Efficacy and safety of laparoscopic liver resection versus radiofrequency ablation in patients with early and small hepatocellular carcinoma: an updated meta-analysis and meta-regression of observational studies

Background Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 90% of cases worldwide and a significant contributor to cancer-related deaths. This study comprehensively compares the safety and efficacy of laparoscopic liver resection (LLR) versus laparoscopic or percutaneous radiofrequency ablation (LRFA or PRFA) in patients with early and small HCC. Methods We systematically searched Cochrane Library, PubMed, Scopus, and Web of Science databases to include studies comparing LLR versus LRFA or PRFA in patients with early HCC meets the Milan criteria (defined as solitary nodule < 5 cm or three nodules ≤ 3 cm with no extrahepatic spread or vascular invasion). Pooled results were examined for overall survival, disease-free survival, recurrence-free survival, local, intrahepatic and extrahepatic recurrence rates, and complications. We conducted subgroup analyses based on the type of RFA. Meta-regression analyzed the association between overall survival, local recurrence, and various factors. The quality of the included studies was assessed using the Newcastle–Ottawa Scale. We analyzed the data using the R (v.4.3.0) programming language and the “meta” package of RStudio software. Results We included 19 observational studies, compromising 3756 patients. LLR showed higher 5-year overall survival compared to RFA (RR = 1.17, 95% CI [1.06, 1.3], P > 0.01). Our subgroup analysis showed that LLR had higher 5-year survival than PRFA (RR = 1.15, 95% CI [1.02, 1.31], P = 0.03); however, there was no significant difference between LLR and LRFA (RR = 1.26, 95% CI [0.98, 1.63], P = 0.07). LLR was associated with higher disease-free survival) RR = 1.19, 95% CI [1.05, 1.35], P < 0.01; RR = 1.61, 95% CI [1.31, 1.98], P < 0.01(and recurrence-free survival) RR = 1.21, 95% CI [1.09, 1.35], P < 0.01; RR = 1.45, 95% CI [1.15, 1.84], P < 0.01(at 1 and 3 years. LLR was associated with lower local (RR = 0.28, 95% CI [0.16, 0.47], P < 0.01) and intrahepatic recurrence (RR = 0.7, 95% CI [0.5, 0.97], P = 0.03) than RFA. However, complications were significantly higher with LLR (RR = 2.01, 95% CI [1.51, 2.68], P < 0.01). Our meta-regression analysis showed that younger patients had higher risk for local recurrence (P = 0.008), while age wasn’t significantly linked to overall survival (P = 0.25). Other covariates like total bilirubin, alpha-fetoprotein levels, and tumor size also showed no significant associations with either overall survival or local recurrence. Conclusion LLR offers improved long-term outcomes and lower recurrence rates than PRFA. However, no significant distinctions were observed between LRFA and LLR in overall survival, recurrence-free survival, and local recurrence. More robust well-designed RCTs are essential to validate our findings. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-023-03292-3.


