Comparative analysis of curative efficacy and prognostic factors across treatment modalities for early-stage hepatocellular carcinoma (BCLC 0/A)

Abstract

BACKGROUND

While the prognostic impact of radiofrequency ablation (RFA) vs liver resection (LR) remains controversial for Barcelona Clinic Liver Cancer (BCLC) stage 0/A hepatocellular carcinoma (HCC).

AIM

To comparatively analyze prognostic outcomes across therapeutic approaches.

METHODS

We conducted a multicenter retrospective analysis of treatment-naïve HCC patients meeting BCLC stage 0/A criteria at the First Affiliated Hospital of Shihezi University and Shandong Provincial Hospital between January 2012 and December 2022, stratifying patients into three therapeutic cohorts: LR monotherapy (LR; n = 30), RFA alone (RFA; n = 40), and combined therapy (LR plus adjuvant treatment; n = 32), with primary endpoints of five-year overall survival (OS), progression-free survival (PFS), and median survival time analyzed using Kaplan-Meier (K-M) methodology.

RESULTS

A total of 102 patients with HCC were included, and they were followed up until December 31, 2023. The follow-up rate was 100%. Treatment modalities significantly impacted five-year OS (P = 0.03). Cox regression confirmed both LR [hazard ratio (HR) = 0.297; 95% confidence interval (CI): 0.104-0.848; P = 0.02] and combination therapy (HR = 0.331; 95%CI: 0.118-0.931; P = 0.04) significantly reduced mortality risk versus RFA. Furthermore, K-M analysis demonstrated significant differences in OS among the three treatment modalities (RFA, LR, and combined treatment; log-rank test, P = 0.02), and the LR group exhibited significantly improved 5-year OS compared to the RFA group (P = 0.047). Similarly, significant differences in PFS were observed among the three treatment modalities (log-rank test, P = 0.009), and both the LR group (P = 0.049) and combined therapy group (P = 0.033) exhibited significantly longer PFS compared to the RFA group.

CONCLUSION

We recommend LR as the first-line therapeutic option for early-stage HCC, while advocating active pursuit of combination therapy regimens for high-risk early-stage HCC patients to obtain comparable survival outcomes with LR alone.

Key Words: Hepatocellular carcinoma; Overall survival rate; Progression free survival rate; Radiofrequency ablation; Curative resection

Core Tip: Our findings support liver resection (LR) as the first-line preferred treatment modality for hepatocellular carcinoma (HCC) patients with Barcelona Clinic Liver Cancer 0/A stages. Simultaneously, we observed that combination therapy regimens achieve non-inferior overall survival and progression-free survival benefits compared to LR alone. Therefore, treatment-eligible early-stage HCC patients clinically indicated for combination therapy should actively pursue such regimens to attain similarly favorable prognostic outcomes.

INTRODUCTION

Primary liver cancer is the third leading cause of cancer mortality worldwide and currently ranks as the sixth most common malignancy[1]. Primary liver cancer is both the fourth most prevalent malignant tumor and the second leading cause of cancer death in China, with 367700 incident cases and 316500 fatalities reported in 2022[2]. Despite persistently low early detection and fiveyear survival rates[3], early intervention and surveillance for hepatocellular carcinoma (HCC) remain clinically vital to reduce recurrence risks[4]. We compared clinical outcomes and identified prognostic risk factors in Barcelona Clinic Liver Cancer (BCLC) 0/A stage HCC patients who underwent radiofrequency ablation (RFA) vs surgical resection, with the goal of developing predictive criteria for postoperative recurrence monitoring.

