Addition of Intra-Arterial Therapy to Immunotherapy Improves Outcomes in Unresectable Hepatocellular Carcinoma: Taiwan Multicenter Cohort Study

Abstract

Introduction

Evidence supporting the combination of immunotherapy with intra-arterial therapy (IAT) for unresectable hepatocellular carcinoma (HCC) remains limited. This study aimed to evaluate whether the addition of IAT to first-line immunotherapy improves survival outcomes.

Methods

Using the Taiwan Liver Cancer Association (TLCA) Research Group database, we identified patients with unresectable HCC who initiated first-line immunotherapy between May 2017 and January 2024. Patients with Barcelona Clinic Liver Cancer (BCLC) stage A or D disease, prior liver transplantation, or follow-up of <6 weeks were excluded. Eligible patients received either IAT (transarterial chemoembolization, radioembolization, or hepatic arterial infusion chemotherapy) at the initiation of immunotherapy or immunotherapy alone. After 1:3 propensity score matching, 90 and 270 patients were included in the IAT and control groups, respectively. Overall survival (OS) was analyzed using adjusted hazard ratios (aHRs) in a time-dependent model.

Results

The IAT group achieved a higher objective response rate (46.7% vs. 26.3%; p < 0.001) and a longer duration of response (median 19.0 [IQR: 9.7–36.6] vs. 11.0 [IQR: 8.4–23.1] weeks; p = 0.009) than the control group. IAT was independently associated with improved OS (aHR 0.53, 95% CI: 0.37–0.75; p < 0.001). Factors associated with worse OS included Child-Turcotte-Pugh class B (aHR 1.41, 95% CI: 1.01–1.97; p = 0.042), albumin-bilirubin grade >1 (aHR 1.58, 95% CI: 1.11–2.27; p = 0.012), tumor burden beyond the up-to-7 criteria (aHR 1.67, 95% CI: 1.02–2.74; p = 0.043), and portal vein invasion (aHR 1.67; 95% CI: 1.19–2.35; p = 0.003). Five-year OS was higher in the IAT group than in the control group (28.7% [95% CI: 17.8–46.2] vs. 16.4% [95% CI: 10.7–25.2]; p = 0.007). Landmark and subgroup analyses consistently supported the OS benefit of IAT.

Conclusion

In unresectable HCC, the addition of IAT to first-line immunotherapy improves response rates, prolongs the duration of response, and enhances OS.

Introduction

Immune checkpoint inhibitor (ICI) therapy is currently the standard of care for patients with advanced-stage hepatocellular carcinoma (HCC) [1–3], and is also recommended for selected patients with intermediate-stage disease who are unsuitable for locoregional therapies, such as transarterial chemoembolization (TACE) [4]. Although ICIs provide more durable responses when compared with tyrosine kinase inhibitors (TKIs), their objective response rates (ORRs) remain limited [5–7], and only a minority of patients achieve long-term survival. Thus, more effective treatments with higher ORRs are urgently needed for unresectable HCC.

Intra-arterial therapy (IAT), including TACE, transarterial radioembolization (TARE), and hepatic arterial infusion chemotherapy (HAIC), can offer effective control of intrahepatic tumors, with TACE having long been the standard treatment for intermediate-stage HCC [4]. These modalities share a common procedural principle, namely, the delivery of therapeutic agents directly into liver tumors via the hepatic arterial system, and this grouping has been commonly utilized in prior clinical studies. Furthermore, growing laboratory evidence suggests that IAT may enhance antitumor immunity, potentially augmenting the efficacy of systemic immunotherapy [8]. With its ability to achieve high intrahepatic response rates and its potential immune-boosting effect, IAT represents a promising partner for immunotherapy in the management of unresectable HCC [9]. However, clinical evidence supporting this approach remains limited, particularly regarding its overall survival (OS) benefit in advanced disease.

Several randomized controlled trials, primarily involving patients with Barcelona Clinic Liver Cancer (BCLC) stage B disease, have demonstrated that combining TACE with immunotherapy can delay tumor progression [10, 11]. However, these studies did not show an OS benefit, likely influenced by confounders after first-line treatment and immature follow-up data. In BCLC stage C disease, single-arm trials have reported promising ORRs and potential survival benefits [12], but confirmatory evidence from randomized controlled trials is lacking [13]. Real-world evidence is also limited to a few small-scale studies [14–16]. Therefore, we aimed to investigate the OS benefit of combining IAT with immunotherapy as a form of first-line treatment for unresectable HCC in a multicenter cohort study with a comparable control group.

