Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma in the Era of Systemic Therapies (2020–2025)

Abstract

Background

Management of advanced hepatocellular carcinoma (HCC) has evolved rapidly in recent years. Following the publication of the IMbrave150 study in 2020, which established atezolizumab-bevacizumab as first-line therapy, multiple systemic therapies have been approved and incorporated into global clinical guidelines. However, outcomes remain suboptimal in high-risk cases (e.g., extensive tumor burden, macrovascular invasion).

Summary

This review examines the role of hepatic arterial infusion chemotherapy (HAIC) in the context of modern systemic therapy for advanced HCC. A literature search (2020–2025) was conducted employing a PICO framework (Patients: advanced HCC; Intervention: HAIC; Comparison: any or no alternative therapy; Outcomes: efficacy and safety). HAIC is a regional chemotherapy approach delivered via the hepatic artery, allowing high intratumoral drug concentration with manageable systemic toxicity. It is popularly used in East Asia and has demonstrated promising survival benefits in patients with portal vein tumor thrombosis (PVTT) or large tumors – subgroups where systemic therapies or transarterial chemoembolization frequently fail. HAIC is an integral modality for advanced HCC, especially for patients with extensive liver tumors or PVTT. It provides critical bridge-to-curative options by downsizing tumors and improving systemic treatment effects. To integrate HAIC into global practice, standardization of techniques, patient selection, biomarkers, and confirmatory trials in non-Asian populations is needed. HAIC can change the standard of care by improving outcomes in patient subsets poorly served by current therapies.

Key Messages

Paradigm shift to synergy: HAIC has transitioned from a palliative locoregional tool to a central pillar of “triple therapy” (HAIC + tyrosine kinase inhibitor + immune checkpoint inhibitor), leveraging immunogenic cell death to improve systemic treatment efficacy. Superiority in high-risk subsets: This modality demonstrates exceptional survival benefits in patients with high tumor burden and major PVTT (Vp4 PVTT) – subgroups where standard systemic monotherapies frequently fail. A bridge to cure: HAIC-based combination regimens significantly increase conversion-to-surgery rates by inducing rapid tumor necrosis and downstaging, thereby providing curative opportunities for initially unresectable patients. Global standardization needs: Future adoption relies on international consensus to standardize delivery protocols and biomarker-driven model validation for precise patient selection.

Introduction

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a leading cause of cancer-related mortality [1]. Early-stage HCC can be cured with resection, ablation, or transplantation, whereas the majority of patients are diagnosed at intermediate or advanced stages, where systemic therapies are the mainstay [2].

Over the past decade, molecular targeted agents (e.g., sorafenib, lenvatinib) and immune checkpoint inhibitors (ICI; e.g., pembrolizumab, nivolumab, ipilimumab, atezolizumab, durvalumab) have revolutionized the management of advanced HCC [3]. The landmark IMbrave150 trial in 2020 established the combination of atezolizumab plus bevacizumab as the preferred first-line regimen, substantially improving survival over sorafenib. Significant challenges persist, despite these advances. HCC is highly heterogeneous, and subsets of patients demonstrate intrinsic treatment resistance [4]. Moreover, immunotherapy produces a remarkable “long-tail effect,” with a minority of patients achieving durable remission; however, many others eventually experience disease progression. Notably, current systemic therapies underperform in certain high-risk scenarios, including tumors with very high intrahepatic burden (HTB) or those with major vascular invasion, where responses remain suboptimal [5].

Hepatic arterial infusion chemotherapy (HAIC) is a locoregional treatment that delivers chemotherapeutic agents directly into tumor sites via the hepatic artery (Fig. 1) [6]. HAIC achieves higher intratumoral drug concentrations while minimizing systemic toxicity by confining drug exposure to the liver. In recent years, HAIC has emerged as a promising strategy for advanced HCC, especially in East Asia, although it is not included in Western guidelines. Multiple studies have demonstrated survival benefits with HAIC in advanced HCC, particularly among patients with portal vein tumor thrombosis (PVTT) or HTB [7]. Further, HAIC has demonstrated utility as a salvage option after failure of first-line systemic therapy [8]. Furthermore, combining HAIC with systemic therapies may generate synergistic effects, which improve overall treatment efficacy [9].

Fig. 1.

Mechanisms of hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC).

This review summarizes the progress in HAIC for advanced HCC from 2020 to 2025 (Fig. 2), emphasizing critical clinical evidence and the potential integration of HAIC into contemporary treatment paradigms. This review focuses on a critical synthesis of outcomes, highlighting how HAIC complements systemic therapy, and discusses the challenges and future directions required to incorporate HAIC into international standards of care.

Fig. 2.

Ten key perspectives outlining the comprehensive clinical and scientific considerations of hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC).

Methods

Search Strategy and PICO Framework

We conducted a literature search guided by the PICO framework (Population: advanced HCC; Intervention: HAIC; Comparison: any or no alternative therapies; Outcomes: efficacy and safety). The search strategy in the PubMed database used Medical Subject Headings (MeSH) terms and keywords with the following Boolean logic: ([hepatocellular carcinoma] OR [HCC] OR [Liver cancer]) AND ([hepatic arterial infusion chemotherapy] OR [Hepatic artery infusion] OR [HAIC] OR [HAI]). Further, we manually screened reference lists of relevant articles.

Selection Criteria

Eligible studies met the following criteria:

• Study type: randomized controlled trials (RCTs), systematic reviews, meta-analyses, retrospective cohort studies, case reports, and letters to the editor reporting relevant clinical data.

• Focus: studies specifically investigating the application, efficacy, or safety of HAIC in the context of HCC.

• Language and date: articles published in English between January 2020 and March 2025.

Screening and Data Extraction

Two researchers independently screened titles and abstracts of identified studies and subsequently conducted full-text assessments of potentially relevant studies. Disagreements were resolved through consensus with a third reviewer. Relevant data on study design, patient population, treatment regimen, and outcomes were extracted for qualitative synthesis. The search and selection were finalized on April 15, 2025. Of the screened publications, 179 relevant articles were identified (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000551934).

Results and Discussion

Global Management of Advanced HCC: A Regional Divergence in Philosophy

A comparative analysis of six major international guidelines – American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), Asian Pacific Association for the Study of the Liver (APASL), China Liver Cancer Staging system (CNLC), Korean Liver Cancer Association (KLCA), and Japan Society of Hepatology (JSH) – reveals a fundamental consensus on the definition of advanced HCC (Fig. 3). All societies agree that macrovascular invasion (MVI) and/or extrahepatic spread (EHS) define advanced HCC. However, a critical divergence exists in how these guidelines translate this definition into a therapeutic strategy.

Fig. 3.

Global treatment guidelines for advanced hepatocellular carcinoma (HCC) and the current status of hepatic arterial infusion chemotherapy (HAIC) within therapeutic strategies.

The “Systemic-First” Paradigm

Western guidelines (e.g., AASLD, EASL) greatly follow the Barcelona Clinic Liver Cancer (BCLC) staging system. Under this framework, BCLC Stage C encompasses a broad spectrum of patients (e.g., Child-Pugh [CP] A–B, Eastern Cooperative Oncology Group [ECOG] 1–2) with either MVI or EHS. The therapeutic recommendation is notably rigid: locoregional treatments are generally not recommended once MVI/EHS are present. Systemic therapy is prioritized as the near-exclusive cornerstone. AASLD conditionally considers selective internal radiation therapy (SIRT), also known as transarterial radioembolization (TARE), in highly selected cases, whereas EASL maintains a strict focus on systemic modalities.

The “Multimodal Tailoring” Paradigm (Asia)

Asian guidelines (APASL, CNLC, KLCA, and JSH) take a more granular stratification by subdividing advanced HCC into two distinct clinical scenarios.

