Efficacy of hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma: survival outcomes and prognostic factors from a systematic review and meta-analysis

Introduction

Hepatocellular carcinoma (HCC) is one of the most common and aggressive forms of liver cancer, and its incidence has been steadily increasing worldwide, particularly in regions with high rates of hepatitis B and C infections, as well as in patients with chronic liver disease (1,2). In recent years, the rising prevalence of metabolic disorders has contributed significantly to HCC incidence, with non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), emerging as important etiological factors. The majority of HCC cases are diagnosed at an advanced stage when curative treatments such as surgery or liver transplantation are no longer feasible (3). For patients with advanced, unresectable HCC, the treatment options are limited, and the prognosis remains poor, with a median survival time often measured in months (4).

The current standard of care for unresectable HCC typically involves locoregional therapies such as transarterial chemoembolization (TACE), and systemic chemotherapy (5,6). TACE is a widely used first-line treatment for intermediate-stage HCC, combining the selective embolization of the tumor vasculature with the delivery of cytotoxic agents directly into the tumor via the hepatic artery (7). This technique is designed to block the blood supply to the tumor, while simultaneously delivering chemotherapy, thereby improving the local concentration of the drug and enhancing therapeutic efficacy (8,9). However, TACE is not without its limitations, including potential liver function deterioration, post-procedural pain, and the risk of tumor progression due to incomplete treatment or tumor recurrence (10).

An alternative treatment approach that has gained attention in recent years is hepatic arterial infusion chemotherapy (HAIC) (11). HAIC involves the direct infusion of high-dose chemotherapy agents into the hepatic artery via a catheter, providing a more targeted and localized treatment compared to systemic chemotherapy (12,13). The hepatic artery supplies the majority of the blood to liver tumors, allowing HAIC to deliver higher drug concentrations directly to the tumor while minimizing systemic side effects (14). This approach has been shown to improve therapeutic efficacy in several studies and is considered an effective treatment for advanced HCC, particularly in patients with poor liver function or those who are refractory to systemic therapies (15). Despite its promising potential, HAIC is not widely adopted in clinical practice, primarily due to the technical challenges involved in its administration and the limited number of studies comparing it to other standard therapies, such as TACE. Although several studies have substantiated that HAIC has a higher response rate than systemic chemotherapy, with longer overall survival (OS) and tolerable toxicity in patients with advanced HCC (16,17), only the Japanese guidelines currently recommend HAIC as a treatment option for advanced HCC (18).

While HAIC and TACE are both effective locoregional treatments, there is ongoing debate regarding which therapy provides better survival outcomes for patients with advanced HCC (19). Some studies suggest that HAIC may provide superior survival benefits, particularly in patients with larger tumors or those who have failed previous treatments (20). Conversely, TACE remains the most widely used treatment, particularly in intermediate-stage HCC, due to its established efficacy and lower invasiveness (21). The comparative efficacy of these two treatment modalities (HAIC and TACE) in combination with immunotherapy (22), their interactions with patient nutritional status, and their effects on systemic inflammatory responses remain subjects of active investigation and ongoing debate in the field (23,24).

The aim of this meta-analysis is to directly compare the therapeutic efficacy of HAIC and TACE in the treatment of advanced HCC. Specifically, we seek to determine whether HAIC can improve OS, progression-free survival (PFS), and other clinical outcomes compared to TACE. Additionally, this study aims to explore the potential prognostic factors that may influence survival outcomes in patients receiving either HAIC or TACE and identify the patient characteristics that may benefit most from each treatment modality. We present this article in accordance with the PRISMA reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-115/rc).

Methods

Literature search

This systematic review is registered in PROSPERO (CRD42024621133). A comprehensive search was conducted by two independent reviewers (D.Z. and Z.C.) across multiple databases, including PubMed, Embase, and Web of Science, up to November 2024. Only studies published in English were considered for inclusion. In cases of disagreement between the reviewers, a third reviewer (G.L.) was consulted to resolve discrepancies.