Methods

Study Design

This retrospective multicenter cohort study analyzed patients receiving ICI-based immunotherapy for HCC using data taken from the Taiwan Liver Cancer Association (TLCA) Research Group (TRG) database. The TRG database is a comprehensive registry designed to collect and manage clinical data from patients undergoing systemic therapy for HCC across multiple medical centers in Taiwan. As of the end of April 2025, a total of 11 medical centers were participating in the registry. Detailed demographic, clinical, and treatment information from each site is systematically recorded. This study adhered to the prevailing ethical guidelines and principles of the Helsinki Declaration, and received approval from the Institutional Review Board of Taichung Veterans General Hospital (IRB number: CE24331B). The Institutional Review Board waived the need for written informed consent due to the retrospective nature of the study.

Study Population and Data Collection

As shown in Figure 1, we screened all patients registered in the TRG database and identified 723 individuals with HCC who initiated first-line immunotherapy between May 2017 and January 2024 and were followed until the end of April 2025. HCC was diagnosed by histological or typical image findings based on the clinical practice guidelines [1–3]. After excluding patients diagnosed with BCLC stage A or D, those having prior liver transplantation, insufficient imaging follow-up, or a follow-up duration of less than 6 weeks, 638 patients who received ICI-based therapy as first-line treatment for unresectable HCC were included. Eligible patients were categorized into two cohorts: (1) the IAT cohort, comprising those who had received TACE, TARE, or HAIC within 4 weeks of initiating immunotherapy; and (2) the control cohort, comprising those who had received immunotherapy alone. Locoregional therapies with curative intent were permitted in the control cohort. Finally, patients were, respectively, included in the IAT group and the control group following propensity score matching (PSM) to balance their baseline characteristics.

Fig. 1.

Flowchart of patient selection. BCLC stage, Barcelona Clinic Liver Cancer stage; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; IAT, intra-arterial therapy; ICI, immune checkpoint inhibitor; LRT, locoregional therapy.

We retrieved comprehensive data from the TRG database for analysis, including patient demographic characteristics (e.g., age, gender, and body mass index); liver disease etiologies (e.g., hepatitis B virus [HBV] infection, hepatitis C virus [HCV] infection, and alcohol use); underlying comorbidities (e.g., liver cirrhosis and diabetes mellitus); laboratory data (e.g., Child-Turcotte-Pugh [CTP] score, aspartate aminotransferase, alanine aminotransferase, platelet count, fibrosis index based on four factors [FIB-4] score, albumin, bilirubin, and albumin-bilirubin [ALBI] grade); tumor characteristics (e.g., maximum intrahepatic tumor size, number of liver tumors, up-to-7 criteria status, infiltrative tumor morphology, portal vein invasion, extrahepatic metastasis, BCLC stage, and alpha-fetoprotein [AFP] levels); and ICI regimens. ICI regimens were categorized into three groups: (1) ICI monotherapy (e.g., nivolumab, pembrolizumab or durvalumab); (2) ICI plus TKI combinations (e.g., atezolizumab + bevacizumab, pembrolizumab + lenvatinib, nivolumab + sorafenib, nivolumab + lenvatinib, pembrolizumab + sorafenib, nivolumab + bevacizumab, or nivolumab + bevacizumab + lenvatinib); and (3) ICI plus ICI combinations (e.g., nivolumab + ipilimumab or durvalumab + tremelimumab).

Study Outcomes

The primary endpoint of this study was OS of the study subjects. For adequately investigating the treatment efficacy of IAT in this study, tumor responses were accessed based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria (e.g., complete response [CR], partial response [PR], stable disease, and progression disease) [17]. ORR and disease control rate [DCR] were also calculated. In addition, duration of tumor response, duration of immunotherapy, treatment discontinuation due to treatment-related adverse effects, and subsequent systemic therapy were all recorded.

Statistical Analysis

Data are expressed as median values with interquartile ranges (IQR, 25–75% percentiles) for continuous variables, and as counts with percentages for categorical variables. As appropriate, the Student’s t test was used to compare continuous variables, while either the chi-square test or Fisher’s exact test was used to compare categorical variables. A time-dependent multivariable Cox proportional hazards regression model was applied to identify independent factors associated with OS, with IAT exposure treated as a time-varying variable. Clinically relevant covariates were selected for the multivariable analysis, and a backward elimination method with a selection criterion of 0.157 was used [18]. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were reported. The Kaplan-Meier method was used to estimate the cumulative incidence of patient mortality, while the log-rank test was applied to compare survival distributions between the two study groups. A p value <0.05 was considered statistically significant. Baseline characteristics were balanced using PSM. Given that an SMD <0.1 indicates adequate balance, the PSM procedure was refined accordingly rather than relying solely on p values. The “cmprsk” package in R was used to construct the Cox proportional hazards models. Data management and statistical analyses were conducted using the SAS Enterprise Guide.

