https://orcid.org/0000-0002-9792-7747
Figures
Abstract
Introduction and objectives
Despite both hepatic arterial infusion chemotherapy (HAIC) and sorafenib being efficacious for hepatocellular carcinoma (HCC), choosing between them for Barcelona Clinic Liver Cancer (BCLC) stages B/C patients remains controversial. This meta-analysis aims to compare their therapeutic outcomes and prognoses in such patients.
Methods
Pubmed, EMBASE, and Web of Science databases were searched. The primary outcome of this meta-analysis is Overall Survival (OS), while secondary outcomes include Progression-Free Survival (PFS), tumor response rate, and the incidence of adverse events. The analysis has included a total of 18 studies, comprising 3008 patients in aggregate.
Results
The analysis revealed a combined Hazard Ratio (HR) for OS of 0.57 (95% CI 0.38–0.86) and for PFS of 0.46 (95% CI 0.38–0.57). Subgroup analysis by different HAIC regimens: FOLFOX-based HAIC regimens 0.28 (95% CI: 0.16–0.50), FP regimen 0.68 (95% CI: 0.25–1.87), New-FP regimen 0.60 (95% CI: 0.47–0.77), cisplatin-based HAIC 0.63 (95% CI: 0.47–0.85). The pooled ORs were: Complete Response (CR) 3.88 (95% CI 1.56–9.65), Partial Response (PR)4.72(95% CI 2.44–9.13), Stable Disease (SD) 0.83 (95% CI 0.45–1.53), Progressive Disease (PD) 0.35 (95% CI0.25–0.48, Objective Response Rate (ORR) 5.32 (95% CI 2.54–11.13), Disease Control Rate (DCR) 2.03 (95% CI 1.05–3.92). For adverse events (AEs), the overall incidence Odds Ratios (OR) was 0.53 (95% CI 0.06–4.82) and for grade 3−4 events, 0.49 (95% CI 0.28–0.85).
Citation: Chen Z, Fan Y, Luo Y, Ye X, You Z (2026) Hepatic arterial infusion chemotherapy (HAlC) versus sorafenib for hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) B/C: A systematic review and meta-analysis. PLoS One 21(2): e0342495. https://doi.org/10.1371/journal.pone.0342495
Editor: Do Young Kim, Yonsei University College of Medicine, KOREA, REPUBLIC OF
Received: July 13, 2024; Accepted: January 24, 2026; Published: February 18, 2026
Copyright: © 2026 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: HCC, Hepatocellular carcinoma; OS, Overall survival; PFS, Progression-free survival; HAIC, Hepatic artery infusion chemotherapy; BCLC, Barcelona clinic liver cancer; CR, Complete response; PR, Partial response; SD, Stable disease; PD, Progressive disease; ORR, Objective response rate; DCR, Disease control rate; AEs, Adverse events; HR, Hazard Ratio; OR, Odds Ratio; mRECIST, the modified Response Evaluation Criteria in Solid Tumors; RECIST, the Response Evaluation Criteria in Solid Tumors
1. Introduction
Liver cancer, predominantly hepatocellular carcinoma(HCC) accounting for 75–85% of cases, ranked as the world’s sixth most diagnosed cancer and fourth top cancer death cause in 2018, with 841,000 new cases and 782,000 deaths [1–4]. There are many staging criteria for liver cancer, such as clinical staging, TNM staging, and Barcelona staging, Barcelona clinical liver cancer (BCLC) staging is a very commonly used method in clinical practice. Advanced BCLC stage B/C hepatocellular carcinoma, featuring larger tumors, vascular invasion, and metastases, is typically incurable with significantly shorter patient survival compared to early-stage BCLC A [5]. Sorafenib is a drug that inhibits multiple kinases, including those in the RAF/MEK/ERK signaling pathway.[6,7] Its efficacy in improving overall survival (OS) and prolonging time to disease progression has been proven in two Phase III randomized controlled trials for patients with advanced HCC [8,9]. Moreover, Sorafenib is still recommended as first-line systemic therapy for HCC with advanced liver cancer [10]. It can be seen that sorafenib is one of the important drugs in the treatment of advanced hepatocellular carcinoma. However, due to its poor solubility, rapid metabolism, and low bioavailability, the clinical application of sorafenib has been significantly limited [11].
In addition to sorafenib, Hepatic Artery Infusion Chemotherapy (HAIC) represents another treatment option for advanced-stage liver cancer [12]. HAIC employs catheter techniques to administer chemotherapeutic agents directly and continuously to the tumor site. As per earlier reports, HAIC stands out from systemic chemotherapy due to its heightened local control efficacy, accompanied by reduced systemic toxicity [13]. Recently, there has been a growing body of evidence supporting the efficacy of HAIC in treating advanced hepatocellular carcinoma [14–16], and HAIC has been adopted as an alternative therapy to sorafenib in Japan and several other Asian nations for the treatment of advanced hepatocellular carcinoma [17–19]. The benefits of HAIC as an alternative option for advanced hepatocellular carcinoma patients remain controversial. A previous systematic review and meta-analyse has compared the efficacy of sorafenib and HAIC in treating advanced hepatocellular carcinoma [20], whereas a direct comparison of their efficacy in BCLC stage B/C hepatocellular carcinoma has not yet been undertaken.
