Efficacy of sorafenib combined with transarterial chemoembolization in the treatment of advanced hepatocellular carcinoma: A meta-analysis

Abstract

BACKGROUND

The combination of sorafenib with transarterial chemoembolization (TACE) is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma (HCC).

AIM

To evaluate the efficacy of this combined treatment strategy in enhancing overall survival (OS) and progression-free survival (PFS) compared to monotherapies.

METHODS

A systematic review was conducted following the PRISMA guidelines. A comprehensive search was performed across PubMed, EMBASE, Web of Science, and the Cochrane Library up to May 8, 2024. Studies were included if they compared sorafenib plus TACE to sorafenib alone or TACE alone in adults with advanced HCC. Primary outcomes were OS, PFS, response rates, and safety profiles. Data extraction and quality assessment were independently performed by two reviewers. Heterogeneity was assessed using the I² statistic, and a random-effects model was applied for pooling data. Sensitivity analysis and publication bias assessment were also conducted.

RESULTS

A total of twelve studies involving 1174 patients met the inclusion criteria. Significant heterogeneity was observed for both OS (I² = 72.6%, P < 0.001) and PFS (I² = 83.7%, P < 0.001). The combined treatment of sorafenib with TACE significantly improved OS [hazard ratio (HR) = 0.60, 95% confidence interval (CI): 0.44-0.76] and PFS (HR = 0.54, 95%CI: 0.38-0.69). Sensitivity analysis confirmed the robustness of these findings. Funnel plots and Egger's test indicated no significant publication bias.

CONCLUSION

Sorafenib combined with TACE significantly enhances both OS and PFS in patients with advanced HCC compared to monotherapy. This combination therapy represents a promising approach to improving clinical outcomes in advanced liver cancer.

Key Words: Sorafenib; Transarterial chemoembolization; Hepatocellular carcinoma; Overall survival; Progression-free survival; Meta-analysis

Core Tip: This meta-analysis synthesizes current research to assess the efficacy of combining sorafenib with transarterial chemoembolization (TACE), aiming to enhance survival outcomes in patients with advanced hepatocellular carcinoma (HCC). Our comprehensive review, adhering to PRISMA guidelines, included twelve studies and 1174 patients, revealing that the combination therapy significantly improves both overall survival and progression-free survival compared to sorafenib or TACE alone. These results advocate for the integration of this combined approach in clinical practice, potentially setting a new benchmark in the treatment protocols for advanced HCC.

INTRODUCTION

Hepatocellular carcinoma (HCC) is among the most common and fatal cancers globally, constituting the third primary cause of cancer-related mortality worldwide. The care of advanced HCC is a considerable therapeutic challenge, especially in individuals ineligible for curative interventions such surgical resection or liver transplantation[1-3]. The advancement of systemic therapeutics and combination treatments has emerged as a primary research focus to enhance survival rates and quality of life for affected persons. Sorafenib, an oral multikinase inhibitor (MKI), is recognized as a standard treatment for individuals with advanced HCC. It functions by inhibiting many pathways implicated in tumor proliferation and angiogenesis, including the vascular endothelial growth factor (VEGF) receptors and the Ras/Raf/MEK/ERK pathway[4-6]. Although sorafenib is effective in extending overall survival (OS), its advantages are frequently limited, leading to research on combination therapies that may augment its therapeutic impact.

Transarterial chemoembolization (TACE) is a widely utilized method for treating HCC, especially in its intermediate phases. TACE administers chemotherapeutic medications directly into the hepatic artery that supplies the tumor, subsequently embolizing the artery to retain the drugs within the tumor, thereby optimizing tumor exposure and reducing systemic toxicity. The effectiveness of TACE in advanced HCC stages is constrained, as it fails to tackle the possibility of distant metastasis or the vascular characteristics of hepatocellular tumors[7,8]. The integration of sorafenib with TACE has surfaced as a promising approach for managing advanced HCC. This therapeutic strategy is posited to leverage the synergistic processes of each therapy modality: Sorafenib inhibits systemic and intratumoral angiogenesis, potentially enhancing tumor sensitivity to the localized cytotoxic effects of TACE. Recent studies indicate that this combination may result in improved tumor response rates, reduced tumor progression, and increased survival compared to either treatment individually[9,10].