Results

Baseline Characteristics

Figure 1 illustrates the patient selection process. In the crude cohort before matching (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000552375), several baseline characteristics differed between the IAT and control groups, including diabetes mellitus, FIB-4 index, tumor burden beyond the up-to-7 criteria, and infiltrative tumor morphology. These baseline imbalances underscore the importance of using PSM to reduce potential confounding when comparing survival outcomes between treatment strategies. Following a 1:3 PSM ratio, 90 patients in the IAT group and 270 patients in the control group were included in the final analysis. As shown in Table 1, baseline characteristics did not differ significantly between the two groups. Overall, most patients were in late middle age, predominantly male, more than 50% HBV-infected, had compensated liver function, and were presented with a high tumor burden (approximately 90% beyond the up-to-7 criteria, >50% with portal vein invasion, >40% with extrahepatic metastasis, with approximately 85% at BCLC stage C). More than 80% of patients received ICI plus TKI combination therapy. The cohort was stratified into two equal time periods (2017–2020 and 2021–2024), and patient distribution was well balanced between groups. Within the IAT group, 64.4%, 27.8%, and 7.8% of patients received TACE, HAIC, or TARE, respectively, at the initiation of immunotherapy. The median interval between ICI initiation and IAT was 1.5 (IQR: 0.2–2.7) weeks. The median number of IAT was 1.0 (IQR: 1.0–2.8). In the overall cohort, the median observation period was 37.0 (IQR: 18.5–70.2) weeks, and a total of 205 (56.9%) death events were recorded during the study period.

Table 1.

Baseline characteristics of the study subjects

Variables	IAT group (n = 90)	Control group (n = 270)	SMD	p value
Age, years	63.5 (53.9–72.2)	63.5 (56.5–69.8)	0.034	0.840
Male, n (%)	71 (78.9%)	223 (82.6%)	0.037	0.529
HBV infection, n (%)	49 (54.4%)	145 (53.7%)	0.016	0.893
HCV infection, n (%)	16 (17.8%)	46 (17.0%)	0.013	0.910
Alcohol drinking, n (%)	19 (21.1%)	59 (21.9%)	0.007	>0.999
Diabetes mellitus, n (%)	37 (41.1%)	86 (31.9%)	0.093	0.140
BMI, kg/m2	23.3 (21.4–26.3)	23.4 (21.2–26.2)	0.043	0.976
Liver cirrhosis, n (%)	39 (43.3%)	142 (52.6%)	0.093	0.162
CTP class	​	​	0.063	0.274
A	74 (82.2%)	205 (75.9%)	​	​
B	16 (17.8%)	65 (24.1%)	​	​
AST, U/L	54.0 (38.0–94.0)	61.5 (41.2–97.0)	0.100	0.456
ALT, U/L	40.5 (27.0–62.5)	39.0 (25.0–66.0)	0.044	0.483
Platelet, k/mm3	199.5 (142.0–284.5)	189.5 (137.0–274.8)	0.068	0.665
FIB-4 index	2.9 (1.7–4.7)	3.2 (2.0–5.2)	0.049	0.140
Albumin, g/dL	3.8 (3.4–4.2)	3.7 (3.4–4.1)	0.042	0.578
Bilirubin, mg/dL	0.8 (0.5–1.3)	0.9 (0.6–1.3)	0.056	0.248
ALBI grade	​	​	0.085	0.116
1	43 (47.8%)	98 (36.3%)	​	​
2	45 (50.0%)	159 (58.9%)	​	​
3	2 (2.2%)	13 (4.8%)	​	​
Liver tumor size (Max.), cm	8.1 (4.8–12.0)	8.9 (4.0–12.1)	0.013	0.994
Liver tumor number	​	​	0.083	0.187
≤3	45 (50.0%)	111 (41.1%)	​	​
4–5	10 (11.1%)	24 (8.9%)	​	​
≥6	35 (38.9%)	135 (50.0%)	​	​
Tumor burden beyond up-to-7 criteria	82 (91.1%)	233 (86.3%)	0.048	0.311
Infiltrative tumor morphology	12 (13.3%)	53 (19.6%)	0.063	0.235
Portal vein invasion	48 (53.3%)	154 (57.0%)	0.037	0.624
Extrahepatic metastasis	37 (41.1%)	112 (41.5%)	0.004	>0.999
BCLC stage	​	​	0.037	0.466
B	14 (15.6%)	32 (11.9%)	​	​
C	76 (84.4%)	238 (88.1%)	​	​
AFP >400 ng/mL	41 (45.6%)	135 (50.0%)	0.044	0.543
ICI regimens	​	​	0.031	0.370
ICI monotherapy1	14 (15.6%)	30 (11.1%)	0.044	0.353
ICI + TKI combination2	74 (82.2%)	228 (84.4%)	0.022	0.741
ICI + ICI combination3	2 (2.2%)	12 (4.4%)	0.022	0.531
Case enrollment period	​	​	0.033	0.646
2017–2020	26 (28.9%)	87 (32.2%)	​	​
2021–2024	64 (71.1%)	183 (67.8%)	​	​
Combined IAT
TACE	58 (64.4%)	–	​	​
TARE	7 (7.8%)	–	​	​
HAIC	25 (27.8%)	–	​	​
Interval between IAT and ICI, weeks	1.5 (0.2–2.7)	​	​	​
Number of IAT	1.5 (1.0–3.0)	–	​	​