Consequently, the main objective of this systematic review and meta-analysis is to compare the efficacy and prognosis of HAIC versus sorafenib in BCLC stage B/C hepatocellular carcinoma patients, focusing on overall survival, tumor response, and adverse events, thereby providing practical guidance for clinical practice.
2. Materials and methods
2.1. Study protocol
This systematic review and meta-analysis were carried out following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) [21]. This study did not require formal Institutional Review Board approval or patient informed consent, as it was a secondary analysis involving publicly available datasets. This meta-analysis was registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) with the registration number CRD42024538180.
2.2. Literature search
Literature searches were conducted in the EMBASE, PubMed, and Web of Science for studies published up until May 2024. Additional studies were identified through manual checks of references from included publications. The search strategy is detailed in S1 File.
2.3. Exclusion criteria and data extraction
The systematic review process was initiated by two independent reviewers, CZQ and LUT, who conducted the initial search, eliminated duplicate entries, and assessed titles and abstracts for relevance. They decided on the inclusion or exclusion of records based on this assessment. For the conclusive phase of screening, full texts were obtained for articles whose relevance couldn’t be definitively determined from their abstracts alone. Any disagreements regarding article selection were resolved through dialogue and consensus between the two reviewers. In instances where consensus was unattainable, a third reviewer, FYT, acted as an arbitrator to settle the discrepancies, ensuring a consistent and fair selection process.
The following criteria were used to include studies in the meta-analysis:(i) Patients confirmed to have HCC in BCLC B/C in the study population; (ii) Assessing the effectiveness of HAIC versus sorafenib; (iii) The study population consisting solely of humans; (iv) Studies that can provide data on Overall survival, Progression-Free-Survival (PFS), tumor response rates, and adverse reaction incidence. No limitations were imposed on the sample size or the duration of follow-up. when BCLC staging is not explicitly reported but can be reasonably inferred from clinical features (e.g., presence of portal vein tumor thrombosis or macrovascular invasion), a clinically pragmatic classification will be applied.
Tumor responses (including Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), Overall Response Rate (ORR), and Disease Control Rate (DCR)) and Progression-Free-Survival were evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [22]. Overall Survival is the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. It is often used as a measure of the effectiveness of a particular treatment. Progression-Free Survival is defined as the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. It is another important endpoint in clinical trials, indicating how long patients remain free from disease progression. Complete Response refers to the disappearance of all target lesions.. Partial Response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease means that the tumor neither grows nor shrinks significantly. Progressive Disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. Overall Response Rate was defined as the sum of Complete Response and Partial Response. Meanwhile, Disease Control Rate was defined as the cumulative incidence of Complete Response, Partial Response, and Stable Disease. An Adverse Event (AE) refers to any undesirable experience associated with the use of a medical product, such as a drug or medical device, in patients. Adverse events (AEs) can range from mild symptoms to severe reactions and may occur during clinical trials or post-marketing surveillance.Adverse Events were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE) established by the National Cancer Institute [23–25].
The exclusion criteria of this meta-analysis were as follows: (i) Patients undergoing therapies for HCC that differ from both Sorafenib and HAIC; (ii) Patients receiving combined therapy of sorafenib and HAIC; (iii) Lacking a comparator group; (iv) Editorials, letters, abstracts, reviews, and case reports. (v) Missing or Unextractable Outcome Data.
2.4. Data extraction
Two investigators, named CZQ and LYT, separately gathered information from selected full-text articles using a standardized data extraction form. Any discrepancies in the data collected were resolved through mutual discussion between the reviewers. From each study included, the following details were recorded: first author’s last name, year of publication, country, study design, sample size, number of patients, demographic data (gender and age), previous treatment, etiology, BCLC staging, Child-Pugh class, Eastern Cooperative Oncology Group (ECOG) performance status, alpha-fetoprotein (AFP) levels, transaminase levels, bilirubin levels, Des-Gamma-Carboxy Prothrombin levels, platelet count, macroscopic vascular invasion (MVI) status, extrahepatic spread, lesion size, number of focal lesions, and clinical outcomes(tumor response, adverse events, Overall survival and Progression-free survival).
2.5. Study quality assessment
The quality and risk of bias in the randomized controlled trials (RCTs) were assessed using Cochrane Bias Risk Assessment Tool. The quality of observational studies was evaluated based on the modified Newcastle-Ottawa Scale (NOS), which encompasses three criteria: participant selection, comparability of study groups, and assessment of outcomes. Studies were scored on a scale of 0–9 to categorize their quality. Studies receiving a score of 6 or higher were deemed to be of high quality. The results of the quality assessment are shown in S2 File.
