Efficacy and safety of transcatheter arterial embolization combined with ablation and regorafenib for unresectable hepatocellular carcinoma patients failing first-line treatment: a real-world study

Introduction

Primary liver cancer ranks sixth among the most commonly diagnosed cancers and is the third leading cause of cancer-related death (1). Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases and may arise from infection with hepatitis B virus or hepatitis C virus, chronic alcohol abuse, or metabolic syndrome (2-4). Many patients with HCC have progressed to the intermediate or advanced stage when diagnosed and are ineligible for radical and curative therapies (5). The 5-year survival rate for HCC is only 20%, while the 5-year survival rate of patients in the middle or late stage is even lower (6). Therefore, the intermediate- and advanced-stage HCC remains a focus of liver cancer treatment globally, and novel therapeutic modalities are urgently needed.

Transarterial chemoembolization (TACE) is the first-choice therapy in patients with intermediate-stage HCC and is also widely used in the treatment of advanced HCC without clearly demonstrated survival benefit; moreover, it yields a median progression-free survival (mPFS) of only 5 months (7,8). For advanced-stage HCC, systemic treatment is the preferred therapeutic strategy (9,10). From now on, immune checkpoint inhibitors (ICIs) in combination, or paired with an anti-angiogenic agent, are the gold standard treatment, offering a median overall survival rate of around 20 months (11). When contraindicated, the multityrosine kinase inhibitor (TKI) sorafenib is a first-line treatment as it exerts an antiangiogenic effect, which can extend the median overall survival (mOS) of patients with advanced-stage HCC from 8 to 11 months (12). In the noninferiority REFLECT trial (a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma), lenvatinib had similar mOS to that of sorafenib but attained a higher mPFS and objective response rate (ORR) (9). Nonetheless, the mPFS was only 7.4 months, indicating that patients’ benefit remained limited, with the majority of patients experiencing tumor progression (9). A randomized controlled phase III trial demonstrated the effectiveness of regorafenib in patients with disease progress after sorafenib treatment (13). Regorafenib has more targets and can simultaneously inhibit EGFR, FGFR, FDGFR, VEGFR, CSF-1R, and TIE2, which may be more effective for first-line treatment-resistant patients in halting tumor progression (14-16). However, outcomes for patients who receive regorafenib after failure of first-line therapy are still worse: the mPFS and mOS are only 3.4 months and 10.6 months, respectively, which does not satisfy the current clinical needs (13).

TACE can increase tumor hypoxia and the expression of hypoxia-inducible factor 1α (HIF-1α), which will upregulate the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) and increase tumor angiogenesis (15-19). This fact forms the theoretical basis for combining TACE with TKI therapy, and clinical data have further confirmed that this combination treatment can provide superior therapeutic outcomes to those of individual treatments. The TACTICS trial (A Phase 2, Prospective, Multicenter, Single-Arm Trial of Transarterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Intermediate-Stage Hepatocellular Carcinoma) confirmed the superior efficacy of TACE combined with sorafenib over TACE alone for progression-free survival (PFS) (P=0.006) (20). The LAUNCH trial (Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial) found that compared to lenvatinib alone, TACE in combination with lenvatinib significantly prolonged PFS (10.6 vs. 6.4 months; P<0.001) and OS (17.8 vs. 11.5 months; P<0.001) (21). Moreover, two phase III trials have recently confirmed the usefulness of anti-VEGF therapy for TACE in combination with ICIs (22,23). However, studies on regorafenib in combination with local treatment in patients after failure of first-line treatment are still lacking, and its efficacy in this context remains unclear. Therefore, our study aimed to assess the efficacy and safety of regorafenib in combination with TACE and ablation therapy in patients with intermediate or advanced HCC. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-337/rc).

Methods

Patients

In this single-center, retrospective cohort study, we evaluated 73 patients with HCC who underwent TACE plus ablation combined with regorafenib at Beijing You’an Hospital from April 2020 to June 2023. Among the potentially eligible patients, 16 were lost to follow-up. The diagnosis of HCC was based on the guidelines of the American Association for the Study of Liver Diseases (AASLD) (24,25). The inclusion criteria were as follows: (I) age 18–80 years; (II) Barcelona Clinic Liver Cancer (BCLC) stage B and C; (III) Child-Pugh class A and B; (IV) an Eastern Cooperative Oncology Group (ECOG) score of 0–1; and (V) patients in second-line therapy. The exclusion criteria were as follows: (I) uncorrectable coagulopathy; (II) complication with severe heart, brain, lung, kidney, or other dysfunction; (III) allergy to contrast media or regorafenib; (IV) noncompliance with prescribed medicine; and (V) incomplete clinical or follow-up data.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Beijing You’an Hospital, Capital Medical University (No. 2022111). Due to the retrospective nature of the analysis, the requirement for patient written informed consent was waived.