ALT, alanine aminotransferase; AST, aspartate aminotransferase; FIB-4, fibrosis-4; HAIC, hepatic arterial infusion chemotherapy; HBV, hepatitis B virus; HCV, hepatitis C virus; IAI, intra-arterial therapy; ICI, immune checkpoint inhibitor; SMD, standardized mean difference; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; TKI, tyrosine kinase inhibitor.

¹Nivolumab, pembrolizumab or durvalumab.

²Atezolizumab + bevacizumab, pembrolizumab + lenvatinib, nivolumab + sorafenib, nivolumab + lenvatinib, pembrolizumab + sorafenib, nivolumab + bevacizumab, or nivolumab + bevacizumab + lenvatinib.

³Nivolumab + ipilimumab, or durvalumab + tremelimumab.

Analysis of Treatment Responses

Table 2 summarizes the treatment responses of the study population. Overall, the ORR was significantly higher in the IAT group when compared with the control group (46.7% vs. 26.3%; p < 0.001), as well as being driven by higher rates of CR (16.4% vs. 5.6%) and partial response (32.2% vs. 20.7%). The disease control rate was also significantly higher in the IAT group (75.6% vs. 61.5%; p = 0.022). Notably, compared with the control group, the IAT group exhibited a significantly higher rate of clinical CR, defined as a CR with normalized tumor markers maintained for ≥ 6 weeks (12.2% vs. 4.4%; p = 0.018) [19]. The IAT group also had a greater proportion of patients who achieved curative conversion after curative-intent locoregional therapies (10.0% vs. 2.6%; p = 0.006), including hepatectomy (6.7% vs. 1.9%; p = 0.032). While detailed treatment continuation strategies after CR were heterogeneous and not protocolized, a numerically higher but not statistically significant proportion of patients in the IAT group achieved clinical CR with drug-free status (6.7% vs. 3.7%; p = 0.376). Furthermore, both the median duration of tumor response (19.0 weeks, IQR: 9.7–36.6 vs. 11.0 weeks, IQR: 8.4–23.1; p = 0.009) and the median duration of immunotherapy (20.5 weeks, IQR: 11.0–43.1 vs. 15.6 weeks, IQR: 7.5–28.6; p = 0.011) were significantly longer in the IAT group than in the control group.

Table 2.

Clinical outcomes of the study subjects

Variables	IAT group (n = 90)		Control group (n = 270)		p value
Tumor response, n (%)1	​	​	​	​	0.003
CR	13	(14.4)	15	(5.6)	​
PR	29	(32.2)	56	(20.7)	​
SD	26	(28.9)	95	(35.2)	​
PD	22	(24.4)	99	(36.7)	​
ORR	42	(46.7)	71	(26.3)	<0.001
DCR	68	(75.6)	166	(61.5)	0.022
Clinical CR2	11	(12.2)	12	(4.4)	0.018
Curative conversion3	9	(10.0)	7	(2.6)	0.006
Curative conversion by hepatectomy	6	(6.7)	5	(1.9)	0.032
Clinical CR with drug-free status	6	(6.7)	10	(3.7)	0.376
Duration of response, week	19.0	(9.7–36.6)	11.0	(8.4–23.1)	0.009
Immune therapy duration, week	20.5	(11.0–43.1)	15.6	(7.5–28.6)	0.011
Discontinuation due to TRAE, n (%)	8	(8.9)	30	(11.1)	0.692
Subsequent systemic therapy, n (%)	19	(21.1)	47	(17.4)	0.529