Introduction
Liver cancer poses a global health challenge, with expanding incidence worldwide.It is expected that one million individuals annually will face liver cancer by 2025 [1].Hepatocellular carcinoma (HCC) dominates, accounting for 90% of cases of liver cancers.It is the fifth most common cancer worldwide and the second major cause of cancer-related deaths due to its aggressiveness [2].In East Asia and Africa, HCC exhibits notable prevalence and mortality rates, with China at the forefront, housing 466,000 HCC patients -accounting for 55% of global cases -among the yearly count of 854,000 new cases [3,4].Additionally, the emergence of increasing cases is evident in various regions of Europe and the USA [1].
Chronic liver disease is the predominant cause of HCC, contributing to 90% of cases.Cirrhosis is the most significant risk factor for HCC, regardless of its etiology.HCC is now the leading cause of death in cirrhotic patients, with an annual occurrence rate of 1-6%.HCC risk factors involve persistent alcohol use, diabetes, and nonalcoholic steatohepatitis related to obesity and HBV or HCV infection [1].
The Barcelona Clinic Liver Cancer (BCLC) algorithm outlines diverse treatment choices for HCC, spanning liver transplantation, surgical resection, and ablation [5].Due to donor scarcity, liver transplantation is seldom the primary choice.In addition, the effectiveness of surgery and ablation remains a topic of ongoing discussion.
Open hepatic resection is a key curative approach for HCC; however, it presents certain risks and can negatively impact liver function.As a result, this method may not be ideal for patients with severe cirrhosis [6].Radiofrequency ablation (RFA) emerges as an alternative for small HCC cases, noted for its minimally invasive nature and simplicity.In fact, only 30% of HCC patients are considered good candidates for hepatic resection, underscoring the importance of RFA.Studies indicate that RFA produces comparable outcomes to open resection but with shorter hospital stays and fewer complications.Therefore, both RFA and hepatectomy are recommended for treating early-stage HCC [7].
Recent developments in laparoscopic technology expand the treatment options for HCC, with laparoscopic liver resection (LLR) and laparoscopic radiofrequency ablation (LRFA) gaining traction, especially for cases with small HCC.LLR combines the strengths of RFA and open resection to reduce recurrence risks [8].While percutaneous RFA is widely used for early-stage HCC, its limitations arise from tumor visibility and positioning.LRFA offers a solution for challenging cases, like subcapsular tumors, where percutaneous methods face difficulties.Previous research emphasizes LRFA's effectiveness and safety for subcapsular HCCs [9][10][11][12][13].
The debate over the most effective and safe treatment for hepatocellular carcinoma is ongoing [9,14,15].Based on previous research, there is a recognized need for a comprehensive assessment of the effectiveness and safety of LLR, LRFA, and PRFA in patients with early HCC.While previous meta-analyses [16][17][18][19] have made valuable contributions, they have been limited in study numbers and scope, potentially missing essential insights.For example, Mou-Bo Si et al. [16], Shan Jin et al. [17], and Xiaocheng Li et al. [20] included 6, 7, and 10 studies, respectively.In contrast, Zhijun Li et al. [19] adopted a more focused approach, scrutinizing Chinese literature and solely including studies from China, with a total of 19 articles (3 in English and 16 in Chinese).However, new studies have emerged in the English literature, providing an opportunity to bolster the impact of the meta-analysis.Surprisingly, previous meta-analyses have yet to concentrate on comparing LLR and LRFA.
Given the advancements in medical knowledge and techniques, an updated systematic review and meta-analysis is essential.This updated analysis aims to fill crucial gaps by directly comparing LLR and laparoscopic/percutaneous RFA and giving the medical community scientifically informed insights to facilitate enhanced clinical decision-making.

Methods
Our methodology and findings followed systematic review and meta-analysis guidelines, including PRISMA 2020 [21] and the Cochrane Handbook [22].Transparency was ensured by registering our protocol on PROS-PERO with reference "CRD42023436948."

Literature search
We performed an extensive search across various databases, including the Cochrane Library, PubMed, Web of Science, and Scopus.Our search spanned from the databases' earliest records to July 31, 2023.We used the following key terms: laparoscopic liver resection, radiofrequency ablation, and hepatocellular carcinoma.We provide our detailed search strategy in the Supplementary file.

Eligibility criteria and study selection
Two authors (B.E.and N.Y.) screened the article to determine their eligibility for our study focusing on RCTs, non-randomized comparative studies, and observational studies (prospective and retrospective cohorts).Initial screening involved titles and abstracts, followed by a detailed review of chosen study texts.
We included studies comparing LLR versus RFA (percutaneous or laparoscopic) in patients with early-stage HCC meets the Milan criteria (defined as solitary nodule < 5 cm or three nodules ≤ 3 cm with no extrahepatic spread or vascular invasion) [23] or meets University of California San Francisco criteria (defined as a solitary tumor smaller than 6.5 cm or up to three nodules, each less than 4.5 cm in diameter) [24].Furthermore, eligible patients should exhibit liver function classified as Child-Pugh class A or B (less than 10% fall into the Child-Pugh class C).
Our primary investigation centered on direct comparisons of clinical effectiveness, evaluating parameters such as overall survival, recurrence-free survival rate, disease-free survival rate, local recurrence, intrahepatic recurrence, and extrahepatic recurrence.In terms of safety assessments, we examined the overall incidence of all complications, major complications rated as grade 3 or above, 90-day mortality, 30-day mortality, as well as hospital stay duration.Discrepancies were resolved by a third author.