2.6. Statistical analysis
The statistical analyses were carried out using R version 4.3.2 software. For analyzing tumor response and Adverse events, pooled odds ratios (ORs) along with 95% confidence intervals (CIs) were computed. Meanwhile, for the evaluation of Overall survival and Progression-free survival, pooled hazard ratios (HRs) accompanied by 95% CIs were determined.This meta-analysis primarily focuses on the combined analysis of outcome measures. If the relevant outcome data are missing, the studies will not be included in the analysis.
2.7. Heterogeneity exploration
The statistical heterogeneity among the combined estimates was evaluated using I² statistics, with an I² value of 25% indicating low heterogeneity, 50% suggesting moderate heterogeneity, and 75% signifying high heterogeneity. All analyses were conducted using a random effects model, without depending on heterogeneity levels, because research indicates it provides more stable outcome estimates compared to fixed effect models [26].
2.8. Publication bias
Publication bias was evaluated qualitatively by funnel plot and quantitatively by Begg ‘s and Egger’ s tests (S3 File). P < 0.05 was considered statistically significant.
2.9. Sensitivity analysis
In the sensitivity analysis, we sequentially omitted one study at a time to evaluate the influence of each individual study on the aggregate outcome. The outcomes characterized by minimal heterogeneity between studies were deemed as the robust findings of our study. The results of the sensitivity analysis are shown in S4 File.
3. Results
3.1. Search results and study selection
Through database searching, 1087 relevant studies were identified, out of which 198 were found to be duplicates. After screening titles and abstracts, a total of 836 references were excluded. Following this, an additional 37 articles were eliminated during the full-text review stage. Upon scrutinizing the reference sections of all obtained articles, an extra study [27] was discovered that met the predetermined inclusion criteria. Finally, 18 studies [17,27–43] satisfied the inclusion and exclusion criteria and were deemed suitable for both qualitative and quantitative analyses, leading to their inclusion in the meta-analysis. The entire screening process is shown in Fig 1.
3.2. Study characteristics
The 18 selected studies were published within the most recent eight-year period, spanning from 2012 to 2022. Among the included studies, one was conducted in Egypt [35], five in Korea [17,27,39,41,43], eight in Japan [29,30,33,34,36,37,40,42], and four in China [28,31,32,38]. The 18 studies collectively encompassed 3008 patients, with 1520 patients (49.0%) having undergone HAIC, while 1568 patients (51.0%) had been administered sorafenib. According to the Newcastle-Ottawa Scale, the quality of the included literature ranged from 7 to 9 points. The quality of the studies incorporated was generally of a high quality. The major characteristics of the studies and the results of their quality assessment are presented in Table 1.
3.3. Results of the meta-analysis
3.3.1. Overall survival and progression-free survival.
Among the 18 included studies, 15 studies [27–34,36,38–43] reported Hazard Ratio for Overall survival. Through a meta-analysis employing a random-effects model, the combined Hazard Ratio was calculated to be 0.57 (95% CI = 0.38–0.86, P < 0.05). In addition, 4 studies [28,31,32,38] included studies reported Hazard Ratio for Progression-free survival. Through a random-effects model, the combined Hazard Ratio was calculated to be 0.46 (95% CI = 0.38–0.57, P < 0.05). The forest plots for Progression-free survival and Overall survival are depicted in Fig 2.
a Overall survival, b Progression-free survival.
3.3.2. Subgroup analysis for OS by treatment regimen.
Among the 18 included studies, four studies exclusively enrolled patients receiving FOLFOX-based HAIC regimens. A meta-analysis using a random-effects model yielded a pooled hazard ratio of 0.28 (95% CI: 0.16–0.50; P < 0.05). Four studies exclusively used cisplatin plus 5-FU-based HAIC(FP regimen), with a pooled HR of 0.68 (95% CI: 0.25–1.87; P > 0.05) from the random-effects meta-analysis. Two studies exclusively employed fine-powder cisplatin-based HAIC (New-FP regimen), resulting in a pooled HR of 0.60 (95% CI: 0.47–0.77; P < 0.05). Additionally, two studies exclusively utilized cisplatin-based HAIC, showing a pooled HR of 0.63 (95% CI: 0.47–0.85; P < 0.05). Forest plots for these subgroup analyses by treatment regimen are presented in Fig 3.
a FOLFOX-based HAIC regimens, b FP regimen, c New-FP regimen, d cisplatin-based HAIC.
