Clinical outcomes and prognostic factors of systemic therapy combined with interventional treatment in hepatocellular carcinoma: a multicenter retrospective case series

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumour in the world and the third leading cause of cancer deaths (1). Although various treatment modalities are effective and systematic treatment strategy has greatly advanced in the past several years, the prognosis for patients with intermediate and advanced HCC remains poor, with a 5-year survival rate of less than 20% (2). Since liver cancer is often diagnosed at an advanced stage, many patients have already lost the opportunity for curative therapy at the time of diagnosis. Additionally, due to the shortage of donor livers, only a small proportion of patients have the chance to undergo liver transplantation. Transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have long been the cornerstones of locoregional therapy for intermediate or advanced HCC. These approaches aim to induce ischemic necrosis and deliver high concentrations of chemotherapeutic agents directly to the tumor, making them effective for patients with unresectable HCC. However, repetitive procedures and liver function deterioration are main drawbacks of such treatment. Recurrence and treatment resistance are also significant challenges (3).

In recent years, the advent of systemic therapies, particularly targeted therapies and immunotherapies, has revolutionized the treatment landscape of advanced HCC (4). Targeted therapies, such as tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor (VEGF) inhibitors, not only disrupt critical signaling pathways involved in tumor proliferation and angiogenesis but also possess immune-modulating effects that enhance the anti-tumor immune response. Immunotherapies, including immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) and CTLA-4 pathways, reprogram the immune microenvironment, enabling robust anti-tumor responses. The combination of targeted therapy, anti-angiogenesis treatments, and ICIs offers survival benefits for patients with unresectable HCC. However, only a subset of patients exhibits response to such combination (5).

The combination of locoregional therapies like TACE or HAIC with systemic therapies has garnered considerable attention in recent years. Locoregional therapies such as TACE induce ischemic tumor necrosis and have been shown to promote the release of tumor-associated antigens, thereby triggering immunogenic cell death and enhancing antitumor immune priming (6-8). However, TACE inevitably leads to intratumoral hypoxia, which activates hypoxia-inducible pathways and results in the upregulation of VEGF. Elevated VEGF not only promotes angiogenesis and tumor revascularization after embolization but also contributes to an immunosuppressive tumor microenvironment by impairing dendritic cell (DC) maturation, inducing myeloid-derived suppressor cells (MDSCs), and promoting T-cell exhaustion. Bevacizumab, a monoclonal antibody targeting VEGF, can counteract TACE-induced hypoxia-driven angiogenesis and partially normalize tumor vasculature, thereby improving immune cell infiltration and reversing VEGF-mediated immunosuppression. This vascular normalization effect has been shown to enhance the efficacy of ICIs by facilitating cytotoxic T-cell trafficking and sustaining antitumor immune responses (9). In this context, atezolizumab, a PD-L1 inhibitor, may exert enhanced antitumor activity following TACE-induced immunogenic cell death when combined with VEGF blockade. Therefore, the combination of TACE with anti-VEGF therapy and immune checkpoint inhibition is supported by a strong biological rationale and may produce synergistic antitumor effects in patients with advanced HCC (10,11). Concurrently, systemic therapies, including targeted agents and ICIs, mitigate residual tumor growth and inhibit angiogenesis, thereby addressing the limitations of locoregional treatments (7). Based on such synopsis, studies like EMRALD-1 and LEAP-012 and many other real-world studies have demonstrated the clinical benefit of combining systemic therapies with locoregional treatments (12,13). In real clinical practice, patients are more heterogeneous than patients in clinical trials with strict inclusion criteria.

Up to now, there is limited real-life data regarding the efficacy of such combination treatment in northeastern China. Although large real-world cohorts from South Korea, the USA, and China have reported population-level outcomes of locoregional therapy combined with systemic treatment in HCC. The present study focuses on a granular, center-level description of how TACE is integrated with immunotherapy-based systemic regimens in routine clinical practice. Furthermore, it still remains unknown whether there are relevant biomarkers to guide such a combinational strategy. Therefore, we conducted this real-world study without specifically defining the treatment line of the systemic treatment. We hope this would provide additional evidence from a real-world setting and shed a light on the potential predicative biomarkers to guide decision making process. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1915/rc).