Clinicopathologic characteristics

Demographical and clinical data were collected up to 1 week prior to local treatment. The baseline data included age, sex, Child-Pugh classification, tumor number, tumor size, portal vein tumor thrombus (PVTT), extrahepatic metastasis, total bilirubin (TBIL), albumin (Alb), prothrombin time (PT), and alpha fetoprotein (AFP) level. The tumor size and tumor number were obtained through contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI).

TACE procedure

TACE procedures were performed by two experienced interventional radiologists. Under local anesthesia, the modified Seldinger technique was used to puncture the femoral artery. Arteriography was performed through a 5-F catheter (Terumo, Tokyo, Japan) to confirm the patency of the portal vein and the blood vessels supplying the tumor. A microcatheter was inserted into the supply artery of the tumor, and a mixture of doxorubicin and iodine oil was injected. The tumor-feeding artery was then embolized with polyvinyl alcohol particles or gelatin sponge. The blood flow was monitored until complete vessel occlusion was observed. Repeat embolization was administered if the lesion portion was not completely necrotic and the active portion exceeded 50% of the baseline value.

Ablation procedure

Ablation was performed in patients whom the multidisciplinary team (MDT) judged would achieve better local tumor control. The ablation was completed under CT or MRI guidance within 2 weeks of TACE treatment. Routine disinfection and local anesthesia were applied around the puncture points. During radiofrequency ablation (RFA), after measuring the baseline impedance, the power was gradually increased from 80 to 200 W to reach the maximum impedance. For microwave ablation (MWA), after inserting the probe into the tissue, the ablation power was 50–60 W and the time setting was 5–8 minutes. Cold saline was injected into the electrode cavity using a pump to keep the tip temperature below 20 ℃ at all times. In addition, to achieve complete ablation, the safe margin for complete ablation of the tumor was 0.5 cm; otherwise, the procedure was defined as an incomplete ablation. All patients underwent an immediate contrast-enhanced CT after ablation to assess the success of the procedure and evaluate for possible complications.

Regorafenib procedure

Regorafenib (Bayer, Leverkusen, Germany) was administered 3–7 days following the local treatment. The oral dose of regorafenib was 120 mg per day every day for 3 weeks, followed by 1 week off. One cycle of the treatment was 4 weeks. If 120 mg of regorafenib was not tolerated, the dose was down-titrated to 80 mg, or regorafenib was discontinued. According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, adverse events (AEs) included grade 3 or 4 hematologic toxicity, skin toxicity, hypertension, and/or hepatic dysfunction. Systemic therapy was administered concurrently with TACE.

Follow-up

All patients received regular follow-up at the outpatient department. Treatment response was evaluated by contrast-enhanced CT or MRI at baseline and at 6–12 weeks after treatment initiation. Tumor response was evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) (26), which includes categories of complete response (CR; the disappearance of any intratumoral arterial enhancement in all target lesions), partial response (PR; a reduction in the sum of tumor measurements of at least 30%), stable disease (SD; insufficient changes to qualify as PR or PD), and disease progression (PD; at least a 20% increase in the sum of diameters of target lesions). The ORR was calculated as the percentage of patients achieving CR or PR. Meanwhile, the disease control rate (DCR) was calculated as the percentage of patients achieving CR, PR, or SD. Patients received examinations every 3 months for the first year after therapy and every 6 months thereafter. The follow-up included blood biochemical and imaging examination for detection of recurrence. The primary endpoint of the study was OS, defined as the length of time from TACE until the date of death. The second endpoint of the study was PFS, defined as the length of time from TACE until the date of tumor progression.

Statistical analysis

All statistical analyses were carried out using R version 4.3.1 (The R Foundation for Statistical Computing). We minimized measurement bias by employing standardized data collection procedures and validated tools and controlled for confounding variables through statistical adjustments or matching. Given the scarcity of missing values, we implemented listwise deletion for cases exceeding two missing values and mean imputation for cases with one missing value. Continuous variables are expressed as the mean ± standard deviation, and t-tests or U tests were used to compare differences between groups. Categorical variables are expressed as frequencies and percentages, and differences were compared using the Chi-squared test. PFS and OS curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to identify the independent risk factors for survival and progression. A P value less than 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 73 patients were enrolled in our study, including 63 (86.3%) males and 10 (13.7%) females. Among these patients, 16 (21.9%) had PVTT and 33 (45.2%) patients had extrahepatic metastasis. There were 53 (72.6%) patients with multiple tumor numbers and 23 (31.5%) with large tumors (>30 mm). The first-line treatment for all patients was TKI therapy, of which 21 (28.8%) received TKI in combination with ICI therapy. All patients received TACE combined with regorafenib, while 37 (50.7%) had additional ICIs and 36 (49.3%) did not. The majority of patients (n=61, 83.6%) in our cohort received ablation therapy. There were 22 (30.1%) patients with an AFP level >400 U/L (Table 1).