• Locally advanced (MVI+/EHS−): in this scenario, Asian societies advocate for an aggressive, diversified approach. Rather than relying solely on systemic therapy, these encourage integrating locoregional therapies – including HAIC, transarterial chemoembolization (TACE), surgical resection, or radiotherapy – to directly control intrahepatic tumor load.

• Metastatic (EHS+): there is consensus that systemic therapy remains the foundation of treatment, similar to Western practice, for disseminated disease in this subgroup.

The Emerging Role of HAIC

This regional divergence reflects a shift in East Asian clinical practice toward optimizing local control to improve overall survival (OS) in specific subgroups [6, 10]. Western frameworks emphasize uniform systemic therapy and tend to exclude HAIC or other invasive locoregional approaches from advanced-stage management, whereas the Asian model – supported by a growing body of evidence – prioritizes the integration of local (e.g., HAIC) and systemic therapies to manage the complexities of MVI, emphasizing the need for global consensus and high-level evidence for HAIC’s role.

Evolution of HAIC Protocols: From Classical Regimens to Modern Optimization

Evolution of Treatment Regimens: FP to FOLFOX

Historically, the combination of 5-fluorouracil (5-FU) and cisplatin (the FP regimen) established the backbone of HAIC in Japan and South Korea [11–18]. Early trials revealed that FP-HAIC was feasible – achieving objective response rates (ORR) of 33%–38.5% and median OS of ∼15 months in advanced HCC [13, 19] – the quest for higher efficacy led to significant protocol modifications [20–23].

To improve efficacy, Japanese investigators introduced modifications, including the “New-FP” regimen, which suspends cisplatin in lipiodol to function as a microembolic drug carrier. “New-FP” prolonged intratumoral drug retention and generated striking outcomes [6, 24–26].

• Superiority over sorafenib: in patients with MVI, New-FP achieved superior median OS compared with sorafenib (OS: 30.4 vs. 13.2 months; ORR: 71% vs. 10%) [27]. Further, it produced higher complete response rates and enabled surgical resection (conversion therapy) in a subset of patients.

• Downstaging potential: beyond palliation, New-FP has demonstrated high utility in conversion therapy, achieving a 16.3% conversion rate and a remarkable 5-year OS of 56% in patients successfully bridged to surgery [26].

More recently, Chinese centers have shifted toward an oxaliplatin-based regimen: FOLFOX-HAIC (oxaliplatin + infusional 5-FU/leucovorin) [10]. Oxaliplatin demonstrated a strong radiosensitizing and immunogenic cell death effect, and FOLFOX-HAIC has exhibited promising efficacy. The FOHAIC-1 randomized trial from China definitively established FOLFOX-HAIC as superior to sorafenib in advanced HCC, doubling median OS (13.9 vs. 8.2 months) in treatment-naïve patients. Variations of FOLFOX are being investigated to improve convenience and tolerability – for example, using a 1-day high-dose infusion instead of 2-day infusions [28] or substituting 5-FU with raltitrexed to simplify administration [29, 30]. The shift toward FOLFOX represents the higher potency of oxaliplatin and the need to align HAIC with modern systemic regimens.

Technical Execution – Delivery Systems and Perfusion Precision

The clinical success of HAIC depends not only on the drugs but also on the standardized delivery technique. Two main catheterization strategies are employed, each with trade-offs [31, 32].

• Implantable portal systems: surgical placement of a subcutaneous arterial port connected to the hepatic artery enables repeated infusions without new arterial punctures. Port-based HAIC demonstrates high technical success and enables long-term therapy, but carries procedural risks. These systems boast high technical success rates (∼87.9%) [33]. However, they are hindered by a 22%–28% postoperative complication rate, primarily involving pump-pocket infections, catheter migration, or hepatic artery occlusion [34–37]. To improve safety, Japanese professional associations issued clinical practice guidelines in 2022, standardizing port placement and maintenance [38]. Newer proprietary (“System-i”) have attempted to simplify the procedure (shortening operative time to 40 min). However, surgical expertise and cost remain barriers to universal adoption [9].

• Percutaneous catheterization: several recent trials adopt a percutaneous transarterial approach for each HAIC cycle (inserting a catheter into the hepatic artery for infusion, then removing it). This approach avoids long-term implants and eliminates port-related infections/occlusion risks. Furthermore, it provides flexibility: interventional radiologists reposition the catheter each cycle to consider tumor changes or variant vascular anatomy. The drawback is the need for repeated arterial punctures and hospital visits for each infusion, which affects patient convenience.

Precision Perfusion: The Role of Imaging and Anatomy. A synthesis of techniques highlights two essential pillars for optimizing intrahepatic perfusion:

• Assessment modalities: achieving precise intratumoral drug perfusion is another crucial aspect. Vascular anatomical variations or extrahepatic artery shunting cause uneven drug distribution [39]. To ensure adequate coverage, digital subtraction angiography, intraoperative staining tests, and postoperative nuclear imaging [40] are used to confirm that the chemotherapy actually reaches the intended tumor territory.

• Vascular modification: selective embolization of competing vessels redistributes flow so that the chemotherapy uniformly bathes the tumor nodules if a tumor’s blood supply originates from an accessory artery. Such measures help prevent “nontarget” delivery that injures the gallbladder or stomach and maximizes drug delivery to tumor tissue [32, 41]. In summary, careful multidisciplinary coordination (e.g., surgeons, interventional radiologists, oncologists) is warranted to optimize HAIC technique and safety.

Influence of Host Factors on HAIC Outcomes

Patient-related “host” factors – particularly underlying liver function, tumor etiology, and patient age – profoundly influenced the efficacy and safety of HAIC. These factors collectively define the therapeutic window for HAIC in advanced HCC and guide patient selection [16, 42–49] (Fig. 4; Table 1).

Fig. 4.

Role of background liver disease in hepatic arterial infusion chemotherapy (HAIC).

Table 1.

Summary of baseline characteristics of selected studies

Study, year (country)	Sample size, n	Etiology (HBV/HCV/other), %	Median age, years	Sex (M/F), %	CP-A/B, %	ECOG 0–1, %	PVTT, %
Li et al. [44], JCO 2022 (China, HAIC-FO vs. TACE)	315	HBV 88/HCV 1/other 11	54	82/18	83/17	100	Excluded PVTT
He et al. [45], JAMA Oncol 2019 (China, sorafenib + HAIC-FO vs. sorafenib)	247	HBV 81/HCV 5/other 13	49	85/15	CP ≤7 (mostly A, exact NR)	100	100
Li et al. [46], JCO 2023 (China, adjuvant HAIC-FO after resection with MVI)	315	HBV major (∼80%), exact NR	52	85/15	Mostly CP-A (surgical cohort)	100	Excluded PVTT
Iwamoto et al. [47], Cancers 2022 (Japan, New-FP-HAIC vs. sorafenib, real-world, PSM)	1,262 (PSM n = 198/group)	HBV 28/HCV 37/other 35	66	80/20	CP-A5–6 (majority)	100	Mixed (some PVTT, % not specified)
SILIUS trial, Kudo et al. [16], Lancet Gastroenterol Hepatol 2018 (Japan, sorafenib±low-dose FP-HAIC)	206	HBV 26/HCV 52/other 22	71	77/23	CP-A: 100	100	64
Lyu et al. [48], J Hepatol 2020 (China, HAIC-FO vs. sorafenib)	315	HBV 85/HCV 3/other 12	53	86/14	90/10	98	45
Lyu et al. [49], JCO 2022 (China, HAIC-FO vs. sorafenib)	262	HBV 92.3/HCV 1.5/other 6.2	54	88.5/11.5	67.6/32.3	96	72.3

HAIC, hepatic arterial infusion chemotherapy; 5-FU, 5-fluorouracil; TACE, transarterial chemoembolization; HAIC-FO, HAIC with fluorouracil, leucovorin, and oxaliplatin; FP-HAIC, HAIC with 5-fluorouracil (5-FU) and cisplatin (CDDP); MVI, microvascular invasion; PSM, propensity score matching; HBV, hepatitis B virus; HCV, hepatitis C virus; CP, Child-Pugh; NR, not reported; ECOG, Eastern Cooperative Oncology Group; PVTT, portal vein tumor thrombosis.