Methods

Study population

This retrospective study included patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC ineligible for curative therapies between May 2020 and December 2024 at three tertiary cancer centers in China: Tianjin Medical University Cancer Hospital, Harbin Medical University Cancer Hospital, Jilin Provincial Cancer Hospital. Patients received TACE combined with ICIs and an anti-VEGF agent. Atezo plus Bev could have been administered as either first-line or subsequent-line therapy, depending on individual clinical decision.

Eligible patients were required to meet the following inclusion criteria: age ≥18 years, adequate liver function, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and the presence of at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients were excluded if they had a known history of autoimmune disease, incomplete baseline clinical or imaging data, or were lost to follow-up during the study period. A total of 44 patients were initially screened. After applying the predefined inclusion and exclusion criteria, 11 patients were excluded due to incomplete baseline data or loss to follow-up, leaving 33 patients for the final analysis. All baseline variables for the included patients were complete, and therefore no missing data were present in the final analytic cohort.

The albumin-bilirubin (ALBI) score was applied to evaluate liver function, based on serum albumin and total bilirubin concentrations (14). A total of 33 eligible patients were included in the analysis. Patients were classified into ALBI grade 1 (score ≤−2.60), grade 2 (−2.60< score ≤−1.39), or grade 3 (score >−1.39) according to established cutoff values. The ALBI grading system provides an objective and validated measure of hepatic functional reserve in patients with HCC. A total of 33 eligible patients were included in the analysis.

Treatment regimens were classified as first-line if administered as the initial systemic therapy for HCC, and as second-line if given following any prior systemic treatment. Both treatment-naïve and previously treated patients were eligible for inclusion. For atezolizumab, it was administered intravenously at a fixed dose of 1,200 mg every three weeks, while bevacizumab was administered at a median dose of 7.26 mg/kg [standard deviation (sd) =1.52], adjusted according to patient tolerance and clinical experience. Treatment was continued until radiologic disease progression or the development of unacceptable toxicity.

TACE procedure

This study standardized adopted a “on-demand” approach for conventional TACE (cTACE). All TACE procedures were performed through super selective catheterization and embolization, prioritizing maximal preservation of liver function. The selection and dosage of chemotherapeutic agents and embolic materials during TACE were adjusted according to clinical guidelines and drug availability. For patients with viable tumors observed on follow-up imaging or those exhibiting intrahepatic recurrence, repeat TACE procedures were considered in accordance with clinical guidelines (15).

Statistical analysis

Kaplan-Meier survival analyses were performed to estimate the distributions of PFS and OS across subgroups stratified by key clinicopathologic variables. Group differences were evaluated using the log-rank test, and results were presented with corresponding P values. All analyses were conducted using R software (version 4.10). The “survival” and “survminer” packages were used for Kaplan-Meier analyses. A two-sided P value <0.05 was considered statistically significant.

Outcome

The primary endpoints of this study were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from the initiation of combination therapy (TACE plus systemic treatment) to the first documented disease progression or death from any cause, whichever occurred first. OS was defined as the time from the initiation of treatment to death from any cause. Patients who had not experienced an event at the time of data cutoff were censored at their last follow-up visit.

The secondary endpoint was the objective response rate (ORR), assessed according to both the modified RECIST (mRECIST) and RECIST version 1.1 guidelines. Tumor response was evaluated by independent radiologic review based on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) performed at baseline and every 6–12 weeks during treatment. ORR was defined as the proportion of patients achieving complete response (CR) or partial response (PR).