This systematic review and meta-analysis seeks to assess the effectiveness of sorafenib in conjunction with TACE for the treatment of advanced HCC. This study aims to deliver a thorough evaluation of the treatment outcomes linked to this combination medication by synthesizing data from multiple clinical trials and cohort studies. This paper seeks to consolidate available information and clarify the advantages and disadvantages of this integrated therapeutic approach, therefore aiding in the refinement of treatment protocols and improvement of patient outcomes in this complex clinical setting.

MATERIALS AND METHODS

Search strategy

During this systematic review, we adhered to the PRISMA guidelines[11]. We conducted a comprehensive literature search on May 8, 2024, utilizing four electronic databases: PubMed, EMBASE, Web of Science, and the Cochrane Library. No restrictions were imposed concerning the publication date. Our search strategy was meticulously designed to incorporate a broad array of key terms related to the study's focus: "sorafenib", "Transarterial Chemoembolization", "hepatic arterial infusion chemotherapy", "HAIC", "advanced", "hepatocellular carcinoma", and "HCC". These terms were selected to cover all aspects of the Patient, Intervention, Comparison, Outcome (PICO) framework, ensuring an exhaustive collection of pertinent studies. Additionally, there were no constraints based on the language of publication. To further enhance the depth of our search, we also manually screened the reference lists of all identified articles to discover any additional studies that could be relevant for inclusion in this meta-analysis.

Inclusion criteria and exclusion criteria

Inclusion criteria: Study design: We incorporated randomized controlled trials (RCTs), cohort studies, and controlled clinical trials that offered a direct comparison between the combined therapy of sorafenib and TACE and each therapeutic modality administered independently in the management of advanced HCC.

Participants: Research should include adult patients diagnosed with advanced HCC, as verified by histological or radiological standards. The advanced stage was determined using the Barcelona Clinic Liver Cancer (BCLC) staging system or comparable classifications.

Interventions: Eligible studies needed to compare the efficacy and safety of sorafenib in conjunction with TACE to sorafenib monotherapy or TACE monotherapy. Comprehensive information regarding the dosage and administration regimens for sorafenib, together with the techniques and agents utilized in TACE, should have been supplied.

Outcomes: The primary outcomes of interest encompassed OS, progression-free survival (PFS), response rates (according to RECIST or mRECIST criteria), and safety/tolerability profiles.

Exclusion criteria: Single therapy studies: Studies assessing sorafenib or TACE as isolated treatments, lacking a comparator group that included combination therapy or an alternative single modality, were eliminated.

Review articles and non-empirical studies: Systematic reviews, meta-analyses, narrative reviews, letters, opinions, editorials, and case reports were omitted to concentrate on empirical research data.

Incomplete data: Studies that inadequately reported data on predefined outcomes or lacked essential information that could not be supplemented from alternative sources were eliminated.

Duplicate studies: We excluded studies presenting overlapping data from the same patient cohorts to avoid redundancy and potential skewing of results.

Data extraction process

The data obtained from each study encompassed the following: Author(s) names, publication year, study design, country of study, patient group sizes, patient demographics including age and gender, Child-Pugh scores, alpha-fetoprotein levels, and treatment regimen specifics. Outcome metrics, including OS, PFS, and objective response rate (ORR), were documented. When pertinent data were absent from the published reports, we reached out to the original study investigators via email to obtain the missing information. In our systematic review and meta-analysis, literature screening and data extraction were rigorously performed independently by two evaluators to guarantee the objectivity and precision of the gathered data. Each assessor verified the extracted data of their counterpart. Discrepancies identified during this step were resolved by discussions among the reviewers, with the possibility of consulting a third-party reviewer if consensus was unattainable.