According to the BCLC strategy for prognostic prediction and treatment recommendation, RFA or microwave ablation is designated as first-line therapy for patients with BCLC stage 0 HCC[5,6]. Where ablation is precluded by tumor anatomy or concerns about efficacy, surgical resection constitutes the alternative. Should resection be contraindicated, transarterial chemoembolization (TACE) emerges as the primary salvage modality, with transarterial radioembolization (TARE) also showing substantial therapeutic value[7,8]. In BCLC stage A HCC, the foundational treatment strategies comprise ablation, TACE, and TARE. Important evidence-based distinctions exist: Surgical resection and RFA offer comparable survival for lesions ≤ 2 cm, whereas the optimal choice between resection/ablation and TACE for patients with ≤ 3 nodules requires prospective validation. Liver transplantation is a viable option for cirrhotic patients at prohibitive surgical risk or with a high likelihood of recurrence post-resection[7,8]. Supporting this, two meta-analyses concluded that for solitary HCC ≤ 2 cm at the very early stage, although short-term outcomes were similar between liver resection (LR) and RFA, resection conferred better long-term survival[9,10]. A meta-analysis revealed the survival superiority of LR over both RFA and TACE in oligo-nodular BCLC A HCC patients, particularly evidenced by significantly improved disease-free survival (DFS) outcomes, thereby validating the therapeutic hierarchy concept and positioning resection as the preferred treatment modality despite current BCLC guidelines[11]. For recurrent HCC (≤ 3 nodules ≤ 3 cm) after curative resection in BCLC stage 0-A patients, repeat resection (re-resection) demonstrated superior recurrence-free survival (RFS) and overall survival (OS) compared to RFA[12]. Despite LR demonstrating superior overall and DFS in broader early-stage HCC cohorts, a meta-analysis revealed that RFA achieves comparable long-term survival to LR in strictly defined BCLC stage 0 HCC, and notably exhibits equivalent OS efficacy for solitary lesions ≤ 3 cm[13]. For patients with early-stage HCC, RFA exhibited comparable OS to LR, yet achieves superior RFS outcomes. Notably, LR maintains a favorable procedural safety profile with significantly reduced hospitalization costs[14,15].

Overall, conflicting perspectives persist regarding the short- and long-term prognostic outcomes of LR vs RFA for early-stage HCC, particularly in BCLC stage 0/A patients. This retrospective analysis included 102 eligible patients stratified into three therapeutic cohorts (surgical resection, RFA monotherapy, and surgical resection plus adjuvant therapy), followed by an evaluation of comparative clinical outcomes and an exploration of prognostic risk factors.

MATERIALS AND METHODS

Study participants and design

Clinical records from patients with BCLC stage 0/A primary HCC were retrospectively obtained at two hospitals, First Affiliated Hospital of Shihezi University and Shandong Provincial Hospital, between January 2012 to December 2022. The initial cohort comprised 138 eligible HCC patients meeting the BCLC 0/A criteria after screening.

Inclusion criteria: (1) Patients diagnosed with primary HCC; and (2) Tumor clinical stage conforming to BCLC stage 0 or A.

Exclusion criteria: (1) Incomplete data; and (2) Unavailability of necessary follow-up information, including survival status and recurrence. After excluding 36 cases due to incomplete medical documentation (n = 10) or loss to follow-up (n = 26), 102 subjects were ultimately enrolled in our study.

Based on therapeutic modalities received, patients were stratified into surgical resection cohort (n = 30), RFA cohort (n = 40), and combined surgery-adjuvant therapy cohort (n = 32), including surgery with systemic pharmacotherapy, surgery with TACE or surgery with adjunctive RFA (Figure 1).

Figure 1 Flowchart of patient screening and grouping. BCLC: Barcelona Clinic Liver Cancer; HCC: Hepatocellular carcinoma; LR: Liver resection; RFA: Radiofrequency ablation.

We stratified patients with BCLC stage 0/A disease into three groups based on the first-line curative treatments they received: LR Group: This was indicated for patients with technically resectable tumors, preserved liver function (Child-Pugh A with adequate future liver remnant), and no major surgical contraindications. RFA Group: This approach was applied to patients with small (typically ≤ 3 cm), few (≤ 3 nodules), or deep-seated tumors, as well as those with significant comorbidities, borderline liver function, or who declined surgery. Combination Therapy Group: This incorporated multidisciplinary strategies. Preoperative sorafenib primarily targeted high-risk microvascular invasion or portal vein tumor thrombosis. Preoperative TACE was often used to enable resection in patients with larger tumors. Adjuvant RFA addressed satellite nodules, suspicious margins, or new deep-seated small lesions found intraoperatively. Specifically, adjuvant RFA performed concurrently after anatomic resection targeted satellite/micro-lesions (in same or different lobes) that were unsuitable for additional resection. This study was conducted in accordance with the Declaration of Helsinki (2013 revision) and received approval from the Ethics Committee of the First Affiliated Hospital of Shihezi University (Approval No. KJX2022-073-01). Given the retrospective design, the Institutional Review Board granted a waiver for informed consent.

Data collection

Age and gender, chronic hepatitis B virus (HBV) infection history, cirrhosis status, tumor nodule number, maximum tumor diameter, BCLC stage, liver function parameters [total bilirubin (TBIL), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)], indocyanine green retention rate at 15 minutes (ICG-R15), and platelet count (PLT) were collected to analyze prognosis-related risk factors.