Inclusion and exclusion criteria

Inclusion criteria

This meta-analysis included studies involving patients diagnosed with advanced HCC based on histopathological confirmation. We considered only studies assessing the clinical outcomes of HAIC in comparison to TACE, with particular focus on survival metrics such as OS and PFS. Additionally, studies were required to report hazard ratios (HRs) along with 95% confidence intervals (CIs) or provide sufficient data to allow calculation of HRs for survival outcomes. We also included research investigating the impact of various prognostic factors on survival, including but not limited to age, liver function, and tumor burden, in patients receiving HAIC or TACE treatment. Studies focusing on the effectiveness of locoregional therapies for HCC, particularly those comparing HAIC with TACE, were eligible for inclusion.

Exclusion criteria

We excluded studies on non-HCC liver cancers, such as cholangiocarcinoma or gallbladder cancer, unless separate data for HCC were provided. Studies that did not directly compare HAIC and TACE in terms of their therapeutic outcomes in advanced HCC patients were also excluded. Additionally, we excluded research lacking essential statistical information (such as HRs, CIs) or failing to report survival data. Case reports, letters, review articles, conference abstracts, or studies with fewer than 10 participants were not considered. Lastly, we excluded studies focusing on non-interventional treatments, such as systemic chemotherapy alone, or those not involving advanced or unresectable HCC.

Statistical analysis

Survival data were pooled and analyzed using a random-effects model to account for the inherent variability between studies. The primary measure for the analysis was the HR with corresponding 95% CIs. Categorical data were analyzed using HR. The presence of statistical heterogeneity among the included studies was assessed using I² statistics and Cochran’s Q test. A threshold of 25%, 50%, and 75% was used to classify heterogeneity as low, moderate, or high, respectively.

For each meta-analysis, potential publication bias was evaluated using funnel plots, followed by Egger’s test to quantify bias statistically. If significant asymmetry was detected (P<0.05), this would indicate a potential publication bias. Sensitivity analyses were performed to examine the effect of individual studies on the overall results, helping to ensure that no single study disproportionately influenced the pooled estimates. A two-tailed P value of less than 0.05 was considered statistically significant. While the PROSPERO registration included plans to analyze additional outcomes, some were not reported in the final meta-analysis due to limited available data across the included studies. All studies meeting eligibility criteria provided extractable data for the primary endpoints (OS and PFS) and key secondary outcomes (adverse events, subgroup analyses), which form the basis of this report.

Quality assessment of studies

The quality of the included studies was evaluated using the Newcastle-Ottawa Scale (NOS), a tool designed to assess the methodological quality of non-randomized studies. Each study was independently reviewed by two investigators (D.Z. and Z.C.), and assigned a score based on three key domains: the selection of participants, comparability of study groups, and the assessment of outcomes. Studies with a score of six or higher were deemed to meet the minimum quality criteria for inclusion. Any disagreements between reviewers were resolved through discussion or with the help of a third reviewer. Detailed results of the quality assessment are provided in Table S1.

Results

Literature search

Initially, a total of 273 articles were retrieved from electronic databases such as PubMed, Embase, and Web of Science. After eliminating duplicates and screening for relevance, 171 full-text articles were assessed for eligibility. Following a thorough evaluation, 14 studies (25-38) met the inclusion criteria and were included in the qualitative analysis. The detailed characteristics of these included studies, including study design, patient demographics, treatment protocols, and reported outcomes, are presented in Table 1. The process of study selection is illustrated in the PRISMA flowchart (Figure 1).

Figure 1 PRISMA flowchart. CI, confidence interval; HR, hazard ratio; OR, odds ratio; RR, relative risk.

Study characteristics and quality assessment

The meta-analysis included data from 3,356 patients diagnosed with HCC, sourced from studies published between 2018 and 2024. Of the 13 studies that compared the effects of HAIC with TACE on patient survival outcomes, five focused on identifying prognostic factors influencing the treatment response. Additionally, three studies explored which prognostic factors might predict a better response to HAIC compared to chemotherapy. Quality assessment using the NOS revealed that the majority of the studies were of high quality, with nine studies scoring seven or higher (full NOS details are provided in Table S1). The PRISMA diagram (Figure 1) outlines the study selection process, and the characteristics of the studies are presented in Table 1.

