Primary treatments for solitary hepatocellular carcinoma ≤ 3 cm: A systematic review and network meta-analysis

Sang-Hoon Kim; Ki-Hun Kim; Byeong-Gon Na; Sung Min Kim; Rak-Kyun Oh

doi:10.14701/ahbps.24-103

Ann Hepatobiliary Pancreat Surg 2024 Nov;28(4):397-411

Published online November 30, 2024; https://doi.org/10.14701/ahbps.24-103

Sang-Hoon Kim, Ki-Hun Kim, Byeong-Gon Na, Sung Min Kim, Rak-Kyun Oh

Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to: Ki-Hun Kim, MD, PhD
Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: +82-2-3010-3510, Fax: +82-2-3010-6701, E-mail: khkim620@amc.seoul.kr
ORCID: https://orcid.org/0000-0002-4016-0995

Received May 13, 2024; Revised July 3, 2024; Accepted July 12, 2024.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract: Various treatment modalities are available for small solitary hepatocellular carcinoma (HCC), yet the optimal primary treatment strategy for tumors ≤ 3 cm remains unclear. This network meta-analysis investigates the comparative efficacy of various interventions on the long-term outcomes of patients with solitary HCC ≤ 3 cm. A systematic search of electronic databases from January 2000 to December 2023 was conducted to identify studies that compared at least two of the following treatments: surgical resection (SR), radiofrequency ablation (RFA), microwave ablation (MWA), and transarterial chemoembolization (TACE). Survival data were extracted, and pooled hazard ratios with 95% confidence intervals were calculated using a frequentist network meta-analysis. A total of 30 studies, comprising 2 randomized controlled trials and 28 retrospective studies, involving 8,053 patients were analyzed. Surgical resection showed the highest overall survival benefit with a p-score of 0.95, followed by RFA at 0.59, MWA at 0.23, and TACE, also at 0.23. Moreover, SR provided the most significant recurrence-free survival advantage, with a p-score of 0.95, followed by RFA at 0.31 and MWA at 0.19. Sensitivity analyses, excluding low-quality or retrospective non-matched studies, corroborated these findings. This network meta-analysis demonstrates that SR is the most effective first-line curative treatment for single HCC ≤ 3 cm, followed by RFA in patients with preserved liver function. The limited data on MWA and TACE underscore the need for further studies.; Keywords : Network meta-analysis; Hepatocellular carcinoma; Overall survival; Recurrence-free survival; Treatment

INTRODUCTION

Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and ranks third as a cause of cancer-related fatalities. While HCC is predominantly observed in Asia and Africa, there has been a noticeable increase in its prevalence in Western countries in recent years. Liver transplantation serves as the primary curative treatment for resectable HCCs that meet the Milan criteria, which include a single liver tumor ≤ 5 cm or up to three nodules each < 3 cm. Despite this, the scarcity of donors and ethical issues necessitate surgical resection (SR) as the initial treatment modality for resectable HCC in individuals with adequate liver function [1-3]. However, less than 30% of HCC patients are deemed suitable for SR due to either limited hepatic reserve from chronic liver conditions or the widespread distribution of tumor nodules [4].

Recent advancements in locoregional therapies for small HCC encompass ablative treatments such as radiofrequency ablation (RFA) and microwave ablation (MWA), as well as transarterial chemoembolization (TACE) [1-3]. These approaches provide several advantages, including minimal invasiveness, increased safety, and cost-efficiency. Radiofrequency ablation, often favored for its efficacy, is comparable to surgical methods in select cohorts [5,6]. Microwave ablation employs a technological approach similar to RFA but offers better thermal efficiency and shorter ablation times [7]. Moreover, it is less affected by the heat sink effect due to large adjacent vessels and proves more effective in treating larger tumors [4]. Transarterial chemoembolization represents another pivotal locoregional therapy, involving the intravenous administration of chemotherapeutic drugs followed by targeted delivery of embolic materials to the tumor’s blood supply, resulting in ischemic necrosis [8]. The optimal treatment options for very early or early-stage HCC are still under debate, largely due to the elevated risk of recurrence stemming from the incomplete eradication of cancer cells [1-3].

Previous research on the primary treatment of solitary HCC ≤ 3 cm is scant. The majority of comparative studies or meta-analyses concerning small HCCs typically address tumors that meet the Milan criteria or multiple tumors. Accordingly, this network meta-analysis aims to evaluate the effectiveness of various primary treatments for solitary HCC ≤ 3 cm by focusing on long-term outcomes and to ascertain the optimal treatment strategy.