Treatment modalities

Surgical operation: We performed LR via standard open laparotomy under general endotracheal anesthesia. The resection extent was guided by preoperative imaging and intraoperative frozen section analysis, aiming for complete tumor removal with histologically confirmed R0 margins.

RFA: Under local infiltration anesthesia, the RFA electrode was percutaneously positioned at the tumor centroid under realtime ultrasound guidance. Power output and duration were optimized based on lesion size and biological features, with final confirmation of electrode placement obtained prior to energy deposition. To achieve adequate oncologic margins, ablation coverage extended at least 1 cm beyond the tumor boundary. Postablation contrastenhanced ultrasound (CEUS) was performed immediately to evaluate technical success: Absence of enhancement within the ablation zone indicated coagulative necrosis, while elimination of peripheral enhancement confirmed margin adequacy. Following verification, the electrode was switched to coagulation mode, and tract ablation was carried out systematically during needle withdrawal, thereby minimizing risks of needletract seeding and hemorrhage. If any residual enhancement was observed on CEUS, additional ablation was delivered until complete necrosis was radiologically confirmed.

Combined surgical-adjuvant therapies: We employed three therapeutic strategies: (1) Surgery combined with neoadjuvant pharmacotherapy, where oral sorafenib (400 mg twice daily) was administered prior to surgery; (2) Surgery combined with TACE, which involved catheter placement into the celiac trunk or common hepatic artery via femoral or radial access using the Seldinger technique. Digital subtraction angiography was then performed, with acquisitions in arterial, parenchymal, and venous phases to assess tumor characteristics including size, multifocality, margins, and vascularity. Chemo infusion employed platinum-doxorubicin dual regimens dosed by body surface area, followed by tumor burden-adapted embolization using 10-20 mL lipiodol (platinum/doxorubicin-loaded) or gelatin sponge particles. Therapeutic response was assessed at 4 weeks via contrast-enhanced computed tomography (CT) and serological markers to determine subsequent intervention timing; and (3) Surgery with adjunctive RFA.

Follow-up

All patients underwent scheduled contrast-enhanced CT or contrast-enhanced magnetic resonance imaging evaluations at 1-3 months post-treatment to detect new lesions, assess therapeutic response, and determine subsequent follow-up intervals. Following hospital discharge, patients were monitored via outpatient visits, medical record reviews, or telephone interviews until death or the study end (database lock date: December 31, 2023). The co-primary endpoints were progression-free survival (PFS) and OS. PFS was defined as the duration from treatment initiation to radiologically confirmed disease progression (RECIST 1.1), death, or last follow-up, while OS extended from treatment start to death or last known vital status. Longitudinal follow-up provided documented 5-year OS and PFS rates for all three therapeutic groups.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics (version 26.0, IBM, Armonk, NY, United States). Categorical variables were compared between groups using the χ² test with continuity correction. Survival analysis employed the Kaplan-Meier (K-M) method with logrank testing (Bonferroniadjusted) to evaluate OS and PFS; median survival times were derived directly from the curves. To identify independent prognostic factors, we fitted Cox proportional hazard ratio (HR) models (univariable screening followed by multivariable adjustment), after verifying the proportional hazards assumption. Normally distributed data are presented as mean ± SD and compared among three groups via oneway ANOVA; nonnormally distributed data are reported as median with interquartile range [IQR; P₅₀ (P₂₅-P₇₅)] and compared using the KruskalWallis test. All tests were twosided, and P values <0.05 were considered statistically significant.

RESULTS

Baseline parameters comparison analysis

This study included 102 patients with BCLC stage 0/A HCC. A 100% follow-up rate was achieved, with the observation period concluding on December 31, 2023. The cohort comprised 77 males and 25 females, aged 34-77 years (mean 55.53 ± 10.00 years). Based on treatment allocation, patients were stratified into three groups, including surgical resection group (n = 30), RFA monotherapy group (n = 40), and surgical resection plus adjuvant therapy group (n = 32). Comparative analyses demonstrated no statistically significant differences (all P > 0.05) across the following baseline characteristics: Age, sex distribution, chronic HBV infection history, cirrhosis status, tumor nodule number, maximum tumor diameter, BCLC stage, liver function parameters TBIL, ALB, ALT, AST, and GGT, ICG-R15, and PLT (Table 1).

Table 1 General clinical characteristics of patients with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma.