CR, complete response; DCR, disease control rate; IAT, intra-arterial therapy; mRECIST, modified Response Evaluation Criteria in Solid Tumors; PR, partial response; SD, stable disease; PD, progression disease; ORR, objective response rate; TRAE, treatment-related adverse effect.

¹Tumor responses were evaluated based on the mRECIST criteria.

²CR with normalized tumor markers maintained for ≥ 6 weeks.

³Curative conversion was defined as a clinical CR after HCC treatments performed with curative intent, including local ablation and surgical intervention.

Only a small proportion of patients discontinued immunotherapy due to treatment-related adverse effects (8.9% vs. 11.1%; p = 0.692). The proportions of patients receiving subsequent systemic therapies after therapy discontinuation were comparable between groups (22.1% vs. 17.4%; p = 0.529).

Survival Benefits in Patients with Objective Responses

Figure 2a illustrates OS during the follow-up period after immunotherapy, with patients stratified into four groups: IAT with objective response (OR), IAT without OR, control with OR, and control without OR. The 5-year OS rates were significantly higher in patients with OR when compared with those without OR: 52.6% (95% CI: 36.2–76.4) in the IAT with OR group, 36.5% (95% CI: 22.1–60.3) in the control with OR group, 9.4% (95% CI: 2.6–33.3) in the IAT without OR group, and 8.7% (95% CI: 4.3–17.7) in the control without OR group (p < 0.001). Achieving an OR was unequivocally associated with improved OS.

Fig. 2.

OS. a Stratified by treatment group and OR status: IAT with OR, IAT without OR, control with OR, and control without OR. b Stratified by treatment group (IAT versus control) during follow-up after initiation of immunotherapy. IAT, intra-arterial therapy; OR, objective response.

Analysis of OS Related to IAT Combination

Table 3 presents the results of a time-dependent multivariable Cox regression analysis of prognostic factors for OS in the PSM-matched cohort. After adjustments for HBV infection, HCV infection, body mass index, CTP class, ALBI grade, tumor burden beyond the up-to-7 criteria, and portal vein invasion, IAT combination was independently associated with improved OS (aHR 0.53, 95% CI: 0.37–0.75; p < 0.001). HBV infection (aHR 0.69, 95% CI: 0.50–0.94; p = 0.021) and HCV infection (aHR 0.61, 95% CI: 0.39–0.94; p = 0.025) were also prognostic factors associated with better OS. In contrast, CTP class B (aHR 1.41, 95% CI: 1.01–1.97; p = 0.042), ALBI grade >1 (aHR 1.58, 95% CI: 1.11–2.27; p = 0.012), tumor burden beyond the up-to-7 criteria (aHR 1.67, 95% CI: 1.02–2.74; p = 0.043), and portal vein invasion (aHR 1.67, 95% CI: 1.19–2.35; p = 0.003) were independent prognostic factors associated with poorer OS. In addition, we performed multivariable Cox regression analysis in the crude (unmatched) cohort to account for residual confounding. As shown in online supplementary Table 2, IAT combination therapy remained independently associated with improved OS (aHR 0.62, 95% CI: 0.45–0.86; p = 0.004), consistent with the PSM cohort.

Table 3.

Time-dependent multivariable Cox regression analysis of prognostic factors for OS