MATERIALS AND METHODS

Data collection and search strategy

This systematic review and meta-analysis was conducted following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions [9], the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [10], and the Assessing the Methodological Quality of Systematic Reviews [11]. Systematic search strategies as outlined in Table 1 were deployed across several electronic databases including Embase, Cochrane Library, Web of Science, and PubMed. Manual searches were also carried out. The literature search was confined to studies published from January 2000 to December 2023.

Table 1 . Search strategies

Database	Search strategy
Embase 01/01/2000 to 31/12/2023 (n = 3,588)	#5 #3 AND #4 AND [2000-2023]/py #4 (#1 OR #2) AND [2000-2023]/py #3 ('hepatocellular carcinoma' OR ('HCC’)) AND [2000-2023]/py #2 ('ablation' OR ('radiofrequency’ AND ‘microwave’ OR ‘locoregional’)) AND [2000-2023]/py #1 (resection OR surgery) AND [2000-2023]/py
Web of Science 01/01/2000 to 31/12/2023 (n = 2,965)	#5 #4 AND #3 #4 #2 OR #1 #3 (ALL=(hepatocellular carcinoma)) OR ALL=(HCC) #2 (ALL=(ablation)) OR ALL=(locoregional) #1 (ALL=(resection)) OR ALL=(surgery)
Cochrane Library 01/01/2000 to 31/12/2023 (n = 491)	#5 #4 AND #3 #4 #2 OR #1 #3 (hepatocellular carcinoma) OR (HCC) #2 (ablation) OR (locoregional) #1 (surgery) OR (resection)
PubMed 01/01/2000 to 31/12/2023 (n = 5,161)	#6 ((#3) AND (#4)) AND (#5) #5 ("2000/01/01"[Date-Publication]:"2023/12/31"[Date - Publication]) #4 (hepatocellular carcinoma) OR (HCC) #3 (#1) OR (#2) #2 (ablation) OR (locoregional) #1 (surgery) OR (resection)

Study selection

Two investigators (SHK and BGN) independently conducted the search for articles to include in this meta-analysis. Disagreements on the selection of eligible individual studies were resolved through discussion and consensus. The inclusion criteria for this study are as follows: 1) Studies including data from patients diagnosed with primary and solitary HCC ≤ 3 cm with preserved liver function; 2) studies reporting long-term outcomes, including overall and recurrence-free survival (OS or RFS); and 3) full-text original articles published in English. Exclusion criteria included: 1) Patients with previous or simultaneous malignancies or prior treatment for HCC; 2) case reports, non-comparative studies, duplicates, studies lacking survival outcomes, and reviews; and 3) unpublished studies.

Data extraction

Two investigators (SHK and BGN) independently conducted data extraction from the included studies. Extracted data comprised the publication year, country, study design, study period, age, sex, Child-Pugh class, etiology of cirrhosis, sample size, types of primary treatment for HCC, history of previous anti-cancer treatment, tumor number, and tumor size. Long-term survival outcomes, including hazard ratios (HRs) for OS and RFS at the 3- and 5-year time points were also extracted.

Quality assessment of studies

We employed the updated second version of the Cochrane tool for assessing the risk of bias in randomized trials (RoB 2) to evaluate the quality of randomized trials [12]. Risk-of-bias judgments were categorized as “low risk of bias,” “some concerns,” or “high risk of bias,” based on responses to the signaling questions recommended by the tool. Additionally, the Newcastle-Ottawa Scale (NOS) [13], ranging from 0 to 9, with a score of ≥ 6 denoting “high quality” was utilized to assess the quality of retrospective studies. The quality assessments of the included studies were independently carried out by two reviewers (SHK and BGN), and disagreements arising during the review process were resolved through discussion and consensus.