Quality assessment of included studies

The quality of the RCTs included in our meta-analysis was rigorously evaluated using the Cochrane Collaboration's risk of bias tool[12]. This assessment covered several critical aspects: The generation of the random sequence, allocation concealment, the blinding of participants and personnel, the completeness of outcome data, the risk of selective reporting, and other potential biases. Each of these domains was classified according to the risk of bias as low, unclear, or high. For observational studies, we employed the Newcastle-Ottawa Scale (NOS) to assess study quality[13]. The NOS evaluates studies based on nine items grouped into three broad categories: The selection of study groups, the comparability of groups, and the ascertainment of either the exposure or outcome of interest. Points were awarded for each quality criterion met within these categories, with each study potentially earning up to nine points. Based on their total scores, studies were categorized as low quality (0-3 points), moderate quality (4-6 points), or high quality (7-9 points). All evaluations were conducted independently by two reviewers. Any disagreements that arose during the quality assessment process were resolved by either discussion among the reviewers or, if necessary, by consulting a third reviewer. This method ensured a consistent and unbiased evaluation of the quality of the studies included in our meta-analysis.

Statistical analyses

In our meta-analysis, we meticulously evaluated the heterogeneity among studies using χ² statistics, measured by the I² value. When the I² value was below 50% and the accompanying P-value was greater than or equal to 0.10, this signified a lack of significant heterogeneity, necessitating the application of a fixed-effect model to calculate the aggregated effect size. If the I² value was 50% or above, or if the P-value was below 0.10, this indicated significant heterogeneity, necessitating the use of a random-effects model to determine the combined effect size. A sensitivity analysis was performed to evaluate the robustness of our findings. This technique entailed the sequential exclusion of each study to assess its influence on the total effect size, thereby identifying any study-specific sources of heterogeneity. Furthermore, to identify any publishing bias, we analyzed the symmetry of the funnel plot. A balanced distribution of studies on both sides of the funnel plot's apex would suggest a low likelihood of results being affected by publication bias. Egger's linear regression test offered additional quantitative evaluation to identify potential publication bias. All statistical tests were bilateral, with a significance level established at a P-value of less than 0.05. The statistical study utilized Stata version 17 (StataCorp, College Station, TX, United States), ensuring a thorough and meticulous review of the data in our meta-analysis.

RESULTS

Search results and study selection

At the onset of this systematic review and meta-analysis, a comprehensive search of several electronic databases yielded an initial total of 1372 potentially relevant articles. We first utilized an algorithm to eliminate duplicate entries, ensuring that each study was uniquely represented. Following this step, a detailed review of titles and abstracts was conducted according to strictly defined inclusion and exclusion criteria. These criteria assessed various aspects, such as study methodology, demographic characteristics of participants, measured clinical outcomes, and the quality of research methods. After this preliminary assessment, 45 articles were selected for a more detailed evaluation. During this in-depth phase, multiple investigators independently reviewed the full texts of these articles to perform a thorough and unbiased assessment. Subsequently, 31 articles were excluded for specific reasons: Review articles (12), sequentially published works (5), studies with insufficient data for meta-analysis (8), and clinical trials lacking control groups (8). Ultimately, 12 studies met all the rigorous criteria established in our protocol and were included in the final meta-analysis[14-25]. This selection process ensured the inclusion of high-quality and relevant studies, critical for deriving robust conclusions (Figure 1).

Figure 1  Study selection flow diagram for the meta-analysis.

Study characteristics of the meta-analysis and systematic review

This meta-analysis and systematic review included a variety of trials to assess the effectiveness of sorafenib in conjunction with different chemoembolization agents for liver cancer treatment. Twelve studies conducted from 2011 to 2022 were included, encompassing a total of 1174 cases that compared either therapy combinations or monotherapies among various patient groups. The studies primarily consisted of RCTs, but also encompassed retrospective cohort studies and a prospective nonrandomized research, indicating a comprehensive methodological range. The average age of participants in these research often spanned from the late forties to early seventies. The dosage of Sorafenib was uniformly delivered at 400 mg bi-daily in the majority of studies, with two exceptions where it commenced at 200 mg and was subsequently escalated to 400 mg, illustrating a standardized dosing methodology across diverse study contexts. The chemoembolization chemicals employed comprised a combination of epirubicin, cisplatin, doxorubicin, mitomycin, oxaliplatin, fluorouracil, and lipiodol, reflecting a comprehensive investigation of chemotherapeutic approaches alongside sorafenib (Table 1).