A total of 29 (39.7%) patients received sorafenib and 44 (60.3%) received lenvatinib as first-line TKI. Fifty (68.5%) patients were treated with TKI monotherapy in the first line, while 23 (31.5%) patients received a combination of TKI and ICI. In addition, 48 (65.8%) patients underwent TACE or ablation during first-line treatment. First-line treatment failure was defined as the occurrence of PD or treatment discontinuation due to intolerance of AEs.

Efficacy

The average follow-up of the cohort was 24.6 months. The median OS was 24.0 months [95% confidence interval (CI): 6.25–41.75 months; Figure 1A] and the median PFS was 7.06 months (95% CI: 4.77–9.36 months; Figure 1B). The mOS was 38.5 months in the BCLC stage B group, whereas it was 21.1 months in the BCLC stage C group. The treatment response is shown in Table 2. The mOS for Child-Pugh A was 38.5 months (95% CI: 18.1–58.8 months), and the mOS for Child-Pugh B was 11.4 months (95% CI: 7.5–15.4 months, P=0.009). According to mRECIST, CR was observed in 10 patients (13.7%), PR in 33 patients (45.2%), SD in 24 patients (32.9%), and PD in 6 patients (8.2%). The ORR was 58.9% and the DCR was 91.8% (Table 2). Five patients with BCLC stage C achieved CR. All the five patients received a quadruple combination therapy comprising TACE, ablation, regorafenib, and PD-1. These patients uniformly presented with small tumors (<3 cm in diameter); two had extrahepatic metastases, and three had PVTT.

Figure 1 KM curves for OS and PFS. (A) KM curve of OS. (B) KM curve of PFS. KM, Kaplan-Meier; OS, overall survival; PFS, progression-free survival; TACE, transarterial chemoembolization.

A subgroup analysis was conducted for patients receiving regorafenib in combination with immunotherapy. The ORR was 52.8%. The mOS for these patients was not reached and the mPFS was 9.07 months (95% CI: 4.88–13.25 months).

Independent prognostic factors of PFS and OS

To investigate the independent risk factors for PFS and OS, univariate and multivariate Cox regression analyses were performed. The result showed that Child-Pugh classification was the independent risk factor for PFS (0.51, 95% CI: 0.28–0.94) and OS (0.36, 95% CI: 0.16–0.80) (Table 3).

Safety

Eleven patients included in the study were evaluated for safety. The most common any-grade treatment-related AEs were hand-foot syndrome (34.25%), diarrhea (23.29%), and hypertension (21.92%). Grade ≥3 treatment-related AEs occurred in 12.3% of the patients. The most common grade 3 treatment-related AE was hypertension (5.48%) (Table 4). Three (4.1%) patients discontinued regorafenib as a result of intolerance to treatment-related AEs.

Discussion

HCC is one of the most common malignant tumors, demonstrating the most rapid increase in morbidity and mortality. Despite the advancement in the treatment of HCC, efficacy remains limited (27,28). Therefore, the aim of our study was to assess the efficacy and safety of combination therapy after failure of first-line treatment. This study constitutes a descriptive analysis of real-world data (RWD). The results of the study showed that TACE plus ablation combined with regorafenib had good efficacy and safety, supporting anti-VEGF therapy plus TACE as a potential treatment for non-surgical HCC, consistent with recent phase 3 trials (LEAP012, EMERALD1) (22,23).

In our study, the mOS of second-line-treated patients receiving combination therapy was 24.6 months, which is significantly longer than the 10.9 months of all patients in the RESORCE study and the 7.9 months of the Chinese subgroup patients. The RESORCE study further reported an mPFS of 3.1 months with second-line treatment with regorafenib, which is shorter than the mPFS of 7.9 months achieved in our study (13). In another study of second-line-treated patients receiving regorafenib in combination with immunotherapy, the ORR and DCR were 33.3% and 60.0%, respectively (29). In the study by Zou et al., TACE combined with regorafenib plus PD-1 achieved ORR of 37.14% and DCR of 71.43%, whereas TACE combined with regorafenib produced the ORR of 19.51% and the DCR of 48.78% (30). The ORR and DCR in our study were 58.9% and 91.8%. Moreover, the majority (67.1%) of the patients in our study were BCLC stage C, among whom 21.9% had PVTT and 45.2% had metastasis. This further suggests the potential efficacy of TACE plus ablation combined with regorafenib.