Variables		LR	RFA	Combined	χ2	P value
Age (year)	≤ 60	24	27	22	1.498	0.473
	> 60	6	13	10
Gender	Male	21	35	21	5.29	0.071
	Female	9	5	11
LC	No	5	12	9	1.775	0.412
	Yes	25	28	23
HBV infection	No	6	6	11	3.979	0.137
	Yes	24	34	21
AFP (μg/L)	≤ 400	25	35	26	0.556	0.757
	> 400	5	5	6
PS score	0	14	40	15	31.484	0.96
	1	13	0	14
	2	3	0	3
Child-Pugh classification	A	27	35	28	0.128	0.938
	B	3	5	4
Number of tumor	1	28	36	30	0.427	0.808
	2	2	4	2
Diameter of tumor (cm)	≤ 2	12	20	14	0.727	0.695
	2-3	18	20	18
BCLC	0	12	18	13	0.221	0.896
	A	18	22	19
TBIL (μmol/L)	≤ 22	30	38	32	3.162	0.206
	> 22	0	2	0
ALB (g/L)	≥ 35	30	39	30	2.164	0.339
	< 35	0	1	2
ALT (U/L)	≤ 50	20	10	28	3.068	0.080
	> 50	10	30	4
AST (U/L)	≤ 59	29	39	32	0.994	0.608
	> 59	1	1	0
GGT (U/L)	≤ 73	28	40	32	4.896	0.086
	> 73	2	0	0
ICG-R15 (%)	≤ 10	29	40	31	1.32	0.517
	> 10	1	0	1
PLT (× 109/L)	≥ 100	28	40	31	2.674	0.263
	< 100	2	0	1

LR: Liver resection; RFA: Radiofrequency ablation; BCLC: Barcelona Clinic Liver Cancer; LC: Liver cirrhosis; HBV: Hepatitis B virus; AFP: Alpha fetoprotein; PS: Performance status; TBIL: Total bilirubin; ALB: Albumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; ICG-R15: Indocyanine green retention rate at 15 minutes; PLT: Platelet count.

Cox regression analysis

As detailed in Table 2, treatment modalities (RFA, LR, and combined treatment) significantly influenced the five-year OS rates (P = 0.03), with RFA, LR, and combined treatment groups demonstrating rates of 65.00%, 86.66%, and 87.50%, respectively. Cox regression analysis revealed that, for OS, both the LR group [HR = 0.297; 95% confidence interval (CI): 0.104-0.848; P = 0.02] and the combined therapy group (HR = 0.331; 95%CI: 0.118-0.931; P = 0.04) were significantly associated with reduced risk of poor prognosis compared to the RFA group. Similarly, for PFS, the LR group (HR = 0.336; 95%CI: 0.133-0.849; P = 0.02) and the combined therapy group (HR = 0.306; 95%CI: 0.118-0.792; P = 0.01) also demonstrated significantly lower risks of adverse outcomes relative to the RFA group.

Table 2 Analysis of factors associated with overall survival in patients with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma, n (%).

Variables		n (n = 102)	5-year OS	χ2	P value
Age (year)	60	73	42 (57.53)	1.000	0.819
	> 60	29	42 (57.54)
Gender	Male	77	42 (57.55)	1.000	0.109
	Female	25	42 (57.56)
LC	No	26	42 (57.57)	1.000	0.871
	Yes	76	42 (57.58)
HBV infection	No	23	42 (57.59)	1.000	0.910
	Yes	79	42 (57.60)
AFP (μg/L)	≤ 400	86	42 (57.61)	1.000	0.442
	> 400	16	42 (57.62)
PS score	0	69	42 (57.63)	2.000	0.290
	1	27	42 (57.64)
	2	6	42 (57.65)
Child-Pugh classification	A	90	42 (57.66)	1.000	0.425
	B	12	42 (57.67)
Number of tumor	1	94	42 (57.68)	1.000	0.871
	2	8	42 (57.69)
Diameter of tumor (cm)	≤ 2	46	42 (57.70)	1.000	0.444
	2-3	56	42 (57.71)
BCLC	0	43	42 (57.72)	1.000	0.444
	A	59	42 (57.73)
TBIL (μmol/L)	≤ 22	100	42 (57.74)	0.058	0.809
	> 22	2	42 (57.75)
ALB (g/L)	≥ 35	99	42 (57.76)	0.304	0.157
	< 35	3	42 (57.77)
ALT (U/L)	≤ 50	58	42 (57.78)	1.000	0.774
	> 50	44	42 (57.79)
AST (U/L)	≤ 59	100	42 (57.80)	1.000	0.963
	> 59	2	42 (57.81)
GGT (U/L)	≤ 73	100	42 (57.82)	1.000	0.769
	> 73	2	42 (57.83)
ICG-R15 (%)	≤ 10	100	42 (57.84)	1.000	0.963
	> 10	2	42 (57.85)
PLT (× 109/L)	≥ 100	99	42 (57.86)	1.000	0.267
	< 100	3	42 (57.87)
Treatment modalities	RFA	40	42 (57.88)	7.024	0.03
	LR	30	42 (57.89)
	Combined	32	42 (57.90)