Table 1 Characteristics of included studies in the meta-analysis and systematic review.

Ref.	Year	Number of cases	Mean age (years)	Design	Dose of sorafenib	Chemoembolization agents
Zheng et al[18]	2022	32 vs 32	56 vs 55	RCT	400 mg twice daily	Epirubicin, cisplatin, doxorubicin, mitomycin
He et al[16]	2019	125 vs 122	49 vs 49	RCT	400 mg twice daily	Mitomycin, doxorubicin
Kondo et al[17]	2019	35 vs 33	72 vs 71	RCT	400 mg twice daily	Oxaliplatin, fluorouracil, epirubicin
Zhao et al[20]	2019	46 vs 58	NA	Retrospective cohort study	400 mg twice daily	Oxaliplatin, epirubicin
Kudo et al[22]	2018	102 vs 103	67 vs 68	RCT	400 mg twice daily	Cisplatin, fluorouracil
Ikuta et al[19]	2018	26 vs 72	72 vs 69	Retrospective cohort study	400 mg twice daily	Cisplatin, fluorouracil, lipiodol
Ikeda et al[14]	2016	65 vs 41	66 vs 64	RCT	400 mg twice daily	Cisplatin
Bai et al[24]	2013	82 vs 164	54 vs 52	Prospective nonrandomized study	400 mg twice daily	Mitomycin, doxorubicin
Muhammad et al[25]	2013	13 vs 30	61 vs 59	Retrospective cohort study	200 mg increased to 400 mg	Doxorubicin
Sansonno et al[23]	2012	31 vs 31	73 vs 72.8	RCT	400 mg twice daily	Mitomycin, doxorubicin
Qu et al[21]	2012	45 vs 45	51 vs 49	Retrospective study	400 mg twice daily	Oxaliplatin, fluorouracil, epirubicin
Kudo et al[15]	2011	229 vs 229	69 vs 70	RCT	200 mg twice daily	Epirubicin, cisplatin, doxorubicin, mitomycin

NA: Not available; RCT: Randomized controlled trial.

Results of quality assessment

The quality and reliability of seven RCTs included in this meta-analysis were assessed using the Cochrane Collaboration's risk of bias tool. Overall, the included studies demonstrated a high level of methodological quality. Most studies showed a low risk of bias in the majority of the evaluated domains. Particularly, random sequence generation and allocation concealment were consistently well-handled across most studies, indicating robust randomization processes and adequate measures to prevent allocation bias. Blinding of participants and personnel, as well as outcome assessment, was also well-managed in the majority of the studies, minimizing performance and detection biases (Figure 2).

Figure 2  Risk of bias evaluation for included studies, depicted with red indicating high risk and green indicating low risk.

The cohort studies included in this meta-analysis were rigorously assessed using the NOS, focusing on selection, comparability, and outcome. These studies generally exhibited high methodological quality, with most achieving scores of 8 or 9 out of 9 possible points. This reflects strong representativeness and selection of cohorts, thorough ascertainment of exposures, and robust outcome assessments. The studies also demonstrated effective control for potential confounders, ensuring reliable comparability between cohorts (Table 2).

Table 2 The quality assessment according to Newcastle-Ottawa Scale of each cohort study.