HAIC vs. TACE: impact on OS in advanced HCC

13 studies evaluated the comparative impact of HAIC and TACE on OS in advanced HCC (25-37). The pooled analysis of these studies demonstrated that HAIC significantly improved OS, with a HR of 0.51 (95% CI: 0.37–0.62, P<0.001) (Figure 2).

Figure 2 Forest plot comparing OS between HAIC and TACE in advanced HCC. CI, confidence interval; HAIC, hepatic arterial infusion chemotherapy; HCC, hepatocellular carcinoma; HR, hazard ratio; OS, overall survival; TACE, transarterial chemoembolization.

HAIC vs. TACE: impact on PFS in advanced HCC

Seven studies investigated the comparative impact of HAIC and TACE on PFS in advanced HCC (26,28,30,31,33,35,37). The pooled analysis demonstrated that HAIC significantly improved PFS, with a HR of 0.55 (95% CI: 0.48–0.62; P<0.001) (Figure 3).

Figure 3 Forest plot comparing PFS between HAIC and TACE in advanced HCC. CI, confidence interval; HAIC, hepatic arterial infusion chemotherapy; HCC, hepatocellular carcinoma; HR, hazard ratio; PFS, progression-free survival; TACE, transarterial chemoembolization.

Prognostic factors affecting the OS outcomes of HAIC vs. TACE in advanced HCC

Five studies assessed 26 prognostic factors affecting OS between HAIC and TACE in advanced HCC (26,29,33,35,37). These factors included age (≤60 vs. >60 years), gender (male vs. female), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. ≥1), Child-Pugh class (A vs. B), alpha-fetoprotein (AFP) levels (<400 vs. ≥400 ng/mL), tumor size (<10 vs. ≥10 cm), tumor number (<3/5 vs. ≥3/5), hepatitis B virus (HBV) status, vascular invasion, extrahepatic metastasis, lymph node metastasis, and portal vein tumor thrombus (PVTT). In nearly all subgroups, HAIC showed superior survival outcomes compared to TACE, with significant differences in the following groups: age >60 years (HR =0.63, 95% CI: 0.45–0.89), age ≤60 years (HR =0.49, 95% CI: 0.32–0.76), male gender (HR =0.57, 95% CI: 0.42–0.78), ECOG 0 (HR =0.51, 95% CI: 0.30–0.88), ECOG ≥1 (HR =0.54, 95% CI: 0.39–0.74), AFP <400 ng/mL (HR =0.59, 95% CI: 0.43–0.81), tumor size ≥10 cm (HR =0.53, 95% CI: 0.33–0.84), tumor size <10 cm (HR =0.50, 95% CI: 0.39–0.64), tumor number ≥3/5 (HR =0.75, 95% CI: 0.61–0.91), HBV positive (HR =0.50, 95% CI: 0.42–0.61), vascular invasion (HR =0.50, 95% CI: 0.28–0.90), extrahepatic metastasis present (HR =0.55, 95% CI: 0.34–0.89), and PVTT present (HR =0.34, 95% CI: 0.24–0.48). However, some subgroups, such as patients with AFP ≥400 ng/mL, showed less pronounced survival benefits (HR =0.47, 95% CI: 0.30–0.75). These results suggest that HAIC generally offers better survival outcomes across multiple prognostic factors in advanced HCC patients, with statistically significant improvements in several key subgroups. Detailed information is presented in Figure 4.

Figure 4 Forest plot of prognostic factors for OS in HAIC vs. TACE. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HAIC, hepatic arterial infusion chemotherapy; HBV, hepatitis B virus; HR, hazard ratio; OS, overall survival; PVTT, portal vein tumor thrombus; TACE, transarterial chemoembolization.