OS: Overall survival; BCLC: Barcelona Clinic Liver Cancer; LC: Liver cirrhosis; HBV: Hepatitis B virus; AFP: Alpha fetoprotein; PS: Performance status; TBIL: Total bilirubin; ALB: Albumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; ICG-R15: Indocyanine green retention rate at 15 minutes; PLT: Platelet count.

Comparative assessment of therapeutic modalities on OS and PFS

As presented in Table 3, the median OS for HCC patients across the three treatment modalities (RFA, LR, and combined treatment) was 1373.5 days (95%CI: 1191.0-1559.8), 1,782.5 days (95%CI: 1499.2-2132.5), and 1455.0 days (95%CI: 1238.0-2194.8), respectively. Additionally, the mean PFS durations were 1164.5 ± 422.1 days, 1704.4 ± 569.8 days, and 1573.9 ± 581.7 days for these groups. Furthermore, K-M analysis demonstrated significant differences in OS among the three treatment modalities (RFA, LR, and combined treatment; log-rank test, P = 0.02). Subsequent multiple hypothesis testing with Bonferroni adjustment for p-values revealed that the LR group exhibited significantly improved 5-year OS compared to the RFA group (P = 0.047). However, no statistically significant differences were observed in 5-year OS of RFA and combined therapy groups (P = 0.072), or LR and combined therapy groups (P = 1.000; Figure 2A). Similarly, significant differences in PFS were observed among the three treatment modalities (RFA, LR, and combined therapy; log-rank test, P = 0.009). Subsequent multiple hypothesis testing with Bonferroni adjustment for P values revealed that both the LR group (P = 0.049) and combined therapy group (P = 0.033) exhibited significantly longer PFS compared to the RFA group. Additionally, no statistically significant difference in PFS was found between the LR group and the combined therapy group (P = 1.000; Figure 2B).

Figure 2 Effect of different treatment modalities on overall survival and progression-free survival in hepatocellular carcinoma patients within Barcelona Clinic Liver Cancer 0/A stages. A: Overall survival; B: Progression-free survival. OS: Overall survival; PFS: Progression-free survival; LR: Liver resection; RFA: Radiofrequency ablation.

Table 3 Five-year median time of overall survival and progression-free survival in Barcelona Clinic Liver Cancer Stage 0/A hepatocellular carcinoma with different treatment modalities, median (interquartile range) or mean ± SD.

Prognosis	RFA (n = 40)	LR (n = 30)	Combined (n = 32)	H/F	P value
OS (day)	1373.5 (1191.0, 1559.8)	1782.5 (1499.2, 2132.5)	1455.0 (1238, 2194.8)	10.96	0.004
PFS (day)	1164.5 ± 422.1	1704.4 ± 569.8	1573.9 ± 581.7	10.49	< 0.001

LR: Liver resection; RFA: Radiofrequency ablation; OS: Overall survival; PFS: Progression-free survival; H: H-statistic; F: F-statistic.

DISCUSSION

This study preliminarily identified that LR demonstrates significant superiority over RFA not only in 5-year OS but also in PFS. Moreover, combined therapy exhibits clinical advantages in prolonging PFS. Compared to RFA, LR provides superior prognosis in BCLC 0/A HCC patients with either two nodules or tumor diameter ≤ 3 cm, indicating its enhanced OS benefit relative to RFA. Furthermore, for early-stage HCC patients requiring multimodal therapy, surgical resection combined with chemotherapy, TACE, or RFA represents an alternative therapeutic approach to facilitate PFS improvement.