Ref.	Selection			Comparability		Outcome			Total score
	Representativeness of the exposed cohort	Selection of the non-exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis	Assessment of outcome	Was follow-up long enough	Adequacy of follow up of cohorts
Zhao et al[20]		1	1	1	2	1	1	1	8
Ikuta et al[19]	1	1	1	1	2	1	1	1	9
Bai et al[24]	1	1	1	1	2	1	1	1	9
Muhammad et al[25]	1	1	1	1	1	1	1	1	8
Qu et al[21]	1	1	1	1	1	1	1	1	8

Efficacy of sorafenib combined with TACE on OS

In this meta-analysis, ten studies were included that reported on OS among patients treated with sorafenib combined with TACE. These studies demonstrated considerable heterogeneity (I² = 72.6%, P < 0.001), suggesting variations in study populations, treatment protocols, or other study-specific characteristics. Due to this observed heterogeneity, a random-effects model was employed to synthesize the data across the included studies. The combined results demonstrated that sorafenib combined with TACE significantly enhanced OS compared to either treatment administered alone. This enhanced survival benefit highlights the potential of combining systemic and local therapies in the management of conditions where sorafenib and TACE are applicable. The pooled hazard ratio (HR) for OS was 0.60 with a 95% confidence interval (CI) ranging from 0.44 to 0.76, indicating a 40% reduction in the risk of death for patients receiving the combined treatment as opposed to those receiving standard therapy alone. The analysis points towards a synergistic interaction between the systemic action of sorafenib and the localized treatment effect of TACE, suggesting a compelling treatment option for enhancing patient outcomes. The graph in Figure 3 visually represents the pooled estimates of the effects of this combined therapy on OS, underscoring the clinical relevance of our findings.

Figure 3  Forest plot showing the impact of combining sorafenib with transarterial chemoembolization on overall survival.

Effectiveness of combined sorafenib and TACE on PFS

This meta-analysis reviewed eight studies to determine the effects of combining sorafenib with TACE on PFS in patients. The studies exhibited a high degree of heterogeneity (I² = 83.7%, P < 0.001), reflecting differences in clinical settings, treatment protocols, and patient demographics, which justified the use of a random-effects model for data synthesis. Analysis of the combined data revealed that treatment with sorafenib plus TACE leads to a significant improvement in PFS. The combined treatment reduced the risk of progression or death by 46%, as indicated by a HR of 0.54 (95%CI: 0.38-0.69). These findings support the clinical advantage of using sorafenib in conjunction with TACE to effectively prolong the time patients live without disease progression. The quantified impact of this therapeutic synergy is graphically represented in Figure 4, highlighting its significant benefits over standard treatments.

Figure 4  Forest plot displaying the benefits of sorafenib and transarterial chemoembolization combination on progression-free survival.

Sensitivity analysis of meta-analysis findings

Due to significant heterogeneity identified across the included studies in our meta-analysis, we undertook a sensitivity analysis to verify the robustness and consistency of the aggregated outcomes. This involved a detailed procedure where each study was individually omitted from the meta-analysis, and the pooled effect sizes were recalculated with the remaining studies. This comprehensive approach to sensitivity testing demonstrated that the overall conclusions of the meta-analysis were not disproportionately influenced by any single study. The effect estimates remained consistent and robust, suggesting that our pooled results are stable and reliable. The continuity of these findings across different subsets of data reassures us of the strength and validity of our conclusions. This methodical verification process, depicted in Figure 5, solidifies the trustworthiness of the meta-analysis results, confirming that they are well-founded and can be confidently applied to broader clinical practices (Figure 5).

Figure 5 Sensitivity analysis graphs confirming the stability of the meta-analysis results for overall survival and progression-free survival. A: Overall survival; B: Progression-free survival.

Assessment of publication bias in the meta-analysis

To evaluate potential publication bias within our meta-analysis, funnel plots were constructed for each analysis based on the included studies. The visual assessment of these plots revealed symmetry, indicating no apparent publication bias (Figure 6). This symmetry suggests that the studies included in our analysis are likely representative of the full spectrum of research, without an overrepresentation of studies with either predominantly positive or negative results. Further statistical assessment using Egger's linear regression test corroborated these findings, showing no significant evidence of publication bias across different variables analyzed (P > 0.05 for all). This statistical result strengthens the credibility of our meta-analysis, suggesting that the effects observed are not due to selective publication of study results.