Hepatic Functional Reserve – Defining the Treatment Threshold

Liver function reserve is crucial for HAIC eligibility. CP and albumin-bilirubin (ALBI) scores are standard predictive tools; however, current evidence indicates a nuanced application:

• The optimal candidate: patients with CP-A or ALBI grade 1 consistently derive the most survival benefit and demonstrate better tolerance to aggressive HAIC combinations [50, 51]. Notably, posttreatment maintenance or improvement in CP scores functions as a strong independent predictor of prolonged OS [51].

• The CP-B controversy: the use of HAIC in patients with CP-B may still derive benefit from HAIC, but careful selection is warranted. Small retrospective series indicate that these patients have higher toxicity and shorter survival than patients with CP-A; however, selected individuals (CP scores 7–8) may achieve a survival benefit, with some even experiencing an improvement in hepatic reserve after tumor response [52–55].

• The exclusion limit: in CP-C or ALBI grade 3 cases (decompensated cirrhosis), HAIC is usually contraindicated. The risk of hepatic failure and treatment toxicity outweighs potential benefits. Thus, a good hepatic reserve (e.g., low bilirubin, high albumin) is a prerequisite for HAIC, and improving liver function (e.g., managing ascites, encephalopathy) should be attempted before considering HAIC [56–58].

Viral Etiology: Regional Success and Global Generalizability

A critical synthesis of existing studies – predominantly from Asia highlights a distinct “etiological skew” that both explains HAICs success and identifies its current limitations [43, 59].

• Viral-driven efficacy: most HAIC trials and cohorts from East Asia predominantly included patients with hepatitis B or C. Whether patients with nonviral HCC (e.g., nonalcoholic steatohepatitis [NASH]/nonalcoholic fatty liver disease, NASH/NAFLD-associated tumors common in Western countries) respond similarly remains unclear. Meta-analyses indicate that biological differences exist between HCC etiologies: viral-related HCC more frequently arises in younger patients with better liver function, whereas NASH-related HCC typically develops in older patients with comorbidities. Some studies indicate that underlying HBV infection might predict better response to HAIC, possibly associated with tumor biology or immune microenvironment differences [60, 61].

• Safety imperative: HBV reactivation is a severe risk during HAIC-based chemotherapy, particularly when combined with immunotherapy. Prophylactic antiviral therapy is recommended for patients positive for HBV undergoing HAIC to prevent hepatitis B reactivation during chemotherapy [62–65].

• Generalizability gap: the current HAIC evidence base is heavily weighted toward viral HCC. To promote global adoption, future trials must prioritize Western cohorts where nonviral etiologies (NASH/NAFLD) are prevalent, to confirm their benefit across etiologies.

Patient Age and Performance Status: Beyond Chronological Limits

Advanced age alone is not a contraindication to HAIC. Moreover, critical analysis of age-stratified data reveals a more favorable outlook.

• Relative survival benefit: absolute survival may be shorter in elderly patients due to comorbidities, whereas their lifespan-adjusted survival benefit frequently exceeds that of younger cohorts [66]. The key is ensuring adequate organ function and performance status. Patients with poor performance status (ECOG ≥2) are excluded from systemic therapy trials; thus, they were generally excluded from HAIC trials. In practice, patients with frailty or those with multiple comorbidities may not tolerate the intensive visits and potential side effects of HAIC. However, HAIC can be effectively and safely used with appropriate dose adjustments, monitoring, and the management of comorbidities for fit elderly patients [67].

Strategic Timing: Integrating HAIC into the Clinical Continuum

The versatility of HAIC enables it to be deployed at various points in HCC management, shifting from a palliative chemotherapy to a strategic tool for surgical bridging and second-line therapy. Figure 5 illustrates representative clinical scenarios. Key applications include the following.

Fig. 5.

a–f Clinical timing strategies for hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC).

Perioperative HAIC: Expanding Surgical Boundaries

Surgery remains the primary curative intent, whereas high recurrence rates in patients with microvascular invasion or PVTT provide a strong rationale for perioperative therapy [68].

• Adjuvant excellence: evidence now supports FOLFOX-HAIC for patients with positive microvascular invasion [46, 69]. A landmark phase III RCT demonstrated that adjuvant FOLFOX-HAIC doubled median disease-free survival (20.3 vs. 10.0 months; hazard ratio [HR] = 0.59) [46]. Further, this regimen significantly improved 2-year OS. The efficacy of this approach is further refined by imaging-based scoring models that associate peritumoral enhancement with treatment response, thereby potentially providing a basis for patient selection [70]. Furthermore, the addition of PD-1 inhibitors to adjuvant HAIC demonstrates potential to further reduce recurrence [71].

• Neoadjuvant exploration: data are currently limited to single-center retrospective studies; however, neoadjuvant FOLFOX-HAIC has demonstrated that preoperative HAIC can downstage borderline-resectable tumors, thereby increasing the chance of achieving an R0 resection and reducing microscopic disease [72].

Conversion Therapy (Downstaging to Resectability)

• In ∼80% of patients who are initially ineligible for surgery due to tumor extent or vascular invasion, HAIC-based conversion therapy aims to shrink tumors and convert these patients to surgical candidates. HAIC shows a unique strength in inducing rapid tumor necrosis and regression of PVTT, in which systemic therapy alone frequently cannot achieve [73]. Published series demonstrate that patients who respond well to HAIC and undergo subsequent surgery have excellent long-term outcomes – one Japanese study reported a 5-year OS of up to 83% [74]. Further, HAIC can be combined with portal vein embolization to increase the liver remnant, thereby safely enabling major hepatectomies in initially unresectable cases [75].

• The most potent conversion regimens involve “Triplet Therapy” Edge (HAIC + tyrosine kinase inhibitors [TKIs] + ICIs). Early data indicate that these multimodal combinations yield the highest response rates. For instance, a multicenter study of high tumor burden (HTB) HCC reported ORRs exceeding 60% and a surgical conversion rate of approximately 13%–16% using HAIC alongside atezolizumab-bevacizumab and TACE [76, 77]. Notably, recurrence remains common even after successful conversion surgery (∼50% at 1–2 years). This underscores the need for careful patient selection and consolidation therapies postoperatively. However, HAIC-based conversion therapy provides a chance at a cure in patients who were once deemed incurable [78].

HAIC with Systemic Therapy – Simultaneous vs. Sequential

• As HAIC enters the era of combination therapy, the question arises: should HAIC be given simultaneously with systemic treatments or sequentially (after one fails)? Retrospective analyses indicate that upfront concurrent therapy yields better outcomes than delayed initiation. A large cohort study (n = 575), combining HAIC with a targeted therapy, revealed that a simultaneous approach significantly improved OS and progression-free survival (PFS). Toxicity was manageable and did not significantly increase with concurrent administration in that study [79, 80]. Conversely, HAIC has also proven valuable as a salvage (second-line) therapy. HAIC is increasingly recognized as a potent salvage option for patients who fail first-line immunotherapy. In this setting, FOLFOX-HAIC has demonstrated an ORR of 40%–50% in the second-line setting [8, 81]. This is markedly higher than historical second-line systemic therapies, indicating the efficacy of HAIC even after immunotherapy failure.