Exploratory endpoints included the identification of predictive factors associated with PFS and OS, including baseline demographic characteristics, liver function status, tumor burden, history of prior liver resection, number of TACE sessions, and presence of extrahepatic metastasis. These factors were analyzed using univariate and multivariate Cox proportional hazards regression models to explore their prognostic significance.

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Jilin Cancer Hospital (approval No. 202506-003-01). Given the retrospective nature of the study, the requirement for informed consent was waived by the ethics committee. The other participating institutions were also informed and agreed the study. All patient data were anonymized and handled with strict confidentiality throughout the research process.

Results

Patient characteristics

Patients were retrospectively identified through electronic medical record systems at the participating centers. Eligible patients represented consecutive cases who received TACE combined with immunotherapy-based systemic treatment during the study period. A total of 33 patients with HCC were enrolled, with a mean age of 55.3 years (sd =8.89). The median follow-up was 15 months for OS and 17 months for PFS, estimated using the reverse Kaplan-Meier method. The cohort was predominantly male (90.9%, n=30), with only 3 female patients (9.1%). Hepatitis B virus (HBV) infection was the primary etiology (97.0%), followed by hepatitis C virus (HCV) infection (3.0%). Based on the Child-Pugh classification, 69.7% of patients were class A and 30.3% were class B. Most patients (97.0%) had an ECOG performance status (PS) of 0, while one patient (3.0%) had a status of 1. According to the China Liver Cancer (CNLC) staging system, 27.3% were classified as stage IIb, 42.4% as stage IIIa, and 30.3% as stage IIIb. Under the BCLC staging system, 24.2% were at stage B and 75.8% at stage C. The ALBI grade was 1 in 60.6% of patients and grade 2 in 39.4%. A history of liver resection was present in 39.4% of the cohort. Vascular invasion was observed in 66.7% of patients, and extrahepatic metastases in 30.3%. With regard to locoregional treatment modalities, 72.7% of patients received TACE alone, 24.2% received TACE combined with HAIC, and one patient (3.0%) received HAIC monotherapy. The mean number of interventional procedures was 4.33 (sd =2.52). Based on body mass index (BMI), 39.4% of patients were classified as overweight (Table 1).

Primary outcomes

PFS and OS were estimated using the Kaplan-Meier method (Figure 1). According to mRECIST or RECIST version 1.1, the median PFS was 8.25 months (95% CI: 7.0–15.0). The Kaplan-Meier-estimated 12-month OS rate was 89.8% (95% CI: 79.4–100%). The estimated 24-month OS rate was 64.1% (95% CI: 39.5–100%); however, due to the limited number of patients remaining at risk beyond 24 months, survival estimates at later time points should be interpreted with caution and were considered exploratory. In contrast, the progression-free rate declined to below 25% by 20 months, indicating relatively early disease progression in a substantial proportion of patients. Despite this, the median OS was 62.13 months (95% CI: 24.0–not reached), suggesting prolonged post-progression survival in a subset of patients.

Figure 1 Kaplan-Meier curves for OS and PFS with median survival times and 95% CIs (n=33). Shaded areas represent the 95% CIs. The number of patients at risk at each time point is shown below the plot. Tick marks indicate censored observations. CI, confidence interval; NA, not reached; OS, overall survival; PFS, progression-free survival.

Secondary endpoint

Tumor response was assessed according to both mRECIST and RECIST 1.1 criteria. Based on mRECIST, the best overall response included CR in 11 patients (33.3%) and PR in 11 patients (33.3%), yielding an ORR of 66.6%. Stable disease (SD) was observed in 11 patients (33.3%), and no progressive disease (PD) was reported, resulting in a disease control rate (DCR) of 100.0% (95% CI: 89.6–100.0%). A similar response distribution was observed using RECIST 1.1, with CR in 12 patients (36.4%), PR in 10 (30.3%), and SD in 11 (33.3%). The ORR and DCR based on RECIST 1.1 were 66.7% (95% CI: 49.6–80.3%) and 100.0% (95% CI: 89.6–100.0%), respectively (Table 2). No cases of PD were observed by either criterion. Treatment-related adverse events were observed during follow-up. Among the 33 patients included in the final analysis, two patients (6.1%) experienced gastrointestinal bleeding, and four patients (12.1%) developed hypertension, which were considered adverse events associated with anti-angiogenic therapy. No unexpected safety signals were observed. There were no treatment-related deaths during the study period.