Exclusion criteria
We excluded case series, case reports, editorials, crosssectional and non-human studies, and.Moreover, studies exploring alternative treatments like trans-arterial chemoembolization and percutaneous ethanol injection were excluded.Finally, non-English studies and those with unreliable data were also excluded.

Quality assessment
Two independents' authors (B.E and M.E) assessed the quality of included studies using the Newcastle-Ottawa Scale (NOS) [25], which covers the following domains selection, comparability, and outcomes.A top score of 9 is possible, with 7 or higher indicating high quality.Discrepancies were resolved through discussion or involving a third reviewer if necessary.

Data extraction and study outcomes
Two authors (N.Y AND B. E) used standardized method for data extraction in a predefined Excel sheet, covering study characteristics, patient descriptions, and outcomes of interest.Disagreements were resolved through discussion or consultation with the senior author.Pertinent data were gathered in a predefined Excel sheet, covering study characteristics, patient descriptions, and LLR and RFA outcomes for safety and efficacy.If any study reported their outcomes at different time points, we extracted the data at each timepoint separately, aiming to perform subgroup analysis to explore the change of this outcome overtime.

Outcome definition
This study rigorously assessed the effectiveness and safety of treatments, employing a comprehensive range of metrics.These measures encompassed overall survival (from treatment onset to death or latest follow-up), recurrencefree survival rate (proportion of patients without HCC recurrence), disease-free survival rate (proportion without disease), hospital stay (duration of patient admission for treatment and recovery), major (grade 3 or above) complications (complications significantly impacting postoperative progress, necessitating interventions), local recurrence (tumor reappearance within liver or nearby original site), intrahepatic recurrence (new tumor nodules or growth within liver separate from primary tumor or previously treated lesions), and extrahepatic recurrence (spread to distant organs).

Data synthesis and heterogeneity assessment
We conducted our analysis using the R (v.4.3.0)programming language and the "meta" package of RStudio software [26].We computed the risk ratio (RR) for dichotomous outcomes using the "metabin" function; however, the "metacont" function was used to pool the standardized mean difference (SMD) for continuous outcomes.Given the substantial heterogeneity among the included studies, we preferred to use the random-effects model.We used the 95% confidence intervals (CI) for all outcomes.A p-value < 0.05 indicated significance; however, a chi-square P value < 0.10 indicated significant heterogeneity among the included studies.We performed subgroup analysis based on the time point of outcome assessment (i.e., at 1, 3, or 5 years).Also, we performed another subgroup analysis based on type of RFA (i.e., LRFA versus PRFA).In addition, we performed sensitivity analyses using the leave-one-out model to explore the effect of each individual study on our results.To assess publication bias, we employed funnel plots, Egger's test, and trim-and-fill analysis [27].Finally, we conducted meta-regression analyses to explore whether there was any significant association between the local recurrence and overall survival at 1 year with continuous covariates, such as the age, tumor size, total bilirubin, and alphafetoprotein [28].

Literature search results
Our comprehensive search yielded 527 records.After removal of duplicates, only 334 records remained for the title and abstract screening.After which, 22 articles seemed eligible for the full-text screening.Finally, we included 19 observational studies in our systematic review and meta-analysis.Reviewing the reference list of all included studies did not retrieve any additional eligible studies.The PRISMA flow diagram is shown in Fig. 1.

Publication bias
The funnel plots for the overall survival at 1, 3, and 5 years were symmetrical.This was confirmed by the insignificant results of Egger's test (P = 0.7; P = 0.1; P = 0.98, respectively), indicating that there was no publication bias in terms of overall survival at 1, 3, and 5 years.In contrast, visual inspection of the funnel plot for the local recurrence showed asymmetry, which was confirmed by the significant results of Egger's test (P = 0.03) (Supplementary file Fig. S51).Finally, the trim and fill analysis revealed that adding five studies showed that LLR was associated with lower risk for local recurrence (RR = 0.41, 95% CI [0.26; 0.64], P < 0.01), which was consistent with our findings (Supplementary Fig. S52).