Prognostic factors affecting the PFS outcomes of HAIC vs. TACE in advanced HCC

Five studies assessed 26 prognostic factors affecting OS between HAIC and TACE in advanced HCC. These factors included age, gender, ECOG performance status, Child-Pugh class, AFP levels, tumor size, tumor number, HBV status, vascular invasion, extrahepatic metastasis, lymph node metastasis, and PVTT. In nearly all subgroups, HAIC showed superior survival outcomes compared to TACE, with significant differences in the following groups: age >60 years (HR =0.67, 95% CI: 0.55–0.80), age ≤60 years (HR =0.45, 95% CI: 0.32–0.64), male (HR =0.60, 95% CI: 0.52–0.68), female (HR =0.60, 95% CI: 0.41–0.88), ECOG 0 (HR =0.49, 95% CI: 0.36–0.65), ECOG ≥1 (HR =0.65, 95% CI: 0.53–0.80), AFP <400 ng/mL (HR =0.59, 95% CI: 0.47–0.75), AFP ≥400 ng/mL (HR =0.48, 95% CI: 0.39–0.60), tumor size ≥10 cm (HR =0.54, 95% CI: 0.45–0.64), tumor size <10 cm (HR =0.62, 95% CI: 0.51–0.75), tumor number ≥3/5 (HR =0.69, 95% CI: 0.57–0.84), tumor number <3/5 (HR =0.49, 95% CI: 0.35–0.70), Child-Pugh A (HR =0.63, 95% CI: 0.51–0.76), HBV positive (HR =0.55, 95% CI: 0.47–0.65), HBV negative (HR =0.61, 95% CI: 0.40–0.94), vascular invasion yes (HR =0.49, 95% CI: 0.27–0.91), vascular invasion no (HR =0.66, 95% CI: 0.52–0.85), extrahepatic metastasis no (HR =0.57, 95% CI: 0.48–0.69), and PVTT present (HR =0.35, 95% CI: 0.22–0.55). PVTT absent (HR =0.52, 95% CI: 0.30–0.91), Barcelona Clinic Liver Cancer (BCLC) Stage C (HR =0.64, 95% CI: 0.52–0.80). These results suggest that HAIC generally offers better survival outcomes across multiple prognostic factors in advanced HCC patients, with statistically significant improvements in several key subgroups. Detailed information is presented in Figure 5.

Figure 5 Forest plot of prognostic factors for PFS in HAIC vs. TACE. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HAIC, hepatic arterial infusion chemotherapy; HBV, hepatitis B virus; HR, hazard ratio; PFS, progression-free survival; PVTT, portal vein tumor thrombus; TACE, transarterial chemoembolization.

Adverse events in HAIC vs. TACE

In the comparison of HAIC and TACE for advanced HCC, HAIC demonstrates a favorable safety profile with lower incidence of severe adverse events, particularly regarding liver function preservation and systemic toxicities. Statistically significant differences were observed in elevated alanine aminotransferase (ALT) levels (HAIC: 2.63–11.3% vs. TACE: 8.33–39.02%; P=0.012). While HAIC showed numerically lower rates of severe neutropenia (0–6% vs. 0.9–8.33%, P=0.38) and gastrointestinal symptoms (≤10.53% vs. ≤19.51%, P=0.21), these differences did not reach statistical significance. As summarized in Table 2, HAIC’s superior hepatic safety profile makes it particularly advantageous for: (I) patients with portal vein invasion where TACE may compromise vascular supply; (II) those with Child-Pugh B cirrhosis who are more susceptible to hepatic decompensation; (III) candidates planned for sequential systemic therapies requiring preserved liver function; and (IV) elderly or frail patients needing better-tolerated treatment options.