Statistical analysis

Survival rates were presented as pooled 3- and 5-year OS and RFS, with HRs being calculated and compared across different time points. The HRs for OS and RFS were reconstructed based on time-to-event data from Kaplan-Meier curves, following the method proposed by Tierney et al. [14]. The Engauge Digitizer 4.1 (http://digitizer.sourceforge.net), a tool for analyzing graphical images and extracting data points from graphs, facilitated the extraction of time-to-event data from Kaplan-Meier curves. We conducted a network meta-analysis employing a frequentist framework with p-scores to rank multiple treatments [15]. Data were analyzed using the random effects model in this meta-analysis. Due to heterogeneous elements such as patient demographics, locations, preoperative and postoperative care, and study duration, all included studies exhibited inter-study heterogeneity, thus justifying the use of a random effects model over a fixed effects model [16]. A sensitivity test was performed by excluding studies assessed as low quality according to the RoB 2 or NOS results. Publication bias was evaluated using a comparison-adjusted funnel plot [9]. Statistical significance was defined as p < 0.05. R version 4.3.3 (https://cran.r-project.org) was utilized for all statistical analyses.

RESULTS

Literature search

Electronic databases retrieved a total of 12,305 studies, and a manual search identified an additional 511 articles. After removing duplicates from the title and abstract screening, 192 articles were assessed for eligibility. Among these, 167 were excluded for failing to meet the criteria, providing data solely for solitary HCC lesions smaller than 2 cm, or not being original articles. Ultimately, 30 articles, including 2 randomized controlled trials (RCTs) and 28 retrospective studies, were included in this meta-analysis. The PRISMA flowchart outlines the process of study selection (Fig. 1).

Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of study inclusion. HCC, hepatocellular carcinoma.

Study characteristics

Table 2 summarizes the baseline characteristics of the included studies. This meta-analysis encompasses two RCTs [17,18], 15 retrospective matched studies [19-33], and 13 retrospective non-matched studies [34-46] published between 2006 and 2023, involving 8,053 patients with solitary HCC measuring ≤ 3 cm. The baseline characteristics of the studies are detailed in Table 2.