In summary, the role of HAIC has expanded from a standalone “local” treatment to a “multifaceted component of advanced care.” Whether used immediately to boost first-line treatment (for maximal tumor shrinkage) or deployed after systemic failure (second-line), HAIC should be dynamically integrated according to the patient’s therapeutic needs – e.g., downstaging for surgery (conversion) or controlling liver-dominant progression (salvage). This flexible timing maximizes the benefit of HAIC as a “systemic-sensitizer” that can both augment and rescue systemic therapy outcomes.

HAIC Monotherapy: Benchmarking Efficacy and Limitations

Single-agent HAIC (without concurrent systemic therapy) has been extensively studied and provides a baseline for evaluating newer combinations. HAIC monotherapy is particularly effective for controlling intrahepatic disease in patients with HTB or PVTT, frequently outperforming the older standard of sorafenib in these subsets.

Therapeutic Efficacy of HAIC Alone

• Cumulative evidence from meta-analyses and trials consistently indicates that HAIC monotherapy achieves higher response rates and improves survival compared with sorafenib in advanced HCC [82–84]. A 2025 meta-analysis of >6,000 patients revealed that HAIC significantly prolonged OS (HR = 0.72), PFS (HR = 0.57), ORR (risk ratio [RR] = 4.29), and disease control rates (RR = 1.33) compared with sorafenib [84]. The benefit was most pronounced in patients from Asian cohorts (HR = 0.24) [83]. A subgroup meta-analysis of HAIC with PVTT revealed that HAIC provides a distinct survival advantage (OS, HR = 0.50; PFS, HR = 0.47) over sorafenib [85]. Real-world studies likewise report median OS approaching 29.2 months for HAIC-treated patients with PVTT, versus 21.8 months for sorafenib and 11.5 months with best supportive care [86].

Most compellingly, the recent FOHAIC-1 phase III trial cemented HAIC’s superiority as initial therapy. FOHAIC-1 demonstrated that FOLFOX-HAIC doubled median OS (13.9 vs. 8.2 months) and achieved a significantly higher tumor response rate (ORR, 46% vs. 11%) compared with sorafenib in untreated advanced HCC [49]. Importantly, the survival advantage of HAIC was observed across high-risk subgroups, including those with bifurcation PVTT and HTB. These data identified HAIC monotherapy as a valid alternative first-line treatment, at least in regions where it is available and expertise exists.

Clinical Considerations: Surgery Feasibility

• HAIC vs. surgery: curative resection remains the gold standard whenever feasible, despite the efficacy of HAIC. Noteworthily, even non-curative or debulking surgery can sometimes yield better survival than HAIC. A nationwide Japanese study of 1,084 patients reported that those who underwent surgical resection (even if margins were positive or recurrence occurred) achieved longer median survival than those treated with HAIC alone (26.0 vs. 10.0 months) [87]. This finding indicates that surgery should be prioritized and HAIC considered an adjunct (neoadjuvant or adjuvant), rather than replacing surgery, if a tumor is technically resectable. In practice, HAIC is frequently reserved for patients who are not surgical candidates due to tumor extent or poor reserve or as a bridge to make surgery possible.

The Limitations of HAIC Monotherapy

Three primary limitations hinder the use of HAIC alone in the modern era:

• Ceiling effect: although effective locally, HAIC monotherapy produces an ORR typically in 20%–30% range in unselected advanced HCC. This is lower than the response rates now achievable with combination regimens. Several tumors will shrink or stabilize with HAIC, but complete responses are rare without additional therapies.

• Systemic disease escape: HAIC primarily treats liver tumors and has a limited effect on distant disease. Up to ∼30% of advanced HCC cases have lung or extrahepatic metastasis at diagnosis, which HAIC alone cannot eradicate. Circulating tumor cells or micrometastases can seed new lesions even in liver-only disease. This propensity requires the combination of HAIC with systemic agents to control local and distant disease [88].

• TACE-refractory tumors: Some evidence indicates that tumors that have failed prior TACE (i.e., are TACE-refractory) may respond less robustly to subsequent HAIC [84]. Repeated TACE may induce biological changes (including hypoxia-driven angiogenesis or chemoresistance) that also confer partial resistance to HAIC. This indicates HAIC might be more effective if introduced earlier, rather than as a last resort after multiple TACE sessions.

HAIC monotherapy remains a powerful tool for intrahepatic control and has clearly demonstrated superiority over sorafenib in patients with select advanced HCC. However, it lacks plateauing response rates when combined with other systemic therapies [29, 49]. Therefore, ongoing research is focused on integrating HAIC into multimodality regimens with TKIs/ICIs.

Synergistic Combination Strategies: HAIC in the Era of Triple Modality Therapy

Building on the HAIC monotherapy experience, a paradigm shift exists toward HAIC-based combination therapies as a new standard. By combining HAIC with other locoregional or systemic therapy, this strategy maximizes local tumor control while simultaneously suppressing systemic spread and recurrence.

HAIC + Locoregional Modalities

Combining HAIC with other liver-directed treatments can improve local tumor control. For instance, HAIC + radiation therapy has been administered in cases of intrahepatic failure or portal vein invasion, which achieves higher tumor necrosis rates and occasionally allows curative second-stage surgery. Small studies combining HAIC with ablation therapies (thermal ablation) significantly extend OS (22.2 vs. 14.5 months) and PFS (8.5 vs. 4.6 months) compared with either alone [89]. The “triple” integration of HAIC, lenvatinib, and sequential ablation has demonstrated even more remarkable outcomes, with median OS exceeding 30 months [90]. Furthermore, TACE-HAIC hybrid therapy is being tested: the embolization effect of TACE starves the tumor of blood flow, whereas the continuous infusion of HAIC delivers chemotherapy to any residual viable tumor after embolization.

HAIC + Systemic Therapy (TKIs/ICIs)

• The most significant paradigm shift is the integration of HAIC with modern systemic drugs (TKIs/ICIs). The rationale is clear: HAIC controls liver tumors, reducing immunosuppressive tumor burden and possibly inducing immunogenic cell death, whereas systemic agents control microscopic disease and distant spread [91].

• The most remarkable results come from triple therapy (HAIC + TKI + ICI): multiple centers have reported that triple therapy achieved tumor regression in the majority of patients. Prospective trials reported an ORR of 77% when adding HAIC to lenvatinib plus an anti-PD-1 antibody with a median PFS exceeding 10 months [9, 92]. Notably, this approach has extended OS to 27.0 months even in patients with extrahepatic metastases [93]. One multicenter study in advanced HCC with inferior vena cava (IVC)/RA tumor thrombus revealed that HAIC + dual systemic therapy (PD-1 inhibitor + TKI) doubled median PFS and significantly improved OS versus the systemic doublet alone.

Precision Medicine: Predictors of Response to HAIC

HAIC is adopted more widely; thus, patient selection is an emerging priority, identifying which patients are more likely to benefit from HAIC and which may not respond. Current evidence has started to uncover multidimensional predictors of HAIC efficacy, ranging from molecular and radiomic models to prior treatment [94–105] (Table 2; Fig. 6).

• Genetic polymorphisms: host genetic factors may affect chemotherapy response. Single-nucleotide polymorphisms, including GALNT14-rs9679162 (GG genotype), are significantly associated with prolonged survival (p = 0.019) [94]. Another study revealed that IL-28B rs8099917 minor genotypes (TG or GG) correlated with better tumor response under HAIC, with the IL-28B minor allele demonstrating higher ORR (51.9% vs. 29.1%) and longer OS (17 vs. 14 months) [95]. These findings indicate a future where simple blood tests for patient genotype could inform HAIC use.