A meta-analysis by Yin et al[9] demonstrated superior long-term outcomes for LR over RFA, with significantly higher 3-year OS (HR = 0.64; 95%CI: 0.41-1.00; P = 0.05) and 5-year OS (HR = 0.63; 95%CI: 0.42-0.95; P = 0.03). Regarding postoperative DFS, LR showed significantly reduced tumor recurrence risk. However, a different pattern emerged in another study[11]. LR demonstrated no significant survival benefit over RFA for 3-year OS (RR = 0.78; 95%CI: 0.37-1.62; P = 0.452) or 5-year OS (RR = 0.74; 95%CI: 0.50-1.09; P = 0.103). In contrast, LR showed statistically superior DFS outcomes: 3-year DFS benefit (RR = 0.70; 95%CI: 0.54-0.93; P = 0.020) and 5-year DFS benefit (RR = 0.82; 95%CI: 0.72-0.95; P = 0.015)[11,16]. Evidence also indicates differential therapeutic efficacy between LR and RFA across HCC stages. For early-stage HCC patients, LR provides superior OS and DFS. However, comparable long-term survival outcomes were observed between LR and RFA in patients with BCLC stage 0 HCC. Moreover, LR and RFA may yield comparable OS benefits under either of the following conditions: Of single-nodule HCC lesions < 3 cm in diameter, or when an ablation margin > 1 cm is achieved[13]. In a long-term follow-up study, the median RFS after salvage therapy was 34.6 months in the LR group vs 16.2 months in the RFA group (HR = 0.574; 95%CI: 0.447-0.737; P < 0.001). Both RFS and OS were significantly better in the LR group compared to the RFA cohort[12]. Although LR may yield slightly inferior prognostic improvement compared to RFA[9,17], studies demonstrate that both RFA and LR are safe and feasible treatment options for patients with early-stage HCC (≤ 3 cm). Moreover, RFA provides comparable OS rates while offering advantages of reduced surgical trauma and shorter hospital stays[14,18]. After propensity score matching adjusting for key clinical covariates, the LR cohort demonstrated significantly superior outcomes compared to the ablation group with OS (HR = 0.62; 95%CI: 0.41-0.93; log-rank P = 0.023) and RFS (HR = 0.58; 95%CI: 0.36-0.94; log-rank P = 0.027). Based on this real-world evidence, LR should be prioritized over ablation as first-line curative therapy for appropriately selected HCC patients within BCLC 0/A stages[19]. Despite extensive research[9,11,13], the therapeutic efficacy of RFA vs LR continues to exhibit stage-dependent variations across different prognostic endpoints and HCC stages. However, multiple studies have demonstrated superior OS benefits with LR compared to RFA[9,12,13]. Our limited-sample study corroborates this finding, revealing significantly better five-year OS outcomes with LR. Consequently, we endorse prioritizing LR as potentially the more effective first-line therapy for HCC patients within BCLC 0/A stages.

For combined therapy approaches, favorable OS outcomes can still be achieved. For instance, TACE combined with ablation therapy demonstrated 1-, 3-, and 5-year OS rates of 97.1%, 89.5%, and 80.4%, respectively, in HCC[20]. Among patients with non-infiltrative HCC, TACE combined with ablation therapy demonstrated comparable OS rates to those achieved with LR after propensity score matching[21]. In comparative study of combined therapy, no significant differences were observed in recurrent OS and recurrent RFS at 1-, 3-, and 5-year between the combination therapy group and the LR group. For multifocal recurrent HCC meeting BCLC stage A criteria, difficult to be completely removed tumors can be managed with LR combined with RFA to minimize complication or bleeding risks; while tumors confined within the same hepatic lobe may be more appropriately treated with LR alone[22]. In summary, our study found comparable OS and PFS between LR alone and LR combined with adjuvant therapies in HCC patients with BCLC 0/A stages. This suggests that high-risk early-stage HCC patients who actively undergo combined therapies (including RFA, TACE, or systemic chemotherapy) can achieve similarly favorable clinical outcomes.

Our study has several noteworthy limitations. First, as a limited sample size, the findings may be susceptible to selection bias. Therefore, these results should be interpreted cautiously and warrant validation through large-scale, multicenter real-world studies. Second, due to insufficient statistical power from the small cohort, subgroup analyses stratified by clinical stage and combination therapy regimens could not be conducted. Third, the current analysis was restricted to five-year survival outcomes without extended long-term follow-up. Future research will incorporate multicenter collaborations with expanded cohorts, enhanced subgroup analyses comparing therapeutic modalities, and complementary longitudinal studies to verify these findings.

CONCLUSION

Taken together, our findings support LR as the first-line preferred treatment modality for HCC patients with BCLC 0/A stages. Simultaneously, we observed that combination therapy regimens achieve non-inferior OS and PFS benefits compared to LR alone. Therefore, treatment-eligible early-stage HCC patients clinically indicated for combination therapy should actively pursue such regimens to attain similarly favorable prognostic outcomes.