3.3.3. Tumor response rate.
Twelve studies [17,27,28,31,32,34,35,38–41,43] compared the tumor response rates between HAIC and sorafenib. A random-effects model was employed to calculate the pooled effect sizes. The combined Odds Ratio for Complete response was 3.88 (95% CI = 1.56–9.65, P < 0.05). For Partial response, the combined Odds Ratio was 4.72(95% CI = 2.44–9.13, P < 0.05). Stable disease showed a combined Odds Ratio of 0.83 (95% CI = 0.45–1.53, P > 0.05). Progressive disease had a combined Odds Ratio of 0.35 (95% CI = 0.25–0.48, P < 0.05). The combined Odds Ratio for Objective response rate was 5.32 (95% CI = 2.54–11.13, P < 0.05), while the Disease control rate demonstrated a combined Odds Ratio of 2.03 (95% CI = 1.05–3.92, P < 0.05). The Forest plots for tumor response rate are showed in Fig 4 and Fig 5.
a Complete response, b Partial response, c Stable disease, d Progressive disease.
a Objective response rate, b Disease control rate.
3.3.4. Adverse events.
This meta-analysis compared the incidence rates of adverse events, including both overall occurrences and those graded as 3−4, between two therapeutic approaches, and summarized the reported adverse events. Among the studies included, seven studies [28,31–33,38,39] provided data on the total number of patients who experienced any adverse event, while five studies [31,32,37,38,43] specifically reported figures for patients encountering grade 3−4 adverse events. Utilizing a random-effects model, the combined Odds Ratio for the overall incidence of adverse events was estimated at 0.53 (95% CI = 0.06–4.82, P > 0.05). Conversely, the pooled Odds Ratio for the incidence of grade 3−4 adverse events was 0.49 (95% CI = 0.28–0.85, P < 0.05). The Forest plots are showed in Fig 6. In Table 2, we provide a summary of detailed studies on treatment-related adverse events, including complications involving the hematologic system, dermatologic system, digestive system, hepatic and renal function, as well as systemic symptoms. Adverse events associated with HAIC are predominantly hematologic in nature; five studies [27,31,34,39,41] reported higher incidences of neutropenia, anemia, and thrombocytopenia in the HAIC group compared to the Sorafenib group. In contrast, Sorafenib-related adverse events are primarily dermatologic, with five studies [27,31,32,38,39] demonstrating a higher incidence of hand-foot syndrome, alopecia, and rash in the Sorafenib group relative to the HAIC group.
a Adverse events, b 3-4 level Adverse events.
3.4. Sensitivity analysis and publication bias
We conducted a sensitivity analysis on the pooled Overall survival values. The sensitivity analysis demonstrated that the outcomes for every endpoint remained consistent and unaffected by the removal of any single study, confirming their stability. The results of sensitivity analysis are depicted in S4 File. Publication bias analysis was confined solely to the pooled Overall survival values in this article, as the number of studies included in other evaluation groups was less than 10. In the meta-analyses of Overall survival, no substantial evidence of publication bias was detected, as inferred from the results of the formal statistical tests applied (for Overall survival: Egger’s test, P-value = 0.8828; Begg’s test, P-value = 0.7662). The funnel plot of the primary outcome displayed symmetry, implying a low likelihood or absence of publication bias (S3 File).
4. Discussion
This study constitutes a systematic review and meta-analysis, aimed at further evaluating the efficacy and safety of sorafenib versus HAIC in the treatment of BCLC B/C stage HCC. Our findings indicate that, for patients with BCLC B/C stage HCC, HAIC demonstrates more favorable outcomes compared to sorafenib in terms of Overall survival, Progression-free survival, Complete response, Partial response, Progressive disease, Objective response rate, and Adverse events. A previous meta-analysis [20] had already compared the efficacy and prognosis of sorafenib versus HAIC in advanced HCC. Given that the BCLC staging system is commonly employed in clinical practice and there remains controversy surrounding the treatment of BCLC B/C stage HCC, our meta-analysis specifically focuses on this patient subgroup. Additionally, this study also conducted subgroup analyses according to different HAIC regimens and evaluated tumor response, including complete response, partial response, stable disease, and progressive disease. Furthermore, the incidence of adverse events, as well as grade 3–4 adverse events, was compared to inform future clinical practice.