• Tumor immune microenvironment (TME): the efficacy of HAIC, especially when combined with immunotherapy, is associated with the baseline immune milieu of the tumor. Responders to HAIC-based triple therapy exhibit high T-cell infiltration and a more “inflamed” immune profile, indicating that TME analysis could be a prerequisite for combination therapy [105]. Researchers are exploring biomarkers, such as CCL28 and others, to predict which high-risk patients will benefit from intensive HAIC-containing regimens versus those who might not [92].

• Imaging characteristics: advanced imaging provides dynamic predictive clues: Certain computed tomography or magnetic resonance imaging features, such as “Infiltrative” growth patterns and ring-like enhancement, popularly portend a poor prognosis, indicating a need for aggressive therapy [96]. Conversely, early changes on imaging during therapy can predict benefit: changes during HAIC-lenvatinib therapy have been correlated with better tumor response and outcomes [97].

• Radiomic models: the integration of magnetic resonance imaging-based radiomics with clinical data has achieved high predictive accuracy, with an area under the curve value reaching 0.87 [98, 99]. These models could help clinicians identify responders early in the course and adjust treatment for non-responders.

• Clinical scoring systems: composite scores using routine clinical and laboratory parameters are being developed. The HAIC-manual and the assessment for retreatment with HAIC (ARH) score are examples that integrate factors, such as tumor burden, liver function, and inflammatory markers, to predict survival after HAIC [100, 101]. Further, simple inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR ≤2.9), have independent prognostic value and tend to have better outcomes [102]. Novel blood-biomarker models have demonstrated superior prognostic power over conventional TNM staging, with C-indices of 0.75 for OS [103].

• Prior treatment (“TACE-exhaustion”): A patient’s previous treatments affect HAIC success. Notably, data indicate that undergoing multiple prior TACE sessions is associated with reduced subsequent HAIC response. Tumors that have withstood several rounds of embolization may have more aggressive biology or altered vascularization, making them less chemosensitive. This insight supports the notion of not overusing TACE in advanced cases – instead, switching to HAIC earlier (before three or more TACE sessions) might generate better results [104].

Table 2.

Predictors of HAIC efficacy

Category	Author	Regimens	Predictive Factors	Key Findings	Clinical Implications
Genetic/gene markers	Lin et al. [94]	Cisplatin and 5-FU	GALNT14, WWOX triple SNP	Predicts sensitivity to systemic chemo or HAIC	Potential for pretreatment personalized decision-making
	Terashima et al. [95]	Cisplatin and 5-FU	IL-28B rs8099917 (TG/GG vs. TT genotypes)	Higher response rate and longer survival in TG/GG	SNP may serve as a predictive tool for HAIC efficacy
Imaging features	Kim et al. [96]	Cisplatin and 5-FU	Tumor growth pattern, rim arterial enhancement	Significant prognostic correlation	Helps identify patients likely to benefit from continued HAIC
	Wu et al. [97]	Oxaliplatin and fluorouracil	Hepatic artery diameter changes	Artery narrowing correlates with reduced efficacy and blood flow	Early imaging biomarker for treatment response
	Quan et al. [98]	Oxaliplatin and fluorouracil	MRI radiomics (InceptionV4 model)	High accuracy in predicting HAIC response	AI-assisted imaging tools show promise
	Yin et al. [99]	Oxaliplatin and fluorouracil	Multimodal MRI deep learning model	Integrates imaging + clinical data for precise prediction	Enables high-accuracy, individualized response assessment
Clinical features and scores	Chen et al. [100]	Oxaliplatin and fluorouracil	Imaging + clinical variables (HAIC-manual score)	HAIC score (0–5): lower scores correlate with longer survival	Improves prognostic stratification for HAIC candidates
	Mei et al. [101]	Oxaliplatin and fluorouracil	AFP, CP, imaging response (ARH score)	ARH score ≥2.5 predicts poor prognosis	Guides decisions on continuing HAIC
	Liu et al. [102]	Oxaliplatin and raltitrexed	NLR	High NLR = poor prognosis	Simple biomarker for efficacy/survival
	Zeng et al. [103]	Oxaliplatin and fluorouracil	Hematologic + clinical variable model	Predictive model for combined therapy response	AI-enhanced clinical parameter analysis
Treatment history	Onishi et al. [104]	Cisplatin and 5-FU	Prior TACE sessions (≥3)	Linked to reduced HAIC response and shorter survival	Excessive TACE may compromise subsequent HAIC efficacy
TME	Chen et al. [105]	Oxaliplatin and fluorouracil	TME status (T-cell activity, MHC expression)	Immunologically “hot” TME correlates with better response	Baseline TME may predict outcomes of combination therapies

HAIC, hepatic artery infusion chemotherapy; SNP, single-nucleotide polymorphism; MRI, magnetic resonance imaging; AI, artificial intelligence; AFP, alpha-fetoprotein; NLR, neutrophil-to-lymphocyte ratio; TACE, transarterial chemoembolization; TME, Ttumor microenvironment; MHC, major histocompatibility complex.

Fig. 6.

Factors affecting the efficacy of hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC).

Predictive Research for HAIC Is Converging on a Holistic Selection Model

The current evidence indicates that no single factor is a perfect predictor. Future efforts are recommended to focus on a combination of genetic markers, immune profiling, imaging indicators, and clinical history that together stratify patients. The goal is to develop a standardized “HAIC suitability score” to identify ideal candidates. Prospective validation of these predictors is warranted. As we move toward precision oncology, such tools will ensure that HAIC is used in those most likely to benefit, thereby improving overall outcomes and cost-effectiveness.

HAIC for High-Risk Populations: Clinical Breakthroughs

Two subgroups of advanced HCC represent the “hardest-to-treat” cases: patients with HTB and those with Vp4 PVTT (tumor thrombus in the main portal vein trunk or extending to the IVC). Traditionally, these features portend an extremely poor prognosis under standard systemic therapies. Remarkably, recent HAIC-based approaches have started to transform outcomes in these populations, shifting the expectation from only palliative care to meaningful survival extensions and even curative opportunities for these patients.

• HTB (≥10 cm or ≥50%, Liver Involvement): HAIC provides a unique local debulking advantage: surgical bridge and systemic synergy. A strategic multidisciplinary team approach – using HAIC followed by resection – has achieved a remarkable 5-year OS rate of 79.1%, thereby vastly outperforming surgery or HAIC as monotherapies [106]. In patients exceeding the “up-to-11” criteria, combining TACE-HAIC with atezolizumab-bevacizumab generated a 62.2% ORR and a 92.8% 1-year OS [76, 107].

• Vp4 PVTT: Vp4 PVTT is a traditional contraindication for TACE due to the risk of liver failure from ischemia. Systemic therapy alone yields modest benefits in this setting (historically OS ∼3–6 months untreated, ∼8–10 months with sorafenib). HAIC safely treats PVTT cases and has demonstrated superiority over TACE/TAE or sorafenib. A prospective comparison revealed that HAIC monotherapy improved the median OS fivefold versus TACE in Vp4 cases [108]. Similarly, Chinese trials (HAIC vs. sorafenib) reported significant survival gains with HAIC in patients with major PVTT [7]. The advent of HAIC combinations has pushed survival even further. The addition of lenvatinib and tislelizumab to HAIC has increased ORR to 77.1% and extended median OS from 6.9 to 23.2 months compared with HAIC alone [109]. These unprecedented results challenge the old nihilism surrounding Vp4 PVTT; with HAIC-based therapy, a considerable subset of these patients can now live 1.5–2 years or more.