Figure 6  Funnel plot for evaluation of publication bias in the meta-analysis.

DISCUSSION

This systematic review and meta-analysis assess the effectiveness of combining sorafenib with TACE, intending to provide a more comprehensive strategy for controlling advanced HCC by merging the advantages of targeted systemic therapy with a localized intervention. This systematic review and meta-analysis demonstrate the significant advantages of integrating sorafenib with TACE for the treatment of advanced HCC. The data, especially the prolonged OS and enhanced PFS, indicate a strong synergistic interaction between the two regimens. This analysis investigates the possible processes that contribute to these advantages and their association with the pathophysiology of HCC.

HCC is a highly vascular neoplasm that depends significantly on arterial blood flow for its growth and spread[26,27]. This trait renders it an optimal candidate for TACE, which selectively occludes the tumor's vascular supply and administers cytotoxic drugs directly to the tumor location[28,29]. Nonetheless, TACE may elicit angiogenic factors as a result of the hypoxic environment generated by arterial embolization, potentially facilitating tumor recurrence and angiogenesis. Sorafenib, a MKI, targets pathways implicated in tumor proliferation and angiogenesis, including the VEGF and platelet-derived growth factor (PDGF) pathways, essential for the neovascularization necessary for HCC tumors following TACE-induced ischemia[30,31]. Sorafenib inhibits these pathways, hence suppressing compensatory angiogenesis following TACE and augmenting the lethal effects of TACE on tumor cells.

The microenvironment of HCC is intricate, comprising inflammatory cells, stromal cells, and a variety of cytokines and growth factors. The integration of TACE with sorafenib may alter this milieu, rendering it less favorable for tumor development. TACE diminishes tumor burden and directly influences the local tumor microenvironment by decreasing oxygen supply and nutritional availability, which is augmented by sorafenib's inhibition of survival signals commonly elevated under hypoxic conditions[32,33]. The meta-analysis yielded substantial evidence, indicating a HR of 0.60 for OS and 0.54 for PFS when sorafenib was combined with TACE against individual therapies. The enhanced longevity can be ascribed to the proficient treatment of tiny metastases and remaining cancer cells that are undetectable and untargetable by TACE alone. Sorafenib's systemic mechanism effectively manages micrometastatic illness, a crucial factor for long-term survival in cancer treatment.

To effectively address heterogeneity, we employed several established methodological approaches. Heterogeneity was assessed using the I² statistic and χ² test, with an I² value of < 50% and P ≥ 0.10 indicating non-significant heterogeneity, in which case a fixed-effects model was applied. Conversely, an I² value of ≥ 50% or P < 0.10 indicated significant heterogeneity, prompting the use of a random-effects model. These criteria are consistent with standard practices in systematic reviews and meta-analyses. To further explore the impact of heterogeneity on our findings, we conducted sensitivity analyses by systematically excluding individual studies and recalculating pooled effect sizes. The results showed that no single study exerted a disproportionate influence on the overall effect, confirming the robustness of our conclusions. Potential publication bias was assessed through funnel plots and Egger’s regression test, both of which indicated no significant bias (P > 0.05), suggesting that the pooled results were not significantly affected by selective reporting. Notably, the analysis of OS and PFS revealed significant heterogeneity, with I² values of 72.6% and 83.7%, respectively. To account for this variability, a random-effects model was applied, which is appropriate for synthesizing data with substantial inter-study variation. The sensitivity analysis further supported the stability and consistency of our results. In summary, our manuscript clearly outlines the methodologies used to address heterogeneity, including heterogeneity assessment, model selection, sensitivity analyses, and evaluation of publication bias. Despite the observed heterogeneity, these rigorous approaches ensured the validity and reliability of our findings.