The most significant discovery in this meta-analysis’s comparison of therapeutic effects is that BCLC B/C stage patients receiving HAIC demonstrated superior Overall survival relative to those treated with sorafenib. In addition to this, the HAIC group had better Progression-free survival compared to the sorafenib group. In terms of tumor response rates, HAIC demonstrated significantly superior efficacy compared to sorafenib, with higher rates of complete response and partial response, a lower rate of disease progression, and significantly improved objective response rate and disease control rate. However, no statistically significant disparities were evident between HAIC and sorafenib in terms of Stable disease. The aforementioned findings are based on a random-effects model. Conversely, when adopting a fixed-effect model, the pooled results for Stable disease alters to 0.77 (95% CI = 0.62–0.96, P ＜ 0.05) (S5 File). This discrepancy underscores the probable impact of substantial heterogeneity among the studies, necessitating future meta-analyses to incorporate additional research to validate HAIC’s superiority in terms of Stable disease and Disease control rate. We contend that HAIC may confer certain advantages over sorafenib in terms of survival, tumor progression, and tumor response, grounded in several rationales. Firstly, the liver is endowed with dual blood supplies: the portal vein and the hepatic artery; HCC predominantly depends on the branches of the hepatic artery for its blood supply [44,45]. Unlike systemic drug administration, HAIC facilitates the direct, high-concentration delivery of chemotherapeutic agents to the tumor site, thereby enabling a heightened local concentration of anti-cancer drugs, reducing systemic dissemination, and thereby augmenting the potency of these medications. Secondly, given that liver function in HCC patients tends to be impaired, HAIC is tolerable for those with poorer liver function due to its lower toxicity profile, effectively managing tumor progression through both anti-angiogenic and anti-proliferative effects. Lastly, the genetic heterogeneity among HCC cells stemming from diverse etiologies significantly contributes to inherent resistance to sorafenib, which is a pivotal factor undermining the therapeutic effectiveness of sorafenib in some patients [46–48]. In recent years, a randomised phase 3 non-inferiority trial [10] has uncovered that lenvatinib exhibits remarkable efficacy in treating advanced hepatocellular carcinoma, suggesting it as a potential alternative to sorafenib as a systemic therapy option.
Furthermore, given the heterogeneity in HAIC regimens across the included studies—including FOLFOX, FP, New-FP, and cisplatin monotherapy—we performed a prespecified subgroup analysis by chemotherapy backbone. Compared with sorafenib, FOLFOX-based HAIC significantly improved OS (HR = 0.28; 95% CI: 0.16–0.50; P < 0.05). New-FP–based HAIC (HR = 0.60; 95% CI: 0.47–0.77; P < 0.05) and cisplatin-based HAIC (HR = 0.63; 95% CI: 0.47–0.85; P < 0.05) also showed significant OS benefits. The FP regimen demonstrated a favorable trend (HR = 0.68; 95% CI: 0.25–1.87), though not statistically significant, suggesting a need for further validation. These results highlight the importance of regimen selection in HAIC and support FOLFOX as the most evidence-backed HAIC approach for first-line treatment of advanced HCC versus sorafenib. The efficacy of FOLFOX in intermediate-to-advanced or unresectable HCC is largely attributable to its synergy with HAIC. As HCC— including tumors with portal vein tumor thrombus—is primarily hepatic artery–fed, HAIC delivers sustained, high local concentrations of oxaliplatin plus 5-FU/leucovorin, enhancing intrahepatic tumor control while minimizing systemic toxicity and enabling patients with compromised liver function to better tolerate full-course therapy [49]. This “intensified local control” is supported by high-level evidence: the phase III FOHAIC-1 trial showed that HAIC-FOLFOX significantly improved survival and tumor response versus sorafenib, particularly in patients with macrovascular invasion, underscoring its clinical value in advanced HCC driven by high intrahepatic burden and vascular involvement [50].
Sorafenib and HAIC are both first-line options for intermediate- to advanced-stage HCC. Sorafenib has been the standard systemic therapy since 2007 [51], while HAIC has been widely used in Japan since the early 2000s and remains strongly recommended in Japanese and Chinese guidelines for advanced HCC [52,53]. Our study shows that HAIC provides better outcomes than sorafenib, supporting its role as a valid first-line treatment. Recent evidence further suggests that combining HAIC with immunotherapy—typically FOLFOX-HAIC plus PD-1/PD-L1 inhibitors, often with a TKI (triplet regimen)—yields promising efficacy in unresectable or advanced HCC. A phase II trial of lenvatinib + toripalimab + HAIC reported high ORR, prolonged survival, and manageable toxicity [54]. Real-world multicenter studies also confirm that HAIC-based combo therapy significantly improves ORR, PFS, and OS in high-risk patients (e.g., with PVTT or infiltrative HCC) and increases resection conversion rates, with acceptable safety [55–58]. While more RCTs are needed to refine regimens, identify biomarkers, and assess long-term safety, HAIC combined with immunotherapy is poised to become a new standard for advanced HCC. In future work, we will continue to investigate the comparative efficacy of HAIC versus other currently recommended first-line strategies—such as HAIC versus TACE or HAIC versus lenvatinib—and further explore the therapeutic potential of HAIC integrated into multimodal “targeted-immunotherapy” regimens.