Exploratory endpoint

Univariate Kaplan-Meier analyses were performed to evaluate the impact of clinical variables on OS and PFS (Figure 2). In the OS analysis, the presence of macrovascular invasion was significantly associated with worse survival outcomes (P<0.01). No other variables demonstrated statistically significant differences in OS across subgroups. In the PFS analysis, patients with a history of liver resection showed a trend toward improved PFS, although this did not reach statistical significance (P<0.10). Other variables, including tumor burden, PS, and extrahepatic spread, were not significantly associated with PFS.

Figure 2 Univariate analysis for factors associated with OS and PFS. Kaplan-Meier survival curves for OS (A) and PFS (B), stratified by key clinical and pathological variables. Each subplot compares outcomes between two groups (orange = no, light blue = yes), with corresponding log-rank P values indicated. Tick marks represent censored cases. Variables include history of liver resection, AFP response, extrahepatic metastasis, ECOG PS, ALBI grade, tumor burden, number of interventional procedures, treatment line, and others. AFP, alpha-fetoprotein; ALBI, Albumin-Bilirubin; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PFS, progression-free survival; PS, performance status; TMB, tumor mutational burden.

Discussion

The present study provides additional evidence from real world setting that combining locoregional therapy (TACE) with systemic therapies (ICIs and anti-VEGF/TKIs) significantly improves survival outcomes and treatment response in patients with unresectable HCC even after first line. The median OS of 62.13 months and median PFS of 8.25 months observed in the combination therapy group represent a clinically meaningful advancement compared to either treatment alone (16,17).

These findings align with the growing body of literature advocating for multimodal approaches in advanced HCC management (18-20). Recent phase III trials such as LEAP-012 and EMERALD-1 have demonstrated the clinical potential of combining TACE with ICIs and anti-VEGF agents in patients with unresectable HCC (12,13). Our findings are consistent with this emerging evidence, highlighting the feasibility and therapeutic relevance of immunotherapy-based combinations in real-world settings, particularly in this HBV-predominant population. Compared with these large-scale randomized trials, our cohort comprised a higher proportion of patients with advanced-stage disease, vascular invasion, and extrahepatic metastases, which may partly explain the more limited PFS observed. Furthermore, variations in study design, including retrospective data collection and potential heterogeneity in imaging assessments, may have contributed to differences in efficacy outcomes. Nonetheless, the extended OS observed in our study suggests that even among high-risk patients, TACE combined with immunotherapy and anti-angiogenic therapy may offer meaningful long-term benefit. These findings underscore the need for further prospective studies to validate the role of such regimens in more diverse and advanced patient populations.

From a clinical safety perspective, particular concern has been raised regarding the risk of treatment-related adverse events when combining TACE with ICIs and anti-VEGF/TKIs, especially gastrointestinal or variceal bleeding, a recognized complication of anti-angiogenic therapy in patients with cirrhosis (21). In our real-world cohort, gastrointestinal bleeding occurred in two patients, and no treatment-related fatal bleeding events were observed during follow-up. These findings indicate that, with careful patient selection, baseline assessment of liver function, and routine screening and management of portal hypertension, the combination regimen can be administered with an acceptable and clinically manageable safety profile. This observation is clinically relevant, as concerns regarding bleeding risk often limit the use of anti-VEGF-based regimens in patients undergoing locoregional therapies (22).