Sensitivity analyses

In the sensitivity analyses, a random-effects model was applied, and each study was systematically excluded in turn to evaluate the robustness of the prognostic role of HAIC compared to systemic chemotherapy in advanced HCC. Specifically, sensitivity analyses were conducted for studies related to HAIC vs. TACE: impact on OS in advanced HCC and HAIC vs. TACE: impact on PFS in advanced HCC. The analyses demonstrated consistent results, further confirming the reliability of the findings and indicating that the conclusions are robust. Additionally, recalculations performed after excluding studies with smaller sample sizes or lower NOS scores produced consistent results, further supporting the reliability of the findings. These analyses suggest that the conclusions drawn from this meta-analysis are robust and not unduly influenced by any single dataset. Sensitivity analyses were conducted using StataMP 17 software (StataCorp. 2022. Stata Statistical Software: Release 17), and the results confirmed the robustness of the conclusions. Comprehensive details of the sensitivity analyses for each type of adjuvant therapy are provided in the supplementary materials. The results of the above analysis are shown in Figures S1,S2.

Publication bias

In studies comparing HAIC and TACE for OS in advanced HCC, the symmetrical distribution of the funnel plots indicated no significant risk of publication bias. Additionally, Egger’s regression test confirmed this finding, demonstrating an insignificant presence of publication bias with a P value of 0.397. The results of the above analysis are shown in Figures S3,S4.

In studies comparing HAIC and TACE for PFS in advanced HCC, the symmetrical distribution of the funnel plots indicated no significant risk of publication bias. Furthermore, Egger’s regression test confirmed this finding, demonstrating an insignificant presence of publication bias with a P value of 0.539. The results of the above analysis are shown in Figures S5,S6.

As for prognostic factors influencing survival in advanced HCC patients undergoing HAIC therapy and prognostic factors influencing the differences between HAIC and TACE in advanced HCC patients, no assessment of publication bias was performed due to the limited number of original studies focusing on individual factors.

Discussion

In this meta-analysis, we compared the therapeutic efficacy of HAIC and TACE in patients with advanced HCC. Our results show that HAIC significantly improves both OS and PFS compared to TACE. Specifically, HAIC was associated with a reduced risk of death (HR =0.51, 95% CI: 0.37–0.62) and disease progression (HR =0.55, 95% CI: 0.36–0.67). Additionally, HAIC demonstrated superior survival outcomes across multiple prognostic factors, including age, tumor size, vascular invasion, and HBV status. In nearly all subgroups, HAIC provided better survival benefits than TACE, particularly for patients with larger tumors, higher AFP levels, or vascular invasion. These findings suggest that HAIC may offer a more effective treatment option for advanced HCC, especially in patients with poor liver function or those who are refractory to other therapies. These findings suggest that HAIC should be considered a preferred treatment option for patients with advanced HCC, particularly those ineligible for liver transplantation or resection. By providing higher drug concentrations at the tumor site while sparing healthy liver tissue, HAIC enhances therapeutic efficacy and minimizes systemic toxicity, making it an effective and safer alternative to TACE. The superior safety profile of HAIC over TACE, particularly in terms of liver function preservation (ALT elevation: 2.63–11.3% vs. 8.33–39.02%) and systemic toxicities (neutropenia: 0–6% vs. 0.9–8.33%), carries direct implications for clinical practice. For patients with compromised liver function, HAIC may represent a safer alternative, as its localized delivery minimizes further hepatic insult while maintaining antitumor efficacy. However, clinicians must consider that even low-grade neutropenia or gastrointestinal toxicity could be consequential in frail patients with portal hypertension or thrombocytopenia. These findings support prioritizing HAIC in cases where liver function preservation is paramount, such as in bridge-to-transplant scenarios or for patients with marginal reserve. Nevertheless, the optimal approach should integrate these toxicity data with tumor characteristics (e.g., burden, vascular invasion) and institutional expertise. Future studies stratifying toxicity by liver function subclass will help refine these pragmatic decisions.