• Concurrent HTB + Vp4: patients with massive tumors and main PVTT are extremely challenging to treat. Case series indicate that only the most intensive regimens control both issues. For instance, triple regimens (FOLFOX-HAIC + TKI + PD-1) have reported a median OS of 24.6 months and a conversion-to-surgery rate of 16.5% in advanced HCC with PVTT and HTB [110]. Another study added HAIC to lenvatinib and drug-eluting bead (DEB)-TACE, which significantly improved ORR (61.2% vs. 34.1%) and OS (16.7 vs. 12.5 months) compared with lenvatinib and DEB-TACE combinations [111]. These findings emphasize that aggressive combination therapy can yield survival times previously seen only in intermediate-stage disease, thereby effectively changing the prognosis of what was once a terminal condition.

HCC with IVC/Right Atrial Tumor Thrombosis

HCC invading the IVC or extending into the right atrium (RA) represents one of the most aggressive disease phenotypes, historically associated with dismal outcomes and very limited therapeutic options. Recent data indicate that the HAIC-based “triple therapy” is also shifting the paradigm, thereby providing these patients a chance at meaningful tumor control and survival improvements.

• The rationale for HAIC in IVC/RA involvement is comparable to PVTT. It depends on its ability to directly attack tumor thrombus, whereas systemic therapy alone frequently cannot rapidly reduce a large intravascular tumor burden that is causing hemodynamic complications. A comparative study of 115 patients revealed that the addition of HAIC to lenvatinib and PD-1 inhibitors doubled median PFS (13.8 vs. 5.1 months) and significantly extended OS (22.2 vs. 14.4 months) compared with systemic therapy alone [112]. This was accompanied by a marked increase in ORR (68.7% vs. 37.5%) and disease control rate (92.5% vs. 75%).

• A larger multicenter analysis (n = 355) confirmed that triple therapy (ICI-TKI-HAIC) is superior to either ICI-TKI doublets or HAIC monotherapy, with median OS reaching 18.0 months – a significant improvement over the 7.1–7.5 months observed in the comparison groups [113].

Safety and Tolerability: Navigating the Toxicity of Intensive Therapy

As HAIC transitions from monotherapy to complex combinations, the focus has shifted from procedural safety to the management of “systemic-local” toxicity synergies. Overall, HAIC itself is generally well-tolerated when delivered properly; however, combination therapies can lead to overlapping adverse events (AEs).

• HAIC monotherapy toxicity: HAIC alone produces mostly mild to moderate side effects. The most common AEs include increased transaminases (∼50%), hypoalbuminemia (∼57%), and hematologic changes, including anemia (∼43%) and thrombocytopenia (∼35%). These are usually grades 1–2 [114] and manageable with supportive care. Serious complications, such as hepatic decompensation, are uncommon in patients with CP-A, occurring in a minority of cases.

• Added toxicity with TKIs and ICIs: the addition of TKIs introduces specific extrahepatic risks, notably hand-foot skin syndrome (48.0%) and hypertension (49.9%) [114]. The integration with immunotherapy further increases laboratory-based toxicity rates, including neutropenia (82.9%) and transaminase spikes (97.1%) rather than clinical symptoms [114].

• The “triple therapy” combination: this combination demonstrates a higher cumulative incidence of AEs. However, most side effects remain low grade and manageable with dose adjustments, prophylactic medications (e.g., antihypertensives, skin care for hand-foot syndrome), or immunosuppressants for immune-related events. A concept emerging from trials is that triple therapy increases the number of AEs, while maintaining a “beneficial equilibrium” where the therapeutic gain in survival justifies the increased but controllable toxicity burden. The vast majority of side effects are controlled or reversed quickly if recognized early. In experienced centers, treatment discontinuation rates due to toxicity have been relatively low, indicating that clinicians can keep patients on therapy by proactive monitoring and supportive care.

• Specialized complication: HAIC introduces some unique or rare risks. Catheter-related complications for pump implantation, such as infection or thrombosis, have been discussed-strict aseptic technique and routine port flushes mitigate these [115]. Gastroduodenal ulcers (due to chemo reflux into gastric arteries) and chemical cholangitis or biliary strictures (from chemo exposure to bile ducts) are regional side effects of intra-arterial chemo. HAIC-induced biliary strictures can now be successfully addressed through robot-assisted interventions [116]. These are infrequent and can be minimized with proper catheter placement and extrahepatic collateral coiling.

• Organ-specific monitoring: cisplatin-based protocols carry a risk of drug-induced colitis, requiring close gastrointestinal surveillance [117]. The use of intra-arterial lidocaine has proven effective in improving patient tolerance for oxaliplatin-related vascular pain [118].

• Rare but severe events: clinicians must remain alert for tumor lysis syndrome in HTB cases [119]. Appropriate hydration and monitoring of electrolytes help prevent this life-threatening complication. Further, immunotherapy-related rare events, including platelet transfusion refractoriness, require specialized strategies such as human leukocyte antigen-matched transfusions [120].

A critical observation in current literature is that prospective trials report significantly higher AE rates than retrospective studies, likely due to more rigorous standardized monitoring rather than higher actual toxicity. The future of HAIC safety depends on moving from reactive management to proactive prediction. Ongoing efforts aim to develop toxicity predictive tools and standardized AE documentation. A multidisciplinary team-driven approach remains the “gold standard” for early detection. Regular assessment of liver function (e.g., bilirubin, INR, albumin) is warranted to avoid tipping patients into liver failure. Early detection of adverse trends (e.g., rising bilirubin, severe neutropenia) enables timely dose modifications. This proactive monitoring should be translated into routine practice.

Translational Frontiers: Mechanistic Insights and Innovations

The shift toward “HAIC 2.0” is driven by fundamental research focusing on two critical domains: drug delivery bioengineering and TME mechanistic modulation.

• Bioengineering drug delivery: traditional HAIC delivers free chemotherapeutic agents that are rapidly washed out by blood flow. To address this limitation, researchers are developing novel delivery systems to prolong drug retention in the liver. Nanoparticles-encapsulated chemotherapeutic drugs can target tumor tissue more effectively. For instance, Lecithin-modified bismuth nanoparticles, especially when integrated with photothermal therapy, led to significantly improved tumor suppression in a preclinical HCC model [121]. Further, specialized nanoparticle formulations are being engineered to carry dual function – for HAIC, demonstrating dual benefits, both deliver chemotherapy and exert anti-inflammatory properties to protect normal liver tissue [122].

• Sustained-release systems: to address the need for prolonged exposure without prolonged infusion times, novel Pickering emulsions for oxaliplatin have been developed [123]. These systems provide a sustained-release mechanism that increases local drug concentration and therapeutic efficacy, thereby potentially simplifying future clinical protocols.

• Immunomodulation by HAIC: HAIC is increasingly recognized to demonstrate immunological effects that complement its cytotoxicity. For example, oxaliplatin in the HAIC regimen induces immunogenic cell death of cancer cells, specifically via a mechanism called pyroptosis. A recent study revealed that oxaliplatin triggers the caspase-3/GSDME pathway, induces immunogenic cell death, and activates CD8+ T cells. Patients with high tumor GSDME expression experienced greater immune activation and tumor shrinkage, indicating the potential of this pathway to be a biomarker for selecting patients for HAIC + immunotherapy [91].

• Advanced single-nucleus RNA sequencing has demonstrated that HAIC reshapes the TME in favor of the immune response. T-cell infiltration is significantly increased in patients with HCC treated with HAIC plus lenvatinib and a PD-1 inhibitor [105]. Furthermore, HAIC promotes the formation of tertiary lymphoid structures and improves CD4+ T-cell and B-cell activity, indicating the induction of long-term immune memory against HCC [124]. This implies that HAIC is converting “cold” tumors into “hot” ones, making them more susceptible to immunotherapy’s attack. Such findings provide a biological rationale for the remarkable efficacy demonstrated with HAIC-immunotherapy combinations.