The high ORR (66.7%) and DCR (100%) observed in this study suggest that TACE-ICI-VEGF combination therapy effectively bridges the limitations of conventional locoregional treatments. TACE-induced ischemia and localized chemotherapy likely potentiate the systemic effects of ICIs by triggering immunogenic cell death and increasing tumor immunogenicity, as hypothesized in preclinical models (23). TACE can induce tumor cell necrosis, leading to the release of neoantigens, promoting the recruitment and activation of DCs, and transforming the immunosuppressive microenvironment into an immune-supportive microenvironment (24). In this regard, once combined with immunotherapy, TACE can enable immune drugs to exert better effects in the “activated” microenvironment, thereby achieving superior therapeutic outcomes. Some studies also suggest that VEGF is not only a pro-angiogenic factor but also plays a crucial role in the formation of the immunosuppressive tumor microenvironment. Voron et al. found that targeted drugs could reduce the expression of inhibitory receptors induced by VEGF, which mediate the exhaustion of CD8⁺ T cells, suppress DC function and differentiation, and induce MDSCs (9,25). Moreover, VEGF can directly lead to the exhaustion of TOX-dependent T cells. A mouse study showed that anti-PD-1 combined with VEGFR treatment inhibited tumor growth and enhanced anti-tumor immune responses through vascular normalization (6). Given these results, the combination of TACE with anti-angiogenesis therapy and ICIs appears to overcome the intrinsic resistance of tumors to immune responses, thereby achieving better therapeutic effects. Additionally, anti-VEGF agents may counteract TACE-induced hypoxia-driven angiogenesis, reducing the risk of post-embolization revascularization (26).

First, the small sample size (n=33), which is relatively limited compared with existing literature, together with the single-arm design, restricts the generalizability of our findings. In addition, the low recruitment rate and retrospective nature of the study introduce the potential for selection bias, as stringent clinical eligibility criteria may have resulted in a highly selected patient population. Second, the retrospective design inherently limits the internal validity compared with prospective studies; however, it also reflects routine real-world clinical practice, which was one of the objectives of this analysis. Third, combination strategies involving intensified locoregional and systemic treatments may be associated with overlapping and potentially increased adverse events. Owing to the retrospective design and limited sample size, a comprehensive and graded safety analysis was not feasible in the present study. Further prospective studies with systematic adverse event reporting are warranted, as this issue is highly relevant for clinical decision-making and patient management. Finally, TACE was the predominant locoregional modality in this cohort, reflecting current clinical practice. Consequently, the applicability of our findings to combinations involving other locoregional therapies remains uncertain, highlighting an important gap for future investigation.

However, there are still exist many unanswered questions regarding this combination strategy. The optimal sequence of interventional procedure and systemic therapy, the difference of immune system stimulation between various regional therapies, the appropriate treatment course of systemic therapy and the sequential solution for patients with ideal response, these are all hot topics without standard definition. Biomarker-driven studies are also needed to identify subgroups most likely to benefit from this approach, particularly given the variable responses observed in clinical practice. Additionally, investigations into optimizing treatment sequencing (e.g., TACE before or after systemic therapy) and managing toxicity profiles will be critical for refining therapeutic protocols.

Conclusions

In conclusion, our findings reinforce the therapeutic potential of integrating locoregional and systemic therapies in advanced HCC. By addressing both local tumor control and systemic disease progression, this multimodal strategy offers a promising pathway to improve survival in a patient population historically burdened by limited options. Further validation in larger, diverse cohorts is essential to solidify these results and guide clinical practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1915/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1915/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1915/prf

Funding: This study was funded by the Science and Technology Development Plan Program of the Department of Science and Technology of Jilin Province (No. YDZJ202301ZYTS118; to principal investigator: S.Y.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1915/coif). S.Y. reports funding from the Science and Technology Development Plan Program of the Department of Science and Technology of Jilin Province (No. YDZJ202301ZYTS118). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Jilin Cancer Hospital (approval No. 202506-003-01). Given the retrospective nature of the study, the requirement for informed consent was waived by the ethics committee. The other participating institutions were also informed and agreed the study.

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

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