Mechanistically, the superiority of HAIC over TACE can be attributed to its more targeted drug delivery system (39). HAIC exploits the liver’s dual blood supply by delivering high-dose chemotherapeutic agents directly into the hepatic artery, which predominantly supplies blood to liver tumors. In contrast, the portal vein primarily supports normal liver parenchyma (40). This allows HAIC to achieve higher drug concentrations at the tumor site while sparing healthy liver tissue, thereby enhancing efficacy and minimizing systemic toxicity (11). Unlike TACE, which relies on tumor ischemia through embolization, HAIC ensures uniform and sustained drug exposure even in infiltrative or poorly vascularized tumors, addressing one of the key limitations of TACE. HAIC-based conversion therapy had acceptable toxic effects and could effectively stabilize intrahepatic lesions in advanced HCC, improve the survival benefit of patients, and provide some patients with the opportunity for conversion surgery to further improve prognosis (41). Furthermore, the reduced systemic exposure to chemotherapy in HAIC lowers the incidence of treatment-related adverse events, including hematological and gastrointestinal toxicities, as evidenced in this analysis (42). The higher concentration of chemotherapy in HAIC compared to TACE is critical, as TACE relies on embolization-induced ischemia to deliver the treatment, which can be less effective in tumors with poorer vascularization (30,43).

Emerging evidence suggests that combining HAIC with other therapeutic strategies could further improve its efficacy (44). For instance, recent studies combining HAIC with immune checkpoint inhibitors, such as PD-1/PD-L1 inhibitors, and targeted therapies like lenvatinib have shown promising results in advanced HCC (45). These combinations are believed to leverage synergistic mechanisms, wherein HAIC-induced tumor apoptosis and immunogenic cell death enhance the anti-tumor immune response, potentiating the effects of immunotherapy (46,47). Moreover, lenvatinib, a multi-kinase inhibitor, improves the tumor microenvironment by reducing vascular endothelial growth factor receptor (VEGFR)-mediated angiogenesis and suppressing regulatory T-cell infiltration (48). These mechanisms weaken tumor immunosuppression, further enhancing the efficacy of HAIC-based combination regimens. However, these findings remain preliminary and warrant further validation through well-designed randomized controlled trials (49). The selection between HAIC and emerging systemic therapies requires careful consideration of several key factors. First, tumor biological characteristics play a decisive role—HAIC demonstrates particular efficacy in HCC with portal vein invasion, where its high-concentration regional delivery overcomes the vascular access limitations that can compromise systemic drug distribution. Second, disease distribution patterns matter significantly; HAIC shows superior outcomes in liver-dominant disease compared to systemic therapies, while the latter may be preferable for disseminated presentations. Importantly, emerging data suggest these approaches may be complementary rather than competitive, with HAIC potentially serving as an effective debulking strategy to enhance subsequent systemic therapy efficacy. However, optimal sequencing protocols and patient selection criteria for such combined approaches require further prospective validation.

In addition to HAIC’s potential for efficacy enhancement through combination therapies, there is a growing recognition of its ability to improve patient outcomes in specific subsets, particularly in those with large tumor volumes (50). In many patients, liver resection is not feasible due to insufficient future liver remnant (FLR) following surgery, and thus, transarterial therapies like TACE and HAIC are often used as alternative treatment strategies (51). Studies have shown that HAIC can provide better control of tumor growth and enhance FLR, making it a promising option for patients awaiting liver transplantation or conversion hepatectomy (52). In our meta-analysis, HAIC demonstrated longer PFS and better objective response rates (ORR) compared to TACE, underscoring its potential as a treatment of choice for large HCCs, particularly when resection is not immediately possible. The preservation of hepatic functional reserve emerges as a critical determinant of outcomes in advanced HCC management. As highlighted by Burrel et al., the cumulative impact of repeated interventions on liver function significantly influences both therapeutic efficacy and safety (53). Our findings demonstrate HAIC’s dual advantage: superior survival outcomes (HR= 0.48 for OS) coupled with significantly reduced hepatotoxicity (2.63–11.3% vs. 8.33–39.02% ALT elevation) compared to TACE. This pharmacological profile suggests HAIC may be particularly advantageous for patients requiring sequential treatments, as its targeted delivery mechanism preferentially spares functional liver parenchyma. The clinical implications are substantial—by minimizing cumulative liver injury, HAIC may better preserve hepatic reserve, maintaining future treatment options for recurrent or progressive disease. This benefit likely stems from HAIC’s ability to achieve tumor-selective drug delivery without inducing the ischemic parenchymal injury characteristic of TACE, a distinction that becomes increasingly important in the context of modern HCC treatment paradigms where patients often undergo multiple lines of therapy.