Table 2 . Baseline characteristics

Study	Country	Study type	Study period	Patient group	Patients no.	Age	Sex (female, %)	CTP grade
Chen et al. [17] (2006)	China	RCT	1999–2004	SR vs. RFA	42 vs. 37	49 vs. 51	17 vs. 21	A vs. A
Guglielmi et al. [35] (2008)	Italy	R	1996–2006	SR vs. RFA	24 vs. 21	NA	20 vs. 20	A, B vs. A, B
Hiraoka et al. [34] (2008)	Japan	R	2000–2007	SR vs. RFA	59 vs. 150	62 vs. 69	25 vs. 28	A, B vs. A, B
Ueno et al. [36] (2009)	Japan	R	2005–2008	SR vs. RFA	78 vs. 92	67 vs. 66	33 vs. 35	A, B vs. A, B, C
Huang et al. [18] (2010)	China	RCT	2003–2005	SR vs. RFA	45 vs. 57	56 vs. 57	26 vs. 31	A, B vs. A, B
Yun et al. et al. [37] (2011)	Korea	R	2000–2007	SR vs. RFA	215 vs. 255	52 vs. 57	20 vs. 23	A vs. A
Nishikawa et al. [38] (2011)	Japan	R	2004–2010	SR vs. RFA	69 vs. 162	67 vs. 68	28 vs. 41	A, B vs. A, B, C
Wong et al. [39] (2013)	Taiwan	R	2004–2009	SR vs. RFA	46 vs. 36	55 vs. 64	35 vs. 50	A vs. A
Desiderio et al. [40] (2013)	Italy	R	2004–2012	SR vs. RFA	22 vs. 19	66 vs. 64	29 vs. 20	A vs. A
Pompili et al. [19] (2013)	Italy	RM	1999–2010	SR vs. RFA	116 vs. 116	67 vs. 68	19 vs. 41	A vs. A
Imai et al. [41] (2013)	Japan	R	2000–2011	SR vs. RFA	101 vs. 82	63 vs. 67	26 vs. 44	A, B vs. A, B
Kim et al. [42] (2014)	Korea	R	2006–2010	SR vs. RFA	66 vs. 67	55 vs. 59	27 vs. 22	A vs. A
Yang et al. [20] (2014)	Korea	RM	2005–2006	SR vs. RFA	52 vs. 79	55 vs. 57	27 vs. 25	A, B vs. A, B
		RM	2005–2006	SR vs. TACE	52 vs. 66	55 vs. 59	27 vs. 26	A, B vs. A, B
		RM	2005–2006	RFA vs. TACE	79 vs. 66	57 vs. 59	25 vs. 26	A, B vs. A, B
Shi et al. [43] (2014)	China	R	2005–2011	SR vs. MWA	37 vs. 40	33 vs. 34	19 vs. 21	A, B vs. A, B
Kang et al. [21] (2015)	Korea	RM	2006–2010	SR vs. RFA	99 vs. 99	53 vs. 58	25 vs. 23	A, B vs. A, B
Vitali et al. [44] (2016)	Switzerland	R	1998–2012	SR vs. RFA	45 vs. 60	61 vs. 67	33 vs. 13	A, B vs. A, B
Kim et al. [22] (2016)	Korea	RM	2000–2009	SR vs. RFA	152 vs. 152	54 vs. 57	22 vs. 20	A vs. A
Lee et al. [23] (2018)	Korea	RM	2006–2010	SR vs. RFA	62 vs. 62	55 vs. 56	23 vs. 23	A, B vs. A, B
Cha et al. [45] (2020)	Korea	R	2008–2009	SR vs. RFA	145 vs. 178	53 vs. 57	26 vs. 19	A, B vs. A, B
Sun et al. [24] (2020)	China	RM	2004–2012	SR vs. MWA	41 vs. 51	25 vs. 23	19 vs. 21	A, B vs. A, B
Suh et al. [25] (2021)	Korea	RM	2005–2015	SR vs. RFA	657 vs. 653	66 vs. 6	24 vs. 28	A vs. A
		RM	2005–2015	SR vs. TACE	657 vs. 745	55 vs. 59	24 vs. 29	A vs. A
		RM	2005–2015	RFA vs. TACE	653 vs. 745	55 vs. 59	28 vs. 29	A vs. A
An et al. [26] (2021)	China	RM	2012–2018	RFA vs. MWA	70 vs. 74	57 vs. 57	10 vs. 12	A, B vs. A
Lee et al. [29] (2022)	Korea	RM	2005–2015	SR vs. RFA	232 vs. 159	22 vs. 2	27 vs. 25	A vs. A
Zhang et al. [28] (2022)	China	RM	2009–2018	SR vs. RFA	67 vs. 67	58 vs. 58	25 vs. 27	A vs. A
Ko et al. [27] (2022)	Korea	RM	2014–2016	SR vs. RFA	23 vs. 23	56 vs. 60	30 vs. 17	NA
Feng et al. [30] (2022)	China	RM	2011–2019	SR vs. MWA	71 vs. 83	77 vs. 78	20 vs. 24	A, B vs. A, B
Kang et al. [46] (2023)	Korea	R	2009–2018	SR vs. RFA	36 vs. 40	58 vs. 62	31 vs. 15	A vs. A
Wu et al. [31] (2023)	China	RM	2000–2018	SR vs. RFA	277 vs. 254	NA	25 vs. 24	NA
Wang et al. [32] (2023)	China	RM	2010–2019	RFA vs. MWA	137 vs. 75	55 vs. 55	26 vs. 25	A, B vs. A, B
Liu et al. [33] (2023)	China	RM	2002–2017	SR vs. MWA	118 vs. 63	59 vs. 62	12 vs. 88	A, B vs. A, B

CTP, Child-Turcotte-Pugh; RCT, randomized controlled trial; R, retrospective; RM, retrospective matched; SR, surgical resection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; MWA, microwave ablation; NA, not available.

Quality of included studies

The RoB 2 and NOS tools assessed the quality of the two RCTs and 28 retrospective studies included in this meta-analysis. With one exception, the majority of these studies were classified as high quality (Table 3) [36].

Table 3 . Assessment of included studies

RCT (RoB2)

RoB

Chen et al. [17] (2006)

Some concerns

Low risk

Huang et al. [18] (2010)

Low risk

Retrospective (NOS)

Selection

Comparability

Exposure

Total
score

Interpretation

Guglielmi et al. [35] (2008)

★

High quality

Hiraoka et al. [34] (2008)

★

High quality

Ueno et al. [36] (2009)

★

Low quality

Yun et al. [37] (2011)

★

High quality

Nishikawa et al. [38] (2011)

★

High quality

Wong et al. [39] (2013)

★

High quality

Desiderio et al. [40] (2013)

★

High quality

Pompili et al. [19] (2013)

★

★★

★

High quality

Imai et al. [41] (2013)

★

High quality

Kim et al. [42] (2014)