​	N	Events	Univariable analysis		Multivariable analysis1
			HR (95% CI)	p value	HR (95% CI)	p value
IAT combination	90	46	0.60 (0.44–0.82)	0.001	0.53 (0.37–0.75)	<0.001
Age, years	360	205	1.00 (0.99–1.01)	0.712	​	​
Male, n (%)	294	160	0.79 (0.57–1.08)	0.138	​	​
HBV infection, n (%)	194	104	0.81 (0.61–1.06)	0.120	0.69 (0.50–0.94)	0.021
HCV infection, n (%)	62	34	0.81 (0.58–1.14)	0.227	0.61 (0.39–0.94)	0.025
Alcohol drinking, n (%)	78	44	1.14 (0.83–1.58)	0.415	​	​
Diabetes, n (%)	123	72	1.03 (0.78–1.37)	0.828	​	​
BMI, kg/m2	360	205	0.98 (0.94–1.01)	0.234	0.97 (0.94–1.01)	0.147
Liver cirrhosis, n (%)	181	106	1.00 (0.77–1.32)	0.978	​	​
CTP class (B vs. A)	81	56	2.01 (1.47–2.74)	<0.001	1.41 (1.01–1.97)	0.042
FIB-4 index	360	205	1.04 (1.01–1.06)	0.004	​	​
ALBI grade (>1 vs. 1)	219	144	2.13 (1.59–2.86)	<0.001	1.58 (1.11–2.27)	0.012
Tumor burden >up-to-7 criteria	315	186	1.91 (1.24–2.94)	0.003	1.67 (1.02–2.74)	0.043
Infiltrative tumor morphology	65	44	1.53 (1.12–2.09)	0.008	​	​
Portal vein invasion	202	126	2.02 (1.53–2.68)	<0.001	1.67 (1.19–2.35)	0.003
Extrahepatic metastasis	149	85	1.09 (0.82–1.44)	0.552	​	​
BCLC stage (C vs. B)	314	180	1.49 (1.05–2.11)	0.026	​	​
AFP >400 ng/mL	176	102	1.29 (0.98–1.70)	0.069	​	​
ICI regimen (combo vs. mono)	316	178	1.03 (0.68–1.58)	0.884	​	​

AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; BMI, body mass index; CTP, Child-Turcotte-Pugh; FIB-4, fibrosis-4 index; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IAT, intra-arterial therapy; ICI, immune checkpoint inhibitor; N, number.

¹The multivariable model using a backward elimination method with a selection criterion of 0.157, without preceding univariable prefiltering.

Figure 2b illustrates the differences in OS between the two study groups during follow-up after immunotherapy. The 5-year OS rate was significantly higher in the IAT group when compared with the control group: 28.7% (95% CI: 17.8–46.2) vs. 16.4% (95% CI: 10.7–25.2; p = 0.007). However, among patients receiving TACE, TARE or HAIC in the IAT group, the OS rates did not differ significantly (p = 0.314; online suppl. Fig. 1). In addition, the incidence of hepatic decompensation during immunotherapy was not significantly different between the IAT and control groups (33.3% vs. 41.9%; p = 0.192).

Given that IAT was administered within 4 weeks of immunotherapy initiation, we also conducted a 4-week landmark analysis to further mitigate potential immortal time bias. As shown in online supplementary Figure 2, patients who received IAT combination therapy continued to demonstrate significantly improved OS compared with the control group (5-year OS: 28.7% [95% CI: 17.8–46.2] vs. 16.8% [95% CI: 10.9–25.8]; p = 0.011).

Furthermore, sensitivity analyses were conducted using multivariable stratified analysis for patient subgroups. As shown in Figure 3, the HRs for IAT combination versus immunotherapy alone were generally below 1.0 across most subgroups, and the interaction tests were not statistically significant (P for interaction > 0.05), which indicates no evidence of differential treatment effect between subgroups. Statistically significant associations were observed in some subgroups, including age > 65 years, male sex, CTP class A or B, ALBI grade 2–3, tumor burden beyond the up-to-7 criteria, non-infiltrative tumor morphology, presence or absence of portal vein invasion, BCLC stage C, AFP ≤400 ng/mL, and case enrollment period 2021–2014.

Fig. 3.

Subgroup sensitivity analyses of the association between IAT combination and OS. aHR, adjusted hazard ratio; IAT, intra-arterial therapy.

Discussion

Recent randomized trials involving TACE plus ICIs have shown delayed disease progression in unresectable HCC patients; however, most participants had been diagnosed with early or intermediate-stage disease, limiting inferences regarding long-term OS in advanced HCC [10, 11]. To the best of our knowledge, this multicenter, propensity-matched cohort, comprising predominantly BCLC stage C patients and including a comparable control group, is the first to demonstrate an OS benefit when IAT is initiated alongside first-line immunotherapy in unresectable HCC. These findings provide encouraging evidence for this combined-modality approach and suggest potential implications for clinical practice, particularly in patients diagnosed with advanced disease. A proof-of-concept randomized trial is still warranted in order to validate these results and define the optimal integration of IAT with systemic immunotherapy.