The safety profile of HAIC compared to TACE also warrants discussion. While both treatments are associated with risks such as liver dysfunction and biliary toxicity, HAIC appears to have a lower incidence of severe adverse events (25,54). This may be due to the reduced systemic drug exposure achieved by HAIC’s locoregional delivery (55). However, specific complications, such as catheter-related infections and hepatic artery thrombosis, remain concerns and necessitate close monitoring. Future studies should focus on evaluating the long-term safety and quality-of-life outcomes associated with HAIC to better inform clinical decision-making. Recent therapeutic advances have increasingly focused on combining locoregional and systemic therapies for HCC. While TACE has shown promising synergies with molecular targeted agents like lenvatinib and sorafenib, as well as immunotherapy combinations such as atezolizumab-bevacizumab, our analysis suggests HAIC may offer distinct advantages in these multimodal approaches. Mechanistically, HAIC’s continuous drug infusion appears better synchronized with the pharmacokinetics of targeted therapies compared to TACE’s bolus effect. Furthermore, by avoiding the hypoxic microenvironment created by TACE’s embolization, HAIC may preserve tumor immunogenicity more effectively—a theoretical advantage that could translate to enhanced immune checkpoint inhibitor activity. Notably, HAIC’s consistently demonstrated lower hepatotoxicity profile across studies makes it particularly appealing for combination strategies, where preserving liver function is paramount. These characteristics position HAIC as a versatile partner for systemic therapies, especially in clinical scenarios where TACE’s ischemic effects might be poorly tolerated. However, definitive comparative data between HAIC- and TACE-based combination approaches remain limited, highlighting an important area for future investigation. Our analysis demonstrated significantly lower rates of post-procedural hypertransaminasemia in HAIC-treated patients (2.63–11.3%) versus TACE recipients (8.33–39.02%), highlighting HAIC’s superior hepatic safety profile. This difference likely reflects distinct mechanisms of action: TACE induces ischemia-reperfusion injury that damages peritumoral hepatocytes, while HAIC’s selective arterial infusion better preserves normal parenchyma. Interestingly, a research reported that post-TACE transaminase elevations [+52% ALT/+46% aspartate aminotransferase (AST) from baseline] positively correlated with radiologic response [complete response: odds ratio (OR) =4.2, P=0.02; objective response: OR=3.8, P=0.03] (56), suggesting that TACE-induced hepatotoxicity may paradoxically indicate therapeutic efficacy through tumor necrosis and peritumoral inflammation. Our findings present an important counterpoint: HAIC achieved better survival outcomes (HR= 0.51 for OS) despite causing less transaminase elevation. This challenges the conventional association between hepatotoxicity and treatment efficacy, implying HAIC’s benefits may derive from different biological mechanisms. While our study lacked detailed radiologic response data to fully explore this relationship, the results suggest HAIC can provide superior anti-tumor effects without relying on hepatotoxic processes. This paradigm shift warrants further investigation into alternative efficacy biomarkers for HAIC, such as drug concentration gradients or tumor perfusion changes. Future studies should systematically compare these mechanisms to better understand how HAIC achieves its clinical advantages while minimizing liver injury.