★

High quality

Yang et al. [20] (2014)

★

★★

★

High quality

Shi et al. [43] (2014)

★

High quality

Kang et al. [21] (2015)

★

★★

★

High quality

Vitali et al. [44] (2016)

★

High quality

Kim et al. [22] (2016)

★

★★

★

High quality

Lee et al. [23] (2018)

★

★★

★

High quality

Cha et al. [45] (2020)

★

High quality

Sun et al. [24] (2020)

★

★★

★

High quality

Suh et al. [25] (2021)

★

★★

★

High quality

An et al. [26] (2021)

★

★★

★

High quality

Lee et al. [29] (2022)

★

★★

★

High quality

Zhang et al. [28] (2022)

★

★★

★

High quality

Ko et al. [27] (2022)

★

★★

★

High quality

Feng et al. [30] (2022)

★

★★

★

High quality

Kang et al. [46] (2023)

★

High quality

Wu et al. [31] (2023)

★

★★

★

High quality

Wang et al. [32] (2023)

★

★★

★

High quality

Liu et al. [33] (2023)

★

★★

★

High quality

D1, Bias arising from the randomisation process; D2, Bias due to deviations from intended interventions; D3, Bias due to missing outcome data; D4, Bias in measurement of the outcome; D5, Bias in selection of the reported result; Q1, Adequate definition of case; Q2, Representativeness of cases; Q3, Selection of control; Q4, Definition of control; Q5, Study controls for important factor or additional factor; Q6, Ascertainment of exposure; Q7, Same method of ascertainment for cases and controls; Q8, Non-response rate.

RCT, randomized controlled trial; RoB2, risk of bias 2; NOS, Newcastle-Ottawa Scale.

Surgical resection versus radiofrequency ablation

In the analysis of 23 studies [17-21,23,26-28,30,32-40,42,44-46], SR significantly outperformed RFA in terms of 3-year OS, with a HR: 0.67 and a 95% confidence interval (CI) (0.54, 0.83), p < 0.001. The 5-year OS also demonstrated improved results for SR compared to RFA, reflected by an HR: 0.72, 95% CI (0.59, 0.88), and a p-value of 0.002 (Fig. 2A). Additionally, in 17 studies [17,21,26-28,32-34,36-42,45,46], SR was associated with significantly better 3-year RFS (HR: 0.58, 95% CI [0.51, 0.67], p < 0.001) and 5-year RFS (HR: 0.59, 95% CI [0.50, 0.68], p < 0.001) compared to RFA (Fig. 2B).

Fig 2. Meta-analysis of SR vs. RFA. (A) 3-year and 5-year OS. (B) 3-year and 5-year RFS. OS, overall survival; SR, surgical resection; RFA, radiofrequency ablation; RFS, recurrence-free survival; HR, hazard ratio; SE, standard error; CI, confidence interval.

Surgical resection versus microwave ablation

In the pooled analysis of four studies [22,25,29,43], no significant differences were observed in the 3-year OS (HR: 0.82, 95% CI [0.47, 1.46], p = 0.51) or the 5-year OS (HR: 0.68, 95% CI [0.44, 1.06], p = 0.09) between SR and MWA (Fig. 3A). Nevertheless, SR significantly improved the 3-year RFS (HR: 0.65, 95% CI [0.49, 0.88], p = 0.005) and 5-year RFS (HR: 0.59, 95% CI [0.46, 0.75], p < 0.001) compared to MWA (Fig. 3B).

Fig 3. Meta-analysis of SR vs. MWA. (A) 3-year and 5-year OS. (B) 3-year and 5-year RFS. OS, overall survival; SR, surgical resection; MWA, microwave ablation; RFS, recurrence-free survival; HR, hazard ratio; SE, standard error; CI, confidence interval.

Surgical resection versus transarterial chemoembolization

In the analysis of two studies [20,30], there were no significant differences in the 3-year OS (HR: 0.87, 95% CI [0.15, 4.89], p = 0.87) or the 5-year OS (HR: 0.75, 95% CI [0.20, 2.90], p = 0.68) between SR and TACE (Fig. 4). Results for RFS were not reported.

Fig 4. Meta-analysis of SR vs. TACE. 3-year and 5-year overall survival. OS, overall survival; SR, surgical resection; TACE, transcatheter arterial hemoembolization; HR, hazard ratio.