The significantly higher ORR observed with IAT combination therapy is likely the main driver of the improved OS observed. In patients with HCC who achieve an objective response to immunotherapy, tumor responses are often durable. Data from clinical trials suggest that the extent of tumor shrinkage is strongly associated with improved OS, with patients who achieve deep responses deriving the greatest survival benefit [20]. In particular, accumulating evidence indicates that patients achieving CR derive the most substantial long-term survival benefit. Recent studies have demonstrated excellent survival outcomes in patients who achieve CR, whether through immunotherapy alone or via conversion strategies incorporating locoregional therapies [21, 22]. However, the ORRs with immunotherapy alone remain suboptimal [5–7], which may substantially diminish survival benefits in patients who fail to respond [23]. In this context, IAT, such as TACE, is a well-established modality for intrahepatic tumor control, demonstrating a significantly higher ORR than systemic therapy alone in patients with HCC in BCLC stage B, including those with a high tumor burden [24–26]. Thus, it is reasonable to expect that combining IAT with immunotherapy can improve ORR and, in turn, survival outcomes.

The increased ORR observed with IAT combination therapy may result not only from direct tumor control but also from the potentiation of antitumor immune responses elicited by immunotherapeutic agents. Most HCCs are considered “cold tumors” within the tumor immune microenvironment, which helps explain the relatively low ORR with immunotherapy alone [27]. However, emerging evidence suggests that IAT can augment antitumor immune responses by promoting tumor-associated antigen (TAA) release and enhancing tumor-specific T-cell activity [28]. Several studies have reported that IAT therapies may serve as immune boosters to strengthen TAA-specific T-cell responses [29–32]. Although IAT alone may be ineffective in patients with BCLC stage C disease, its capacity to enhance immune responses could provide meaningful benefits when combined with immunotherapy. Although similar biological mechanisms may also be achieved by other locoregional modalities, such as radiotherapy, this study deliberately restricts the analysis to IAT to ensure internal consistency and interpretability. Further studies are warranted to evaluate other locoregional modalities in combination with immunotherapy. Although similar biological mechanisms may also be achieved by other locoregional modalities, such as radiotherapy, this study deliberately restricts the analysis to IAT to ensure internal consistency and interpretability. Further studies are warranted to evaluate other locoregional modalities in combination with immunotherapy.

Despite the observed OS benefit at the population level, the clinical applicability of IAT combination therapy depends critically on appropriate patient selection. In this study, patients in BCLC stage D were excluded as they are generally not candidates for IAT-based combination strategies. Moreover, the baseline characteristics of the unmatched cohort indicate that patients receiving IAT more frequently had a lower FIB-4 index, a higher tumor burden beyond the up-to-7 criteria, and less infiltrative tumor morphology (online suppl. Table 1). These differences likely reflect real-world clinical selection of patients with higher tumor burden but more favorable tumor biology and adequate hepatic reserve for IAT. In addition, our subgroup analyses provide preliminary signals that may help inform patient selection. The association between the IAT combination and improved survival was statistically significant in higher tumor burden, non-infiltrative tumor morphology, BCLC stage C disease, and AFP ≤400 ng/mL. These observations suggest that patients with advanced intrahepatic disease but without unfavorable tumor features may be more likely to benefit from treatment intensification [33, 34]. Interestingly, although IAT has traditionally been associated with hepatotoxicity [35], our subgroup analysis suggests that more vulnerable patients, such as those aged > 65 years, CTP class B, and ALBI grade 2–3, may still derive benefit from IAT combination therapy. Ultimately, achieving a robust tumor response to immunotherapy appears to be the most critical determinant of survival, and the optimal intensity of IAT for these patients warrants further investigation. However, these observations are based on post hoc subgroup analyses and should be interpreted with caution. They are not sufficient to guide clinical decision-making in isolation. Further well-designed studies aimed at identifying predictive factors to better define the population most likely to benefit from IAT combination therapy remain essential.