Summary of the findings
In our meta-analysis, LLR demonstrated higher overall survival (OS) at 1, 3, and 5 years compared to RFA.Subgroup analysis found no significant OS differences at 1 and 5 years among PRFA, LRFA, and LLR, while LLR exhibited improved 3-year survival over PRFA.Notably, LRFA showed no significant difference from LLR. Meta-regression analysis found no significant associations between 1-year OS and factors such as age, bilirubin, AFP, or tumor size.OS Propensity-score matching indicated a significant improvement at 3 years with LLR, while no differences were observed at 1 and 5 years.LLR demonstrated enhanced disease-free survival at 1 and 3 years, and recurrence-free survival analysis favored LLR at 1, 3, and 5 years, particularly over PRFA, but no significant difference was found with LRFA.
LLR exhibited significantly lower local recurrence rates compared to RFA, with PRFA showing a notable reduction; however, no significant difference was seen with LRFA.Meta-regression linked this reduction to age.LLR showcased benefits in decreasing intrahepatic recurrence and 90-day mortality; however, it was associated with longer surgery, higher transfusion rates, more complications, and extended hospital stays.We summarized the results of our analysis in Table 2.

Explanation of the findings
Open hepatectomy (OH) is a well-established method for treating HCCs, but its drawbacks include large incisions, extensive resection, and significant blood loss causing trauma.OH, suits patients with normal liver function; however, it is not suitable for patients with severe cirrhosis.A recent analysis showed that laparoscopic liver resection (LLR) was associated with lower postoperative complications, such as ascites and liver failure than OH.Therefore, LLR emerged as a minimally invasive alternative for OH, particularly in patients with severe cirrhosis [47,48].
However, not all cases are suitable for LLR because LLR is primarily indicated for easily reachable lesions and tumors in the outer part of anterolateral liver segments (segments 2, 3, 5, and 6).Lesions in the posterior or upper liver regions (segments 1, 7, and 8, and the upper part of segment 4) represent technical challenges due to bleeding control and limited visibility difficulties [49,50].LLR is particularly considered the preferred option for small HCC cases, even in cirrhotic patients, when feasible, as its effectiveness matches that of open surgery in achieving a cure [51].
Radiofrequency ablation (RFA) is a widely used minimally invasive approach for treating HCCs.Various randomized controlled trials (RCTs) and meta-analyses have compared RFA with OH [52,53].These studies have consistently demonstrated that RFA is effective for early-stage HCCs, offering comparable prognostic outcomes and a lower complication rate than OH.In recent years, this has led to an increasing focus among surgeons on comparing these minimally invasive methods for the curative treatment of HCCs.
Advancements in artificial hydrothorax, imagingguided localization, and probes have considerably expanded the indications of RFA.RFA procedures are performed under conscious sedation.Furthermore, most patients undergoing RFA treatment experience brief hospital stays of 2 to 3 days; in some cases, they can even be discharged on the same day, eliminating the need for prolonged hospitalization [54].As a result, it is evident that RFA treatment is associated with reduced postoperative complications, shorter surgical durations, and minimized hospitalization periods.It's a viable supplemental therapy for cirrhotic livers without significant damage.