Radiofrequency ablation versus microwave ablation

The pooled analysis of two studies [24,31] indicated no significant differences in the 3-year OS (HR: 0.81, 95% CI [0.42, 1.59], p = 0.54) or 5-year OS (HR: 0.92, 95% CI [0.51, 1.68], p = 0.79) between RFA and MWA. Additionally, no significant differences were detected in the 3-year RFS (HR: 0.91, 95% CI [0.66, 1.23], p = 0.53) or 5-year RFS (HR: 0.92, 95% CI [0.58, 1.46], p = 0.009) between the two treatments (Fig. 5).

Fig 5. Meta-analysis of RFA vs. MWA. (A) 3-year and 5-year OS. (B) 3-year and 5-year RFS. OS, overall survival; RFA, radiofrequency ablation; MWA, microwave ablation; RFS, recurrence-free survival; HR, hazard ratio; SE, standard error; CI, confidence interval.

Radiofrequency ablation versus transarterial chemoembolization

In the analysis of two studies [20,30], no significant differences were observed in the 3-year OS (HR: 0.78, 95% CI [0.62, 1.00], p = 0.046) between RFA and TACE. However, the 5-year OS demonstrated a significant improvement with RFA compared to TACE (HR: 0.78, 95% CI [0.65, 0.94], p = 0.68; Fig. 6). Results for RFS were not presented.

Fig 6. Meta-analysis of RFA vs. TACE. 3-year and 5-year OS. OS, overall survival; SR, surgical resection; RFA, radiofrequency ablation; TACE, transcatheter arterial hemoembolization; HR, hazard ratio; SE, standard error; CI, confidence interval.

Ranking of treatments

We utilized a frequentist framework to rank treatments using random effects p-score, where a score of 1 signifies the best theoretical outcome and 0 signifies the worst. For the 5-year OS, SR, being the reference treatment with an HR of 1.00, achieved the highest p-score at 0.95. Radiofrequency ablation was ranked second with a p-score of 0.59, recording an HR of 1.16 (95% CI [0.95, 1.41]). This was followed by TACE and MWA, both scoring 0.23, with HRs of 1.41 (95% CI [0.95, 2.21]) and 1.40 (95% CI [0.99, 1.98]), respectively (Fig. 7A). Concerning the 5-year RFS, SR posted the highest p-score (0.95, HR: 1.00), followed by RFA with a p-score of 0.31 and an HR of 1.47 (95% CI [1.27, 1.71]), and MWA with a p-score of 0.19 and an HR of 1.53 (95% CI [1.16, 2.03]) (Fig. 7B). Surgical resection demonstrated superior cumulative probabilities of enhancing both OS and RFS as the primary treatment for solitary HCC ≤ 3 cm, indicating its dominance over the other three interventions assessed.

Fig 7. Network meta-analysis for rank of treatments. (A) 5-year OS and (B) 5-year and 5-year RFS. OS, overall survival; SR, surgical resection; RFA, radiofrequency ablation; TACE, transcatheter arterial hemoembolization; MWA, microwave ablation; RFS, recurrence-free survival; HR, hazard ratio; CI, confidence interval.

Sensitivity test and publication bias

Sensitivity analysis was conducted by excluding one study [36] assessed as low quality based on the NOS and by excluding 12 non-matched retrospective studies [34-40,42-46]. When sensitivity analysis was performed for 24 high -quality studies, no significant differences were found in the 5-year OS and 5-year RFS compared with results from the network meta-analysis that included all studies (Table 4). The symmetrical pattern of the comparison-adjusted funnel plot for OS, in which most studies were within the 95% CI, indicated a lack of significant publication bias in this analysis (Fig. 8).

Table 4 . Sensitivity analysis

	5-year OS					5-year RFS
		HR	95% CI	p-score	Rank		HR	95% CI	p-score	Rank
Inclusion of high quality studies	SR	1.00				SR	1.00
	RFA	1.15	0.94–1.41	0.59	2	RFA	1.46	1.25–1.71	0.31	2
	TACE	1.41	0.94–2.12	0.23	3	MWA	1.52	1.14–2.03	0.19	3
	MWA	1.41	0.98–1.99	0.23	4
Inclusion of RCT or RM studies	SR	1.00			1	SR	1.00			1
	RFA	1.22	0.93–1.59	0.55	2	RFA	1.61	1.30–2.00	0.27	2
	TACE	1.44	0.92–2.25	0.26	3	MWA	1.63	1.21–2.19	0.23	3
	MWA	1.44	0.95–2.16	0.25	4

OS, overall survival; RFS, recurrence-free survival; HR, hazard ratio; CI, confidence interval; SR, surgical resection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; MWA, microwave ablation; RCT, randomized controlled trial; RM, retrospective matched.