These translational insights guide future strategies, finding the role of HAIC from a purely cytotoxic intervention to a biological primer. They indicate that future research should move beyond “trying different drugs” toward biomarker-driven HAIC, where the patient’s baseline immune and genetic landscape dictates the choice of regimen. Fundamental research will continue to feed into clinical innovation, ensuring that “HAIC 2.0” is not just about pumping chemo but also about smartly targeting tumor biology.

Health Economic Evaluation: The Value of HAIC in HCC

The cost-effectiveness of HAIC is an important consideration for broader adoption in parallel with clinical efficacy. HAIC involves interventional procedures and potentially hospital stays; thus, it must justify its cost by producing substantial survival or quality-of-life gains. Encouragingly, recent pharmacoeconomic analyses from Asia reveal that HAIC-based strategies provide good value in the advanced HCC setting [100, 125–128] (Table 3). A 2024 Chinese study assessed HAIC plus sorafenib versus sorafenib alone for HCC with portal vein invasion and revealed that adding HAIC yielded additional quality-adjusted life years at an acceptable incremental cost, making HAIC cost-effective under conventional willingness-to-pay thresholds [35]. Another analysis comparing HAIC (FOLFOX) with TACE for large unresectable HCC revealed that HAIC not only improved survival outcomes but also demonstrated greater cost-effectiveness per quality-adjusted life year gained than TACE, due to better tumor control reducing downstream costs of liver failure and hospitalization [126]. Similar studies have favored adjuvant HAIC post-resection in microvascular invasion-positive HCC, indicating that it may promptly prevent costly recurrences and, thus, be economically justified [128].

• Cost-effectiveness differs by region (e.g., depending on drug and hospital costs). However, HAIC moves the needle on survival in advanced HCC; thus, it is a financially viable addition to therapy, especially if focused on the high-risk patients who stand to gain the most. Wider availability of HAIC could actually reduce overall healthcare burden by decreasing the requirement for repetitive TACE or managing end-stage complications that occur with less effective treatments. Health economic data are crucial to convince healthcare systems and payers to support HAIC programs as part of standard HCC care.

Table 3.

Summary of cost-effectiveness studies

Study	Treatment comparison	Key findings	ICER (USD/QALY)	QALY	Cost
Li et al. [125]	SoraHAIC vs. sorafenib (portal vein invasion)	Not cost-effective; needs region-specific WTP thresholds	77,132/QALY	1.18/0.52	$65,254/$14,280
Zhang et al. [126]	HAIC-FO vs. TACE (large HCC)	HAIC-FO cost-effective vs. TACE for large HCC in China	9,247/QALY	2.28/1.27	$19,788/$10,407
Chen et al. [100]	HAIC vs. sorafenib (high-risk HCC)	HAIC cost-effective vs. sorafenib for high-risk HCC	10,190/QALY	0.70/0.34	$16,306/$12,600
Gao et al. [127]	HAIC-FO vs. sorafenib (advanced HCC)	HAIC-FO cost-effective vs. sorafenib for advanced HCC in China	9,720/QALY	1.06/0.65	$22,781/$18,795
Chen et al. [128]	SoraHAIC vs. sorafenib (HCC-Vp3-4)	SoraHAIC cost-effective vs. Sorafenib for HCC-Vp3-4 in China	18,237/QALY	1.66/0.42	$32,972/$10,508

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; USD, united states dollar; WTP, willingness-to-pay; HAIC, hepatic arterial infusion chemotherapy; TACE, transarterial chemoembolization; HCC, hepatocellular carcinoma; SoraHAIC, sorafenib plus hepatic arterial infusion chemotherapy; HAIC-FO, HAIC with fluorouracil, leucovorin, and oxaliplatin.

Comparative Positioning of HAIC, TACE, and SIRT

Clinicians now must decide which approach (or combination) is best suited for a given patient with the clinical utility of liver-directed therapies: HAIC, TACE, or SIRT. Each modality has its strengths and ideal context.

• HAIC vs. TACE: the key difference is that TACE depends on arterial embolization (delivering chemo-drug via DEBs or lipiodol and cutting off blood supply), whereas HAIC delivers continuous, high-dose chemotherapy without ischemia, which may be suboptimal or contraindicated in patients with PVTT. Conversely, in advanced HCC with PVTT, TACE is frequently not feasible because embolization could precipitate liver failure. By maintaining arterial flow, HAIC can safely and effectively treat PVTT cases [129]. Indeed, randomized trials have demonstrated superior outcomes with HAIC in patients with PVTT or large tumors (≥7–8 cm) [44, 130–133]. Further, HAIC serves as a potent salvage strategy for patients who have undergone multiple TACEs and the tumor is no longer responding (TACE-refractory). One study reported that FOLFOX-HAIC doubled OS (17.1 vs. 9.1 months) and achieved a 32% response in patients who failed TACE, compared with switching to sorafenib, which had minimal benefit [134, 135]. Therefore, the current paradigm is emerging. TACE is used for patients who meet traditional intermediate-stage criteria (where embolization works well), but HAIC is favored for patients with MVI or very large tumors where TACE is less effective or unsafe.

• Integration (TACE + HAIC): rather than an either/or choice, some scenarios benefit from combining TACE and HAIC as mentioned. For instance, a patient with huge tumors and PVTT may receive a sequential approach. For patients with huge tumors and PVTT, TACE is initially administered to treat satellite nodules and induce ischemia in parts of the tumor, followed by HAIC to continuously bathe the tumor and thrombus with chemotherapy. Early reports of such a combined approach, especially when combined with systemic therapy, demonstrate remarkable outcomes, achieving ORRs of 60%–83% and 1-year OS rates exceeding 90% [76, 136, 137]. Thus, the boundary between TACE and HAIC is becoming fluid. They can be allies in a treatment plan, not just alternatives.

• HAIC vs. SIRT: while HAIC has extensive roots and widespread utilization in East Asia, SIRT (TARE with yttrium-90 microspheres) is widely adopted in Western clinical practice and is firmly integrated into major Western treatment algorithms. The decision between these two nonocclusive modalities hinges on regional practice patterns, distinct mechanistic properties, and specific clinical scenarios.

Mechanistic and Therapeutic Distinctions

SIRT delivers localized, high-dose internal radiation via microembolic spheres, inducing permanent DNA damage and tumor necrosis. It is typically administered as a single or two-stage procedure, offering a favorable quality-of-life profile. Conversely, HAIC delivers continuous intra-arterial chemotherapy over repeated cycles. This requires catheter maintenance but allows for flexible dose adjustments. Safety profiles differ accordingly: SIRT requires meticulous pretreatment mapping to avoid lung shunting and carries risks of radiation-induced liver disease, whereas HAIC is associated with catheter-related complications and systemic chemotoxicity (e.g., myelosuppression).

Clinical Scenarios and Evidence

Current comparative and indirect evidence suggests different optimal niches. HAIC is frequently preferred for patients with massive, diffuse high intrahepatic tumor burden or major main-trunk PVTT (Vp4). In these scenarios, the wide radiation field required for SIRT increases the risk of hepatic decompensation, whereas HAIC has demonstrated robust survival benefits and rapid tumor shrinkage. Conversely, SIRT is highly favored for localized bulky tumors, segmental or lobar PVTT (Vp2/Vp3), or as a bridge-to-resection/transplant (“radiation lobectomy”), excelling in providing durable radiologic responses and local control. Network meta-analyses reflect this dichotomy, indicating that while HAIC frequently ranks highest for OS in advanced HCC with PVTT [138], SIRT excels in achieving sustained ORRs and tumor volume reduction [139]. Current evidence directly comparing HAIC and SIRT remains limited, and most data are derived from indirect comparisons. These findings highlight their complementary roles rather than strict competition.