Several limitations of this study should be acknowledged. First, as a retrospective observational study, it is unable to establish a definitive causal relationship, even though the association between the addition of IAT and improved OS was consistent across all statistical approaches, including the trial emulation framework, baseline characteristic matching, multivariable regression in both the crude and matched cohorts, time-dependent models, landmark analyses, and subgroup analyses. Additional evidence, preferably from prospective interventional studies, is required before clinical recommendations can be made. Second, the techniques and expertise for performing IAT may vary across hospitals. Nevertheless, this multicenter study still demonstrated a survival benefit through the use of IAT, suggesting that the effect of such a variation is likely to be minimal. Third, two-thirds of patients in the IAT group received TACE, and the number of patients receiving either HAIC or TARE was insufficient for adequately powered subgroup analyses. However, OS did not differ significantly among patients receiving TACE, TARE, or HAIC within the IAT group (online suppl. Fig. 1). While this finding does not establish equivalence, it provides preliminary support that the observed survival benefit is unlikely to be driven exclusively by a single modality. Future studies with larger sample sizes will be essential in order to better compare outcomes among different IAT modalities. Fourth, although the ICI regimens were similar in the two study groups, the majority of patients in our cohort received ICI plus TKI combinations. Therefore, evidence supporting the generalizability of our findings to all immunotherapy regimens should be interpreted with caution, and further studies including more diverse immunotherapy backbones are required to confirm the applicability of our results across different immunotherapy regimens. Fifth, standardized follow-up intervals for liver function assessment across centers were lacking in this retrospective study, limiting additional insight into treatment-related hepatotoxicity. However, the incidence of hepatic decompensation during immunotherapy was not significantly different between the two study groups (IAT vs. control: 33.3% vs. 41.9%), and the observed OS benefit in the IAT group reflects a net clinical benefit that inherently integrates both efficacy and treatment-related risks. Prospective studies incorporating predefined, time-dependent liver function monitoring protocols will be essential to more precisely characterize the hepatic safety profile of IAT in combination with immunotherapy.

In conclusion, this multicenter cohort study provides the first evidence that combining IAT with immunotherapy confers a significant survival advantage in patients with unresectable HCC, particularly those diagnosed with advanced-stage disease. These findings highlight the potential of IAT toward enhancing the efficacy of systemic immunotherapy while also supporting its integration as a combined-modality strategy in this challenging population. A randomized trial remains essential in order to confirm these results and, thus, define the optimal role of IAT in the evolving treatment landscape of advanced HCC.

Acknowledgments

The authors would like to thank the TLCA for providing administrative support and for establishing the TLCA Research Group (TRG) database. We also wish to express our gratitude to our many study assistants who contributed to this work, including Ms. Ti-Jung Yen at Taipei Veterans General Hospital and Ms. Fang-Ling Chou at Taichung Veterans General Hospital, for their assistance with data curation and statistical analyses.

Statement of Ethics

This study adhered to the prevailing ethical guidelines and principles of the Helsinki Declaration and received approval from the Institutional Review Board of Taichung Veterans General Hospital (IRB No.: CE24331B). The Institutional Review Board waived the need for written informed consent due to the retrospective nature of the study.

Conflict of Interest Statement

Teng-Yu Lee reports research funding from Gilead and Roche diagnostics; consulting fees from AstraZeneca, BMS, and Eisai; and honoraria from AstraZeneca, BMS, Eisai, Gilead, Ono Pharmaceuticals, and Roche. Yi-Hsiang Huang reports research funding from Gilead Sciences and consulting fees from Bristol-Meyers Squibb, Ono Pharmaceuticals, Eisai, AstraZeneca, and Roche. The other authors declared no conflicts of interest.

Funding Sources

This work was supported in part by the National Science and Technology Council (NSTC 112-2314-B-075A-010-MY3, NSTC 112-2314-B-A49-032-MY3), Taichung Veterans General Hospital (TCVGH-1140402C, TCVGH-1150403C, TCVGH-VTA113V112, TCVGH-VTA114V112), and Taipei Veterans General Hospital (V115C-113), Taiwan. The funders played no role in the design or conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Author Contributions

Study conception and design and manuscript drafting: T.Y.L. and Y.H.H. Data acquisition, analysis, and interpretation: T.Y.L., P.C.L., Y.C.S., W.F.H., C.W.C., Y.Y.S., T.H.S., P.T.L., C.Y.D., C.S.H., S.C.C., K.M.R., I.C.L., S.R.J., T.H.L., H.C.L., T.E.W., S.M.L., P.C.L., C.H.T., P.Y.C., S.C.W., H.W.W., S.W.L., and Y.H.H. Critical revision for important intellectual content: T.Y.L., Y.C.S., and Y.H.H. All authors contributed to the revision of the final manuscript.

Funding Statement

This work was supported in part by the National Science and Technology Council (NSTC 112-2314-B-075A-010-MY3, NSTC 112-2314-B-A49-032-MY3), Taichung Veterans General Hospital (TCVGH-1140402C, TCVGH-1150403C, TCVGH-VTA113V112, TCVGH-VTA114V112), and Taipei Veterans General Hospital (V115C-113), Taiwan. The funders played no role in the design or conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.