In a 2008 Japanese study, sorafenib extended mOS from 7.9 to 10.7 months and increased the 1-year survival rate from 33% to 44% in patients with advanced HCC (12). The mPFS of lenvatinib was significantly prolonged at 8.9 months as compared with sorafenib at 3.7 months, while the ORR also improved (31). Although the first-line drugs prolonged the survival time of patients, they exhibited limited antitumor activity. Initially, one third of advanced HCC patients could benefit after a first-line systemic treatment. However, a majority succumb to the disease, suggesting that acquired resistance to first-line therapy reduces the beneficial effects and that second-line therapeutic agents are urgently needed (28,32,33). Despite sharing a few structural similarities with sorafenib, regorafenib has a different molecular target profile, with stronger action in the VEGF pathway and inhibition of various targets involved in oncogenesis (34). Regorafenib has wider potency and broader activity against VEGFR kinases, such as the angiopoietin 1 receptor TIE2 and KIT and RET (35,36). In addition to inhibiting VEGF signaling and antiangiogenic effects, regorafenib may directly inhibit pathways regulating tumor growth, proliferation, and metastasis while modulating the tumor immune microenvironment (TIME) (35,37,38). TACE occludes the blood supply artery through epirubicin and lipiodol, promoting ischemia and necrosis in tumor cells. Hypoxia leads to increased VEGF secretion, which ultimately leads to PD (38). Regorafenib can inhibit the tumor neovascularization due to TACE and exert antitumor activity (39). A previous study has demonstrated that TACE enhances the cytotoxicity of regorafenib to local tumor cells, thereby prolonging the disease control time (40).

A phase I/II trial evaluated the safety and efficacy of local ablation plus the PD-1 inhibitor toripalimab for patients with previously treated unresectable HCC. The study found that compared with toripalimab alone, RFA in combination with toripalimab had a higher ORR (33.8% vs. 16.9%; P=0.027), a longer mPFS (7.1 vs. 3.8 months; P<0.001), and a longer mOS (18.4 vs. 13.2 months; P=0.005) (41). The results suggest that incorporating ablation in combination therapy for patients with unresectable HCC improves efficacy and provides an acceptable safety profile. RFA has been found capable of decreasing the volume of tumors, releasing antigens and heat shock proteins, and promoting tumor-specific immune response (42-44). Meanwhile, RFA contributes to dendritic cell maturation, increases the ratio of CD8⁺ T cells to regulatory T cells, and improves CD8⁺ T cell-mediated antitumor immunity (45-47). Moreover, RFA may reduce the tumor vascular permeability, thereby enhancing the concentration of drug and immune cells in the tumor tissue and amplifying the antitumor effect of regorafenib (43).

A few limitations to our study should be mentioned. First, we employed a retrospective design with a small sample size, which introduced a degree of bias. Second, although improved outcomes were observed in patients receiving TACE combined with ablation and regorafenib, the absence of a control group receiving TACE and ablation alone precludes definitive conclusions regarding the additive effect of regorafenib. Prospective, multicenter, large-sample prospective studies are need to produce more reliable results.

Conclusions

TACE combined with ablation and regorafenib is an effective, safe, and promising second-line treatment option for patients with unresectable HCC after progression from first-line therapy. A multimodal approach deserves to be further explored to improve patient prognosis in intermediate/advanced HCC following first-line therapy.

Acknowledgments

The authors highly appreciate all patients who participated in the study. The abstract has been presented at the 2024 American Society of Clinical Oncology (ASCO) conference.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-337/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-337/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-337/prf

Funding: This study was funded by grants from the Beijing Municipal Natural Science Foundation (No. 7191004), the Capital Health Development Project (Nos. 2020-1-2182 and 2020-2-1153), the Beijing Key Laboratory (No. BZ0373), the Beijing Research Center for Respiratory Infectious Diseases Project (No. BJRID2024-007), Construction of Research-Oriented Wards in Beijing Municipality, Laboratory for Clinical Medicine, Capital Medical University (No. SYLH2023-06), and the National Natural Science Foundation of China (No. 82202025).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-337/coif). X.A. receives grants for statistical expenses from Boston Scientific; payment for lectures from Bayer, Roche, Gilead, Servier; support for meetings from Gilead and Roche, outside the submitted work. 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Beijing You’an Hospital, Capital Medical University (No. 2022111). Due to the retrospective nature of the analysis, the requirement for patient written informed consent was waived.

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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