Fig 8. Comparison-adjusted funnel plot showing no significant publication bias. SR, surgical resection; RFA, radiofrequency ablation; TACE, transcatheter arterial hemoembolization; MWA, microwave ablation; RFS, recurrence-free survival.

DISCUSSION

The purpose of this network meta-analysis is to identify the optimal treatment modality for solitary small HCC up to 3 cm in diameter. According to the Barcelona Clinic Liver Cancer guidelines, liver resection and thermal ablation methods such as RFA and MWA, are recommended as first-line treatments for solitary small HCC, as they provide the highest likelihood of cure for patients with preserved liver function [47]. Nevertheless, there is ongoing debate about which treatment is superior. Comparative studies on primary treatments for solitary small HCC are relatively rare [46]. Previous comparative analyses often include multiple tumors or meet the Milan criteria [1,3,48]. Furthermore, only a limited number of network meta-analyses have evaluated the ranking of different treatment modalities for solitary HCC [5]. Thus, conducting a network meta-analysis to compare the relative efficacy of various primary treatments for solitary small HCC is justified.

Previous studies comparing SR and thermal ablation methods such as RFA and MWA for solitary small HCC indicate distinct outcomes among these modalities. SR is generally associated with the highest OS and lowest recurrence rates [33,49,50], while RFA and MWA are known for their minimal invasiveness and lower morbidity, offering nearly equivalent survival benefits [24,31,51-53]. Specifically, MWA offers advantages such as shorter procedure times and potentially lower rates of local tumor progression compared to RFA, though the differences in long-term survival are minimal [24,52,53]. However, both RFA and MWA have demonstrated favorable results for reduced procedural complications and quicker recovery times in meta-analytic reviews, making them particularly advantageous for patients with impaired liver function or those at a higher surgical risk [5]. These findings underscore the importance of making tailored treatment decisions based on individual patient factors and tumor characteristics in the management of small HCC. In the meta-analysis conducted in this study for solitary HCC ≤ 3 cm, SR was associated with better OS and RFS than RFA (Fig. 2). Comparisons between SR and MWA showed no significant differences in OS; however, SR yielded better RFS outcomes (Fig. 3). Additionally, no significant differences in OS or RFS were observed between RFA and MWA (Fig. 5).

Since current guidelines recommend SR or RFA as the first-line treatment for patients with Child-Turcotte-Pugh grade A and solitary small HCC ≤ 3 cm [47,54], TACE may be considered as an alternative therapy. Conducting RCTs comparing transarterial therapy with SR or RFA is challenging due to ethical concerns, particularly concerning survival outcomes after each treatment option. Most studies comparing TACE or SR typically involve cases with large or multiple tumors [55-62]. Only a small number of studies have compared the efficacy of TACE with SR and RFA for solitary HCC ≤ 3 cm, and the results have been inconsistent [20,30]. Consequently, further research is needed to confirm the efficacy of TACE. With the progression of radiation therapy technologies, stereotactic body radiation therapy (SBRT) and transarterial radioembolization (TARE) have emerged as viable treatment options for HCC patients [63,64]. Numerous studies have compared SBRT or TARE with other locoregional treatments as a first-line curative intervention for HCC. However, these studies predominantly included patients with inoperable liver conditions, multiple or larger tumors, or in combination therapies with other locoregional treatments [63-65]. Thus, data from comparative studies including SBRT or TARE were excluded from this meta-analysis.