Combination with Systemic Therapies

Both modalities are increasingly paired with systemic therapies. HAIC, in conjunction with systemic therapy, provides a continuous cytotoxic effect that rapidly reduces tumor bulk and synergizes with PD-1 inhibitors by favorably altering the tumor microenvironment. Parallel to this, SIRT combined with immunotherapy (e.g., atezolizumab-bevacizumab) is actively under investigation, aiming to capitalize on radiation-induced immunogenic cell death to stimulate a broader systemic antitumor immune response. Looking forward, combination and sequencing strategies may further optimize outcomes. Emerging approaches integrating HAIC or SIRT with systemic therapies are under active investigation and may help bridge locoregional and systemic treatment paradigms.

Ultimately, an optimal utilization strategy could be as follows: TACE remains the preferred standard for intermediate-stage disease, with intact portal flow where embolization is most effective. However, HAIC (or TACE + HAIC therapy combined with systemic therapy) emerges as the superior choice due to its higher response rates and proven survival benefits for patients presenting with “advanced” features – specifically PVTT and HTB, or diffuse intrahepatic disease. SIRT occupies a distinct niche, providing superior durable local control and potent tumor reduction through precise radiation delivery.

These modalities are complementary, and the future likely depends on tailored therapy: the treatment selected (or combined) will depend on tumor characteristics (e.g., size, number, vascular invasion), patient condition, regional expertise, and treatment goals (downstaging vs. survival extension vs. symptom control). The upcoming guidelines are anticipated to reflect a more stratified approach.

Limitations of Current Evidence and Future Perspectives

This review highlights many advances regarding the existing literature; however, several inherent limitations must be acknowledged.

• Temporal gap in level 1 evidence: the “modern era” of HAIC is defined by its combination with ICIs and TKIs; however, much of the high-level evidence – specifically meta-analyses [82–85] – incorporates data from the preceding decade. These studies primarily assess HAIC as a monotherapy or combination when sorafenib was the only standard systemic therapy. Thus, they compare HAIC to a now-outdated “standard-of-care” arm. An indirect cross-trial comparison indicates that HAIC may still outperform even modern systemic therapy in patients with high-risk HCC, with improved OS (HR: 0.30, 95% confidence interval: 0.12–0.72) [140]; however, direct evidence is lacking.

• Overlap of meta-analyses: multiple meta-analyses frequently included the same set of primary studies, which can potentially overemphasize positive findings. We have attempted to cite the most recent or comprehensive analyses, but readers should be aware that the apparent volume of evidence is inflated by overlapping datasets reported in slightly different ways.

• Geographic and etiological bias: the majority of the long-term data cited originates from East Asian (e.g., China, Japan, Korea) cohorts with a high prevalence of HBV- or HCV-infected and treated at high-volume centers with specialized HAIC expertise. The results may not fully extrapolate to Western populations, where HCC frequently originates from NASH/NAFLD, and HAIC experience is limited. Ongoing efforts are warranted to globalize HAIC evidence, including trials in Western countries and collaborative studies.

• Standardization challenges: there is heterogeneity in HAIC protocols across studies (e.g., different drugs, dosing schedules, use of port vs. catheter, number of cycles). This makes it challenging to compare outcomes directly and to identify what the “optimal” HAIC regimen is. International consensus on standard HAIC regimens and endpoints would greatly improve the interpretability of future research and the adoption of HAIC in broader practice.

Despite the limitations, the inclusion of earlier foundational studies in our review provides a benchmark of HAIC’s historical performance, upon which the 2020–2025 breakthroughs build. Ongoing evolution of systemic therapy means HAIC must continually prove itself against increasing standards; however, current data indicate that it will remain highly relevant, especially for those challenging cases where systemic therapy alone is insufficient.

Future research priorities include the following: (1) conducting large multicenter RCTs of HAIC + systemic therapy versus systemic therapy alone in the new treatment landscape; (2) investigating biomarkers (e.g., genomic, immunologic, radiologic) in prospective trials to refine patient selection, where HAIC is administered to those who will derive the most benefit; (3) simplifying HAIC delivery – through innovations, such as outpatient pump devices, improved catheter systems, or longer acting drug formulations – to make it more accessible beyond specialized centers; (4) continued cost-benefit analyses in different healthcare settings to understand the effect of HAIC on healthcare economics when widely implemented.

Conclusion: Toward a New Treatment Paradigm in Advanced HCC

The therapeutic landscape for advanced HCC is undergoing a fundamental transformation, with HAIC appearing as a cornerstone of this evolution. Moving beyond its historical role as a localized palliative measure, HAIC has now demonstrated robust clinical efficacy – particularly for high-risk subgroups with PVTT or HTB – where traditional embolic and systemic monotherapies frequently fall short.

The Paradigm Shift: From Monotherapy to Systemic-Local Synergy

The most significant advancement in the 2020–2025 era is the integration of HAIC into multimodal “triple therapy” frameworks. Using the immunogenic cell death induced by intra-arterial chemotherapy (e.g., oxaliplatin) and the rapid debulking of large intrahepatic tumors, HAIC functions as a powerful catalyst that enhances the effects of TKIs and ICIs. This synergy has not only improved response rates and survival outcomes but has also redefined “unresectable,” thereby significantly increasing the conversion-to-surgery rates. Patients once deemed inoperable due to tumor extent are now, in a subset of cases, being downstaged to curative resection with the help of HAIC combinations.

Challenges and the Path Forward

Despite these breakthroughs, three critical hurdles must be overcome to move HAIC from an “Asian-centric” success to a globally adopted standard of care.

• Standardization: international consensus on HAIC protocols is an urgent need. Variations in drug regimens (FOLFOX vs. FP) and delivery methods (ports vs. catheters) must be resolved to ensure reproducibility of findings across centers. Standardizing the administration of HAIC and the measurement of outcomes will facilitate large-scale multicenter trials and regulatory approvals.

• Precision Selection: future research is recommended to move beyond “all-comer” populations toward biomarker-guided strategies to identify which patients benefit most from HAIC. This will maximize benefit and prevent unnecessary risk in non-responders.

• Global integration: the efficacy of HAIC in diverse populations needs to be validated. Trials in Western countries where nonviral HCC is prevalent (e.g., NASH/NAFLD populations) are warranted to confirm that HAIC improves outcomes on top of current systemic therapies. If positive, such data would guide the incorporation of HAIC into Western guidelines, truly establishing it as a global standard for advanced HCC.

In summary, HAIC is no longer just an “alternative” locoregional therapy. It has become an integral component of the modern precision oncology for HCC. Current evidence positions HAIC as a key component in the comprehensive management of advanced HCC. It provides a valuable therapeutic option to improve survival and potentially curative outcomes for patients with large or invasive tumors who previously had limited options. As treatment strategies increasingly move toward more individualized, multimodal treatment algorithms, HAIC is poised to maintain and expand its role, working synergistically with systemic therapies to push the boundaries of what is achievable in advanced HCC.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was supported by the National Natural Science Foundation of China (No. 82402403, No. 82372061, and No. 82072022) and Guangdong Basic and Applied Basic Research Foundation (No. 2025A1515011330).

Author Contributions

Qi-Feng Chen: writing – original draft, visualization, methodology, investigation, funding acquisition, and conceptualization. Song Chen: writing – original draft, validation, methodology, and investigation. Xiongying Jiang: writing – review and editing, validation, supervision, and investigation. Jiongliang Wang: writing – review and editing, validation, supervision, and conceptualization. Ming Zhao: writing – review and editing, validation, supervision, project administration, funding acquisition, and conceptualization. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Funding Statement

This study was supported by the National Natural Science Foundation of China (No. 82402403, No. 82372061, and No. 82072022) and Guangdong Basic and Applied Basic Research Foundation (No. 2025A1515011330).