The impact of sorafenib dosage variations on treatment outcomes warrants consideration as a potential confounder in this meta-analysis. Sorafenib is typically administered at a standard dose of 400 mg twice daily; however, dose reductions are frequently required in clinical practice to manage adverse effects such as hand-foot skin reactions, diarrhea, and hypertension. These dose adjustments may influence treatment efficacy, as higher doses are associated with improved tumor control but increased toxicity, while lower doses may reduce adverse events at the potential cost of reduced efficacy[34-36]. To further elucidate the synergistic effects of TACE and sorafenib, it is essential to consider their combined impact on the tumor microenvironment at a molecular level. TACE, by inducing localized ischemia and hypoxia, activates hypoxia-inducible factors (HIFs) such as HIF-1α, which can promote angiogenesis, epithelial-mesenchymal transition, and tumor invasiveness[37-39]. Sorafenib, through its inhibition of VEGF and PDGF pathways, not only suppresses angiogenesis but may also modulate the inflammatory milieu of the tumor microenvironment[40]. For instance, sorafenib has been shown to polarize tumor-associated macrophages from an M2 (pro-tumorigenic) phenotype to an M1 (anti-tumorigenic) phenotype, thereby enhancing anti-tumor immune responses[39]. Moreover, the combination of TACE-induced hypoxia and sorafenib's systemic inhibition of survival signals might disrupt the crosstalk between stromal cells and cancer cells, reducing matrix metalloproteinase-mediated extracellular matrix remodeling and tumor invasion[40]. These molecular interactions not only enhance the cytotoxic effects of TACE but also mitigate tumor progression, contributing to the observed improvements in OS and PFS[41,42].

Previous studies have explored the efficacy of sorafenib combined with TACE in advanced HCC, providing important insights. For instance, Yang et al's meta-analysis demonstrated that this combination significantly improves OS, PFS, TTP, and DCR compared to sorafenib monotherapy, with manageable safety profiles[43]. Our findings are consistent with Yang et al[43], particularly regarding the synergistic effects on OS and PFS; however, our analysis includes more comprehensive assessments of heterogeneity, sensitivity analyses to validate robustness, and rigorous evaluation of publication bias, thereby enhancing the reliability of our conclusions. Similarly, Mulyadi et al's systematic review reported the superiority of TACE-sorafenib over TACE alone in improving OS for BCLC-C patients but was limited by its qualitative approach due to data constraints[44]. In contrast, our study provides a meta-analytic synthesis that encompasses a broader scope, comparing both sorafenib-TACE and their respective monotherapies, while addressing a wider range of outcomes including PFS and safety. Dong et al's meta-analysis, focusing on TACE combined with various MKI, revealed improvements in TTP and ORR but found no significant benefit for OS or PFS and highlighted notable MKI-induced toxicities[45]. Unlike Dong et al[45], our focused evaluation of sorafenib-TACE demonstrates significant enhancements in OS and PFS, which we attribute to the specific therapeutic synergy of this combination and its precise application in HCC management. Our meta-analysis distinguishes itself by integrating quantitative outcome synthesis with a detailed exploration of heterogeneity, sensitivity, and publication bias, alongside a robust discussion of the molecular mechanisms underlying the synergistic effects of sorafenib and TACE. This comprehensive approach not only corroborates and refines existing findings but also provides novel insights into their impact on the tumor microenvironment, offering a more nuanced understanding that contributes to optimizing treatment strategies for advanced HCC.

The limitations of this meta-analysis include the inherent biases of retrospective studies, potential selection bias, and heterogeneity in treatment protocols, such as variations in sorafenib dosing and TACE techniques. Additionally, small sample sizes and geographical concentration in specific regions (predominantly Asia) may limit generalizability. Data incompleteness and inconsistent follow-up durations across studies further constrain the robustness of our findings. Future research should prioritize well-designed prospective randomized trials with standardized protocols and diverse populations to enhance the reliability and applicability of results.

CONCLUSION

This meta-analysis indicates that the combination of sorafenib and TACE markedly enhances OS and PFS in patients with advanced HCC, relative to either treatment administered independently. The findings endorse the combined application of sorafenib and TACE as a more effective therapeutic approach for improving patient outcomes in advanced liver cancer stages.