According to the 2022 Korean Liver Cancer Association-National Cancer Center Korea practice guidelines [66-68], SR is established as the primary treatment option for a solitary HCC confined to the liver in patients with Child-Pugh grade A, without portal hypertension and hyperbilirubinemia; RFA is recognized as another first-line treatment for HCCs with a diameter of 3 cm or less, offering equivalent survival rates, superior local control rates, and lower complication rates than hepatectomy; MWA has shown comparable outcomes in terms of survival, recurrence, and major complication rates when matched against RFA, based on a limited number of earlier studies; TACE is advised for patients with HCC who are unsuitable for SR, liver transplantation, or other local therapies, on the condition that they have favorable systemic performance status and lack radiological signs of vascular invasion or extrahepatic metastases. This updated meta-analysis revealed that SR is more effective than RFA for both OS and RFS in treating single HCCs ≤ 3 cm in diameter, thereby indicating clear advantages of SR over RFA. Additionally, SR outperformed MWA in terms of RFS, although no significant disparities in OS were identified. The comparison between RFA and MWA did not reveal any significant differences in survival outcomes between the two modalities. Nonetheless, interpreting these outcomes is complicated due to the variable baseline liver functions of the included patients.

Microvascular invasion (MVI) represents a pivotal histopathologic prognostic factor in HCC [69]. Despite their small size (≤ 3 cm), tumors may still demonstrate MVI, elevating the likelihood of local recurrence [70]. Anatomic SR proves more efficacious for non-boundary type HCC owing to the increased risks of MVI and intrahepatic metastasis. Current research indicates that anatomic SR significantly enhances both OS and RFS compared to partial resection in isolated small HCCs (≤ 5 cm) afflicted with MVI [71]. Micrometastases are predominantly located within 10 mm of the principal tumor [72], emphasizing the necessity of removing the main tumor along with at least 10 mm of the adjacent liver tissue to mitigate recurrence risks and effectively manage MVI [70,72]. The incidence of local recurrence post-RFA is higher than that observed after anatomic SR [73]. A particular study assessed the outcomes of TACE versus surgery or RFA based on the presence of MVI in patients encountering recurrent HCC characterized by a median tumor size of 1.5 cm, discovering that TACE significantly enhances OS in patients with early recurrent MVI-positive tumors when compared to surgical or RFA interventions following curative SR for HCC [74].

Heterogeneity of the included studies was assessed by categorizing the values of the inconsistency statistic I² as low, medium, or high heterogeneity at thresholds of 25%, 50%, and 75%, respectively [75]. Although this classification is widely adopted in meta-analyses, it is not universally applicable. Typically, a fixed effects model is employed for studies demonstrating low to moderate heterogeneity, while a random effects model is preferable for cases of high heterogeneity. It is crucial to recognize that studies conducted in various settings may not exhibit a common effect size [16]. Therefore, given the diversity in environments and study designs among the included studies, a pooled data analysis using a random-effects model was conducted. Notably, in the domain of treatment for solitary small HCCs, different centers implemented distinct treatment strategies and protocols, surgical techniques, and levels of experience. Consequently, a random effects model was deemed more suitable than a fixed effect model for this meta-analysis.

This meta-analysis had several limitations. Firstly, the reported HRs for OS and RFS did not originate directly from the raw data of the included studies but were instead reconstructed from the time-to-event survival data extracted from the Kaplan-Meier curves found in the publications [14]. Although this reconstruction may have affected the accuracy, errors were minimized by having two reviewers independently verify and reconcile the calculated values. Secondly, out of the 25 studies included, 12 were unmatched retrospective studies, which might introduce bias. To mitigate the impact of this heterogeneity, a sensitivity analysis was performed that included only matched retrospective studies and RCTs. Thirdly, among the 23 studies reporting SR results, four studies [32,33,44,46] focused on minimally invasive surgery, possibly increasing heterogeneity among the studies. Fourthly, the variability of liver function reserve among the patient groups in the included studies complicates the interpretation of OS and RFS results in this meta-analysis. Finally, the number of studies reporting outcomes for MWA and TACE is minimal, rendering the results of meta-analyses including these treatments preliminary and less dependable; hence, further meta-analyses incorporating more studies are necessary to yield more robust findings.

In conclusion, according to this meta-analysis of the available data, SR emerges as the most effective primary curative treatment for a single HCC measuring ≤ 3 cm, followed by RFA in patients with adequate liver function. Nevertheless, the evidence supporting other interventions, such as MWA and TACE, remains sparse, and additional research is essential to ascertain their effectiveness.

FUNDING: This study was supported by a research grant from the Korean Association for Hepatopancreatic Surgery (KAHPBS-23-07).

CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS: Conceptualization: KHK. Data curation: SHK, BGN, SMK, RKO. Methodology: SHK. Visualization: SHK. Writing - original draft: SHK. Writing - review & editing: KHK.

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