However, local recurrence at the RFA treatment site is a common limitation.Rhim et al. noted this due to limited ablation volume, technical difficulties for certain tumors based on location, and the heat sink effect caused by nearby large vessels.[55].Therefore, our observations of the higher local recurrence rates may be attributed to the incomplete ablation of the primary HCC tumor, the heat sink impact, or venous invasion in the adjacent liver.On the other hand, LLR provides a broader safety margin during treatment and often involves completely removing segments containing tumors.This thorough approach may contribute to lower recurrence rates in HCC patients with LLR [56].
In our subgroup analyses, we found that LLR had better outcomes for OS, RFS, and local recurrence rates compared to PRFA.However, regarding 1 to 5 years of OS, RFS, and local recurrence rates, LRFA and LLR had similar effects.This may be attributed to the ability of laparoscopic techniques to detect microscopic tumor foci.In addition, laparoscopic approaches allow precise electrode placement, especially in difficult tumor locations, through comprehensive exploration and intraoperative ultrasound.[57] Laparoscopic RFA's superiority over the percutaneous approach, especially in complex cases or severe liver disease, broadens the scope of RFA treatments, effectively expanding their applications [58].
The findings from the meta-regression analysis demonstrate that certain factors significantly impact the local recurrence in early-stage HCC.Specifically, the analysis reveals a noteworthy correlation between the age of the patient and the incidence of recurrence.
It is interesting to note that there is an inverse correlation between age and recurrence risk, which may seem counterintuitive since one might expect older patients to have a higher risk due to compromised immune function and overall health.However, this observation is consistent with earlier studies on older breast cancer patients conducted by Anna Z. de Boer et al. in 2020, which found that individuals aged 75-79 were more likely to experience distant recurrence but not locoregional recurrence risk [59].Similarly, research by R. A. M. Damhuis et al. in 1997 demonstrated that older age was associated with reduced local recurrence rates in rectal cancer across three different age groups (15-64, 65-74, and 75 and over).[60] Thus, advancing age may decrease local recurrence rates but potentially increase the likelihood of distant recurrence in the context of HCC.However, it is essential to note that the variability in study designs and patient populations across the included studies limits our findings.Further research is needed to explore the molecular mechanisms and interactions with other unexplored factors.
Also, our meta-regression analysis found no significant link between tumor size and overall survival or local recurrence in HCC patients, challenging the prior  [63] research has also found that for patients without vascular invasion, tumor size matters notably for overall survival in the radiofrequency ablation group, but this association is not observed in either the liver resection or transplantation group.Conversely, for patients with vascular invasion, tumor size affects survival in the liver resection and transplantation group.These findings suggest two possibilities: tumor size may not be as crucial a prognostic factor in HCC as believed, with factors like tumor stage, vascular invasion, and liver function playing more significant roles.Additionally, the relationship between tumor size and HCC survival may be more complex, influenced by age, gender, or underlying liver disease.So, the clinicians should be cautious about relying solely on tumor size for treatment decisions and consider multiple factors for more informed choices.
Given these uncertainties, further research is needed to better understand the tumor size and survival relationship in HCC.
In comparison to the previous meta-analyses conducted by Mou-Bo Si in 2019 [16], Xiaocheng Li in 2019 [20], Shan Jin in 2020 [17], and Zhijun Li in 2021 [19], our current study provides a thorough and up-to-date assessment of various liver resection techniques, with a particular emphasis on the benefits associated with LLR and RFA approaches.