Clinical application of this study highlights the potential of HAIC to improve outcomes for specific subsets of advanced HCC patients. For instance, patients with favorable prognostic indicators, such as ECOG performance status 0–1, localized disease, and low AFP levels, derived the greatest survival benefits from HAIC. Conversely, patients with extensive disease or poor liver function may require alternative or combination therapies. Subgroup analyses provide valuable insights into tailoring treatment strategies to individual patient profiles, thereby improving clinical outcomes while minimizing unnecessary interventions. HAIC can optimize tumor control, enhance FLR, and serve as a bridge to liver transplantation or conversion therapy. Additionally, combining HAIC with systemic therapies, such as immune checkpoint inhibitors and targeted therapies like lenvatinib, may further improve treatment efficacy through synergistic mechanisms. The enhanced efficacy of HAIC in HBV-positive HCC patients may be attributed to synergistic interactions between antiviral immunity and chemotherapy. Chronic HBV infection creates a unique tumor microenvironment characterized by viral antigen persistence and chronic inflammation, which may increase susceptibility to HAIC’s sustained cytotoxic drug exposure. The gradual release of tumor antigens during HAIC treatment could potentially stimulate residual host immune responses against both viral and tumor antigens. While these observations are biologically plausible, we acknowledge the need for prospective studies to validate these mechanisms and establish predictive biomarkers for patient selection. The findings underscore the importance of personalized treatment strategies based on patient profiles and tumor characteristics to maximize therapeutic benefits, reduce adverse effects, and ultimately improve survival and quality of life. Future studies should focus on standardizing HAIC protocols and validating these results in real-world clinical settings. Despite its promising potential, HAIC adoption in clinical practice remains limited due to technical challenges, such as catheter placement and the need for specialized expertise. Additionally, this meta-analysis highlighted the variability in HAIC protocols across studies, including differences in chemotherapeutic agents and administration schedules, which may influence treatment outcomes and introduce heterogeneity. These variations underscore the need for standardized HAIC protocols to ensure consistency and optimize therapeutic efficacy.

The next therapeutic frontier lies in rationally combining HAIC with immune checkpoint inhibitors, where our analysis reveals three synergistic mechanisms: chemo-immunomodulation through HAIC-induced tumor antigen release, vascular normalization via sustained cytotoxic exposure reducing VEGF-mediated immunosuppression, and the liver-sparing effect of HAIC’s lower hepatotoxicity compared to TACE that preserves organ function for subsequent therapies. However, realizing this potential requires addressing four critical challenges: technical standardization as current variability in drug regimens demands consensus guidelines; biomarker development to identify predictive patterns in AFP response kinetics and ctDNA clearance; improving global accessibility through simplified protocols for resource-limited settings; and demonstrating cost-effectiveness through rigorous quality-adjusted life year analyses. These hurdles underscore the need for multidisciplinary collaboration to optimize HAIC’s role in the evolving HCC treatment landscape.

Despite the promising findings, this meta-analysis has several limitations. This meta-analysis has several important limitations. First, the predominance of retrospective studies introduces inherent risks of selection bias and unmeasured confounding factors that may affect outcome validity. Second, the geographic concentration of studies in East Asia may limit generalizability to other populations with different HCC etiologies and healthcare systems. Third, heterogeneity in HAIC protocols regarding chemotherapeutic agents and infusion schedules complicates direct comparisons across studies. Fourth, the lack of long-term follow-up data in most studies prevents assessment of late recurrences or delayed treatment toxicities. Finally, while sensitivity analyses demonstrated robustness of findings, the relatively small number of included studies warrants cautious interpretation of results. Future studies should aim to include larger sample sizes, multicenter collaborations, and long-term follow-up data to better address these limitations and provide more definitive evidence.

Conclusions

In conclusion, this meta-analysis demonstrates that HAIC offers superior OS and PFS compared to TACE in advanced HCC. HAIC shows particular benefits in patients with poor prognostic factors, such as larger tumors or vascular invasion, and provides a favorable safety profile. These findings highlight HAIC as a promising treatment option and emphasize the importance of tailored therapeutic strategies for advanced HCC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-115/rc

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-115/prf

Funding: This work was supported by the Sichuan Province Science and Technology Department Social Development Key Projects (No. 2023YFS0302), the Sichuan Science and Technology Program (Nos. 2024NSFSC0642 and 2024NSFSC0755), the Sichuan Provincial Department of Science and Technology Central-Guided Local Science and Technology Development Program (No. 2023ZYD0074), and the Sichuan University Innovation Research Project (No. 2023SCUH0041).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-115/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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