In terms of adverse events, the pooled Odds Ratio for the incidence of any adverse events was estimated at 0.53 (95% CI = 0.06–4.82, P > 0.05), indicating that the incidence of adverse events in the HAIC group did not increase compared to the sorafenib group. According to previous related reports, the main adverse events associated with sorafenib are hand-foot skin reaction and hypertension, and the most common adverse reactions with HAIC are device-related (22–35%), followed by nausea and anorexia (28–33%), hematological toxicity (11–22%), gastritis (0–26%), and diarrhea (0–13%) [20,59]. Generally, the adverse reactions of HAIC do not overlap with those of sorafenib, suggesting that the combined application of HAIC and sorafenib for the treatment of hepatocellular carcinoma could also be a viable option. In contrast, the pooled Odds Ratio for grade 3–4 adverse event rates was 0.49 (95% CI: 0.28–0.85, P < 0.05), indicating a significantly lower incidence of severe (grade 3–4) adverse reactions with HAIC compared to sorafenib, suggesting potentially higher safety for HAIC treatment. We speculate that this may be due to several reasons. First, with advancements in technology and operational techniques, device- and technique-related complications of HAIC have significantly decreased [20]. Indeed, one study reported that only 0–4% of patients experienced catheter-related adverse events following HAIC [60]. Second, hepatic extraction of chemotherapeutic agents may result in a greater first-pass effect in the liver, minimizing systemic drug concentrations and thereby reducing systemic toxicity [61]. However, given the relatively small number of studies included in the comparison of grade 3–4 adverse events, more research may be required to validate this finding.
When interpreting the results, several limitations of this article should be taken into account: (1) The inclusion of a limited number of randomized controlled trials, with the majority being retrospective studies, may limit the generalizability and power of the findings. (2) Heterogeneity among the included studies in terms of sample characteristics and intervention protocols, such as variations in HAIC administration across different hospitals, can undermine the effectiveness of the combined analysis; To address this, we performed corresponding subgroup and sensitivity analyses to explore the specificity of the observed effects across different HAIC regimens. (3) The subjective judgments made by researchers during study selection, quality assessment, and interpretation of results are inevitable and can potentially introduce bias.
5. Conclusions
Among Asian and African populations, patients with BCLC stage B/C HCC treated with HAIC demonstrated higher overall survival compared to those receiving sorafenib. Moreover, among various HAIC regimens, the FOLFOX regimen conferred the greatest survival benefit. Additionally, HAIC was associated with improved oncologic outcomes, characterized by higher rates of Complete and Partial response, increased Objective response rate and Disease control rate, and a reduced likelihood of Disease progression.
Supporting information
S2 File. Quality evaluation of included studies.
https://doi.org/10.1371/journal.pone.0342495.s002
(XLSX)
S4 File. Sensitivity analysis of overall survival.
https://doi.org/10.1371/journal.pone.0342495.s004
(PDF)
S5 File. Forest plot for the comparison of SD.
https://doi.org/10.1371/journal.pone.0342495.s005
(PDF)
References
- 1. Global Burden of Disease Liver Cancer Collaboration, Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015. JAMA Oncol. 2017;3(12):1683–91.
- 2. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72(2):250–61. pmid:31954490
- 3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. pmid:30207593
- 4. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459–544. pmid:27733281
- 5. Lee S-W, Yang S-S, Lien H-C, Peng Y-C, Tung C-F, Lee T-Y. The combining of tyrosine kinase inhibitors and immune checkpoint inhibitors as first-line treatment for advanced stage hepatocellular carcinoma. J Clin Med. 2022;11(16):4874. pmid:36013120
- 6. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109. pmid:15466206
- 7. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8.
- 8. Llovet JM, Hilgard P, de Oliveira AC, Forner A, Zeuzem S, Galle PR. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008.
- 9. Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. pmid:19095497
- 10. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet Lond Engl. 2018;391(10126):1163–73.
- 11. Kong F-H, Ye Q-F, Miao X-Y, Liu X, Huang S-Q, Xiong L, et al. Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma. Theranostics. 2021;11(11):5464–90. pmid:33859758
- 12. Kokudo N, Takemura N, Hasegawa K, Takayama T, Kubo S, Shimada M, et al. Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update. Hepatol Res. 2019;49(10):1109–13. pmid:31336394
- 13. Ueshima K, Kudo M, Takita M, Nagai T, Tatsumi C, Ueda T, et al. Hepatic arterial infusion chemotherapy using low-dose 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma. Oncology. 2010;78 Suppl 1:148–53. pmid:20616598
- 14. Sung PS, Yang K, Bae SH, Oh JS, Chun HJ, Nam HC, et al. Reduction of intrahepatic tumour by hepatic arterial infusion chemotherapy prolongs survival in hepatocellular carcinoma. Anticancer Res. 2019;39(7):3909–16. pmid:31262920
- 15. Kodama K, Kawaoka T, Aikata H, Uchikawa S, Inagaki Y, Hatooka M, et al. Comparison of clinical outcome of hepatic arterial infusion chemotherapy and sorafenib for advanced hepatocellular carcinoma according to macrovascular invasion and transcatheter arterial chemoembolization refractory status. J Gastroenterol Hepatol. 2018;33(10):1780–6. pmid:29645345
- 16. Kang MK, Park JG, Lee HJ. Comparison of clinical outcomes between sorafenib and hepatic artery infusion chemotherapy in advanced hepatocellular carcinoma: a STROBE-compliant article. Medicine (Baltimore). 2018;97(17):e0611. pmid:29703062
- 17. Jeong SW, Jang JY, Lee JE, Lee SH, Kim SG, Cha S-W, et al. The efficacy of hepatic arterial infusion chemotherapy as an alternative to sorafenib in advanced hepatocellular carcinoma. Asia Pac J Clin Oncol. 2012;8(2):164–71. pmid:22524575
- 18. Kim HY, Park J-W, Nam B-H, Kim HK, Choi J-I, Kim TH, et al. Survival of patients with advanced hepatocellular carcinoma: sorafenib versus other treatments. J Gastroenterol Hepatol. 2011;26(11):1612–8. pmid:21517968
- 19. Hiramine Y, Uto H, Imamura Y, Tabu K, Baba Y, Hiwaki T, et al. Sorafenib and hepatic arterial infusion chemotherapy for unresectable advanced hepatocellular carcinoma: a comparative study. Exp Ther Med. 2011;2(3):433–41. pmid:22977522
- 20. Zhuang B, Li W, Xie XH, Hu HT, de Lu M, Xie XY. Sorafenib versus hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: a systematic review and meta-analysis. Jpn J Clin Oncol. 2019;49(9):845–55.