Agreements and disagreements with previous studies
Our analysis incorporates 19 studies and a substantial pooled sample size of 3756 patients, as presented in Table 3. Prior studies had differing numbers of included studies, ranging from 6 to 19, and sample sizes ranging from 597 to 2038.
After conducting a thorough and detailed analysis, we have discovered significant differences and similarities in the results of various meta-analyses.In the context of overall survival, our findings closely align with those of Xiaocheng Li et al. [20].However, when examining the research conducted by Mou-Bo Si et al. [16] and Zhijun Li et al. [19], their results demonstrate that there were no statistically significant differences observed at the 1 year, whereas the outcomes favored the LLR group at 3 years.
On the other hand, all the meta-analyses indicate that the LLR group has a better disease-free survival rate at one and three years.However, at five years, our study and Xiaocheng Li's et al. [20] highlight a lack of statistical differences.
Across all meta-analyses [16,17,19,20], the RFA group consistently shows higher local recurrence rates and shorter duration of both surgery and hospital stay compared to the LLR group.Additionally, complications are uniformly more prevalent in the LLR group according to all analyses.

Strength points and limitations
To date, our study is the most comprehensive metaanalysis comparing LLR versus RFA in patients with early-stage HCC.We included 19 observational studies, compromising 3756 patients.We covered a five-year follow-up period, analyzing OS, DFS, and RFS using Propensity Score Matching while examining Intrahepatic and Extrahepatic recurrence.In addition, we comprehensively evaluated safety measures in terms of all complications, 30-day and 90-day mortality, and major complications.Moreover, our study is the first meta-analysis in this topic to conduct subgroup analysis based on RFA type, including four laparoscopic RFA studies, which is a significant improvement compared to previous metaanalyses that only featured one study.Finally, our study is the first to perform meta-regression analysis to explore the association between overall survival and local recurrence with multiple covariates such as age, tumor size, total bilirubin, and alpha-fetoprotein.
In addressing the limitations of our analysis, it's crucial to emphasize that our study exclusively incorporated English-language studies.It's also essential to acknowledge that most of the studies we examined were retrospective, potentially introducing an increased risk of bias, particularly concerning the selection of patients.The varying availability of resources and diverse levels of expertise among medical practitioners might have significantly influenced treatment choices, constraining our findings' broader applicability.Moreover, we observed heterogeneity across different outcomes, and indications of publication bias emerged in multiple studies.Our analysis did not compare outcomes such as quality of life, liver functions after treatment, and overall response rate as these data were not reported in our included studies.Furthermore, our ability to perform a subgroup analysis based on portal hypertension, cirrhosis, etiology of the underlying disease, or tumor location was hindered by inherent constraints.

Implications of our findings in practice
Based on our study, LLR provides better long-term survival outcomes at 1, 3, and 5 years compared to RFA, making it the preferred option.However, subgroup analysis indicates that LRFA yields similar survival rates to LLR at these time intervals, providing a less invasive alternative.It is important to consider individual patient characteristics and preferences when making treatment decisions.LLR has advantages in terms of disease-free and recurrence-free survival, especially over PRFA.Age has been identified as a factor in reducing local recurrence rates.Additionally, our research indicates that tumor size may not be as critical a prognostic factor in HCC as previously thought.This information can aid clinicians in making treatment decisions.For instance, clinicians may be less inclined to exclude patients from surgery solely based on tumor size.
Nevertheless, clinicians must balance these benefits against LLR's longer surgery times, higher transfusion rates, complications, and extended hospital stays.Additionally, the study highlights the potential of laparoscopic RFA techniques, as no significant differences were found between LLR and LRFA in several key outcomes, suggesting future research in this area.

Recommendations
To improve HCC management, t is recommended to conduct larger, long-term comparative studies and prioritize well-designed randomized controlled trials.These efforts would validate current findings, assess treatment long-term effects, and provide robust evidence.Additionally, considering both survival outcomes and patients' quality of life is crucial, along with evaluating cost-effectiveness for informed healthcare decision-making.It is crucial to explore the impact of evolving technologies on outcomes, especially within laparoscopic radiofrequency ablation techniques.Incorporating patient-reported outcomes and satisfaction assessments can provide valuable insights into treatment preferences.
Furthermore, additional research is needed to comprehensively understand the correlation between tumor size and HCC survival rates.Additionally, exploring the impact of age on local recurrence, as well as both intrahepatic and extrahepatic recurrence, and to identify other covariates influencing overall survival and local recurrence.By conducting more research, we can better understand HCC management and improve patient outcomes.

Conclusion
In this meta-analysis, LLR yielded better oncological outcomes than RFA for patients with early and small HCC.LLR exhibited superior 5-year overall survival and lower recurrence rates, although it was associated with higher complication rates than RFA.The study also highlighted the potential of enhancing outcomes via laparoscopic RFA techniques, as no significant differences were found between LLR and LRFA in terms of overall survival, recurrence-free survival, and local recurrence.However, it is essential to emphasize that further well-designed prospective studies of high quality are necessary to validate and substantiate the conclusions drawn from this meta-analysis.

Fig. 1
Fig. 1 PRISMA flow diagram for included studies

Fig. 6
Fig. 6 Meta-Regression Analysis of Covariates and local recurrence

Table 1
52, Comprehensive overview of the included Studies

Table 3
Comparison of our meta-analysis with another published meta-analysisAbbreviations: MA Meta-analysis, RFA Radiofrequency ablation, OS Overall survival, DFS Disease free survival, RFS Recurrence free survival, MIS Minimally invasive liver surgery, LH Laparoscopic hepatectomy, LLR Laparoscopic liver resection, PSM Propensity-score matching, AST Aspartate Aminotransferase, ALB Albumin, ALT Alanine Aminotransferase, TBIL Total Bilirubin, AFP Alpha-Fetoprotein, NR Not reported