Pugh C cirrhosis. Furthermore, the limited number of studies directly comparing LR and TACE for multinodular BCLC-A HCC restricts the strength of conclusions for this subgroup. The DFS analysis (LR vs. TACE) was based on a very small sample size and showed high heterogeneity, resulting in limited statistical power. Therefore, any apparent DFS advantage of LR over TACE should be interpreted with caution and underscores the need for additional comparative research. Additionally, some studies did not directly report HRs, requiring extraction from Kaplan-Meier curves, which may introduce imprecision. To address this, we applied standardized statistical methods to ensure consistency in HR calculation across studies, using Tierney et al.²⁸ methods. Variations in patient selection criteria, treatment protocols, and follow-up duration contributed to heterogeneity, potentially affecting the pooled estimates. To address this, we performed sensitivity analyses, including leave-one-out testing, which supported the robustness of our findings. The limited number of studies directly comparing LR and TACE for multinodular BCLC-A HCC also weakens conclusions for this subgroup. To enhance analytic rigor, we included only studies with clearly defined populations and outcomes. In Ueno et al.,³⁶ RFA outcomes were reported separately for percutaneous and surgical approaches, and only percutaneous RFA (p-RFA) was incorporated into the analysis. Because this materially influenced the pooled estimates, an additional sensitivity analysis was conducted to assess the potential bias introduced by this decision.

CONCLUSION

This meta-analysis provides strong evidence that LR offers superior OS and DFS compared with RFA and TACE in multinodular BCLC-A HCC, with low heterogeneity in most results. However, these findings must be interpreted with strict boundaries to avoid dangerous over-generalization.

First, the observed benefit of resection is primarily generalizable to selected patients with well-preserved liver function (Child-Pugh A or select B). Extrapolating these results to patients with significant hepatic decompensation is not supported by these data. Second, while the overall signal favors surgery, the DFS comparison between LR and TACE showed high heterogeneity (I²=87%), indicating a fragile signal that requires cautious interpretation. Finally, given that the majority of included studies are retrospective and subject to inherent selection bias, future prospective RCTs are essential to definitively validate these findings. Updating clinical algorithms to reflect this new evidence could improve long-term outcomes, but only when applied to appropriately stratified candidates.

Article information

Conflicts of Interest

The authors have no conflicts of interests to declare.

Ethics Statement

This review article is based entirely on previously published articles; therefore, ethical committee approval was not required.

Funding Statement

Not applicable.

Data Availability

Not applicable.

Author Contributions

Conceptualization: MFFV

Data Curation: AAB, DCMSV, MFFV

Formal Analysis: MFFV, LBC, AAB, BCMRA

Investigation: MFFV, AAB, LBC, DCMSV, BCMRA

Methodology: MFFV, DCMSV, LBC

Project Administration: MFFV

Supervision: FJFC

Validation: MFFV, LBC, BCMRA, FJFC

Visualization: MFFV, BCMRA, DCMSV, AAB, LBC

Writing - Original Draft Preparation: MFFV, FJFC

Writing - Review & Editing: MFFV, LBC, BCMRA, FJFC

Approval of final manuscript: All authors

Supplementary Materials

Figure 1.

PRSIMA 2020 flow diagram for updated systematic reviews. HCC, hepatocellular carcinoma.

Figure 2.

Forest plot of overall survival (OS) comparing LR×RFA. HR, hazard ratio; SE, standard error; LR, liver resection; RFA, radiofrequency ablation; IV, instrumental variable; CI, confidence interval; HKSJ, Hartung-Knapp-Sidik-Jonkman method.

Figure 3.

Forest plot of disease-free survival (DFS) comparing LR×RFA. HR, hazard ratio; SE, standard error; LR, liver resection; RFA, radiofrequency ablation; IV, instrumental variable; CI, confidence interval; HKSJ, Hartung-Knapp-Sidik-Jonkman method.

Figure 4.

Forest plot of overall survival (OS) comparing LR×TACE. HR, hazard ratio; SE, standard error; LR, liver resection; TACE, transarterial chemoembolization; IV, instrumental variable; CI, confidence interval; HKSJ, Hartung-Knapp-Sidik-Jonkman method.

Figure 5.

Forest plot of disease-free survival (DFS) comparing LR×TACE. HR, hazard ratio; SE, standard error; LR, liver resection; TACE, transarterial chemoembolization; IV, instrumental variable; CI, confidence interval; HKSJ, Hartung-Knapp-Sidik-Jonkman method.

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