- 21. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-34. pmid:19631507
- 22. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60. pmid:20175033
- 23. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [Internet]. U.S.; 2010. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
- 24. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [Internet]. U.S. 2010. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
- 25. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [Internet]. U.S. 2017. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.html
- 26. Tufanaru C, Munn Z, Stephenson M, Aromataris E. Fixed or random effects meta-analysis? Common methodological issues in systematic reviews of effectiveness. Int J Evid Based Healthc. 2015;13(3):196–207. pmid:26355603
- 27. Yang H, Woo HY, Lee SK, Han JW, Jang B, Nam HC, et al. A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function. Clin Mol Hepatol. 2017;23(2):128–37. pmid:28494528
- 28. Li S, Mei J, Wang Q, Shi F, Liu H, Zhao M, et al. Transarterial infusion chemotherapy with FOLFOX for advanced hepatocellular carcinoma: a multi-center propensity score matched analysis of real-world practice. Hepatobiliary Surg Nutr. 2021;10(5):631–45. pmid:34760967
- 29. Iwamoto H, Niizeki T, Nagamatsu H, Ueshima K, Tani J, Kuzuya T, et al. The Clinical impact of hepatic arterial infusion chemotherapy new-FP for hepatocellular carcinoma with preserved liver function. Cancers (Basel). 2022;14(19):4873. pmid:36230795
- 30. Iwamoto H, Niizeki T, Nagamatsu H, Ueshima K, Nomura T, Kuzuya T, et al. Survival benefit of hepatic arterial infusion chemotherapy over sorafenib in the treatment of locally progressed hepatocellular carcinoma. Cancers (Basel). 2021;13(4):646. pmid:33562793
- 31. Huang Y, Zhang L, He M, Lai Z, Bu X, Wen D, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus sorafenib for hepatocellular carcinoma refractory to transarterial chemoembolization: retrospective subgroup analysis of 2 prospective trials. Technol Cancer Res Treat. 2022;21. pmid:36529949
- 32. Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018;69(1):60–9. pmid:29471013
- 33. Zaizen Y, Nakano M, Fukumori K, Yano Y, Takaki K, Niizeki T, et al. Hepatic Arterial Infusion Chemotherapy with Cisplatin Versus Sorafenib for Intrahepatic Advanced Hepatocellular Carcinoma: A Propensity Score-Matched Analysis [Internet]. 2021 [cited 2024 Jun 20]. Available from: https://www.preprints.org/manuscript/202109.0429/v1
- 34. Kondo M, Morimoto M, Ishii T, Nozaki A, Fukuda H, Numata K, et al. Hepatic arterial infusion chemotherapy with cisplatin and sorafenib in hepatocellular carcinoma patients unresponsive to transarterial chemoembolization: a propensity score-based weighting. J Dig Dis. 2015;16(3):143–51. pmid:25495751
- 35. Abdelmaksoud AHK, Abdelaziz AO, Nabeel MM, Hamza I, Elbaz TM, Shousha HI, et al. Hepatic arterial infusion chemotherapy in the treatment of advanced hepatocellular carcinoma with portal vein thrombosis: a case-control study. Clin Radiol. 2021;76(9):709.e1-709.e6. pmid:34116796
- 36. Hatooka M, Kawaoka T, Aikata H, Morio K, Kobayashi T, Hiramatsu A, et al. Comparison of outcome of hepatic arterial infusion chemotherapy and sorafenib in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Anticancer Res. 2016;36(7):3523–9. pmid:27354618
- 37. Kawaoka T, Aikata H, Hyogo H, Morio R, Morio K, Hatooka M, et al. Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma. J Dig Dis. 2015;16(9):505–12. pmid:26121102
- 38. Lyu N, Wang X, Li J-B, Lai J-F, Chen Q-F, Li S-L, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a Biomolecular Exploratory, Randomized, Phase III Trial (FOHAIC-1). J Clin Oncol. 2022;40(5):468–80. pmid:34905388
- 39. Song DS, Song MJ, Bae SH, Chung WJ, Jang JY, Kim YS, et al. A comparative study between sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. J Gastroenterol. 2015;50(4):445–54. pmid:25027973
- 40.
Shiozawa K, Watanabe M, Ikehara T, Kogame M, Matsui T, Okano N. Comparison of sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: a propensity score matching study. 2014.
- 41. Ahn YE, Suh SJ, Yim HJ, Seo YS, Yoon EL, Kim TH, et al. Comparison of sorafenib versus hepatic arterial infusion chemotherapy-based treatment for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Gut Liver. 2021;15(2):284–94. pmid:32307975
- 42. Ueshima K, Ogasawara S, Ikeda M, Yasui Y, Terashima T, Yamashita T, et al. Hepatic arterial infusion chemotherapy versus sorafenib in patients with advanced hepatocellular carcinoma. Liver Cancer. 2020;9(5):583–95. pmid:33083282
- 43. Choi JH, Chung WJ, Bae SH, Song DS, Song MJ, Kim YS, et al. Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. Cancer Chemother Pharmacol. 2018;82(3):469–78. pmid:29982870
- 44. Ginsberg M, Grayson J. Contributions to liver blood flow of the portal vein and hepatic artery. J Physiol. 1952;118(2):16P. pmid:13000726
- 45. Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol. 1954;30(5):969–77. pmid:13197542
- 46. Chen J, Jin R, Zhao J, Liu J, Ying H, Yan H, et al. Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett. 2015;367(1):1–11. pmid:26170167
- 47. Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 2016;64(1 Suppl):S84–101. pmid:27084040
- 48. Amaddeo G, Cao Q, Ladeiro Y, Imbeaud S, Nault J-C, Jaoui D, et al. Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas. Gut. 2015;64(5):820–9. pmid:25021421
- 49. Chinese Society of Liver Cancer. Chinese expert consensus on hepatic arterial infusion chemotherapy for hepatocellular carcinoma (2021 edition). Chin J Dig Surg. 2021;20(7):754–9.
- 50. N L, X W, Jb L, Jf L, Qf C, Sl L, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1). J Clin Oncol Off J Am Soc Clin Oncol. 2022;40(5).
- 51. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.
- 52. National Health Commission of the People’s Republic of China. Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 Edition). J Clin Hepatol. 2024;40(5):893–918.
- 53. The Committee for Revision of the Clinical Practice Guidelines for Hepatocellular Carcinoma, Hasegawa K, Takemura N, Yamashita T, Watadani T, Kaibori M, Kubo S, et al. Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines). Hepatol Res. 2023;53(5):383–90. pmid:36826411
- 54. Lai Z, He M, Bu X, Xu Y, Huang Y, Wen D, et al. Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: a biomolecular exploratory, phase II trial. Eur J Cancer. 2022;174:68–77. pmid:35981413
- 55. Zhang W, Zhang K, Liu C, Gao W, Si T, Zou Q, et al. Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: a real world study. Front Immunol. 2023;14:1127349. pmid:37180098
- 56. Xu J, Wang W, He K, Tang H, Niu S, Ma Z. FOLFOX-HAIC combined with PD-1 inhibitor immunotherapy significantly improves survival in patients with advanced hepatocellular carcinoma. Am J Transl Res. 2025;17(4):2577–90. pmid:40385024
- 57. R L, X W, H L, M W, J W, W W, et al. Hepatic arterial infusion chemotherapy combined lenvatinib and PD-1 inhibitor showed improved survival for infiltrative hepatocellular carcinoma: a multicenter cohort study. J Hepatocell Carcinoma. 2024;11.
- 58. Lin Z, Chen D, Hu X, Huang D, Chen Y, Zhang J. Clinical efficacy of HAIC (FOLFOX) combined with lenvatinib plus PD-1 inhibitors vs. TACE combined with lenvatinib plus PD-1 inhibitors in the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombus and arterioportal fistulas. Am J Cancer Res. 2023;13(11):5455–65.
- 59. Shao Y-Y, Huang C-C, Liang P-C, Lin Z-Z. Hepatic arterial infusion of chemotherapy for advanced hepatocellular carcinoma. Asia Pac J Clin Oncol. 2010;6(2):80–8. pmid:20565419
- 60. Obi S, Sato S, Kawai T. Current status of hepatic arterial infusion chemotherapy. Liver Cancer. 2015;4(3):188–99. pmid:26674592
- 61. Liu M, Shi J, Mou T, Wang Y, Wu Z, Shen A. Systematic review of hepatic arterial infusion chemotherapy versus sorafenib in patients with hepatocellular carcinoma with portal vein tumor thrombosis. J Gastroenterol Hepatol. 2020;35(8):1277–87. pmid:32052876