Abstract
Background/aim
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. For patients with unresectable HCC, transarterial chemoembolization (TACE) combined with either radiofrequency ablation (RFA) or systemic therapy (e.g., sintilimab and bevacizumab) are emerging strategies. This study aims to compare the efficacy and safety of TACE-RFA versus TACE combined with sintilimab and bevacizumab in unresectable HCC.
Patients and methods
This retrospective cohort study included 207 patients with unresectable HCC treated from January 2021 to June 2022: 93 received TACE combined RFA and 114 received TACE combined sintilimab and bevacizumab. Baseline characteristics, laboratory parameters, tumor response, adverse events, and survival outcomes (overall survival [OS] and progression-free survival [PFS]) were analyzed. Statistical analyses employed t-tests, χ² tests, Kaplan-Meier/log-rank tests, and multivariable Cox regression to identify independent prognostic factors.
Results
Baseline characteristics were comparable. The TACE+dual-drug group achieved a higher objective response rate (ORR: 38.60% vs. 24.73%, P = 0.034) and superior survival outcomes, with longer median OS (27.24 vs. 24.17 months, P < 0.001) and PFS (10.42 vs. 8.13 months, P < 0.001). Multivariable Cox regression identified treatment group and BCLC stage as independent predictors of OS. Compared to TACE + RFA, TACE+dual-drug therapy was associated with a significantly lower risk of death (HR = 0.520, 95% CI: 0.370–0.731, P < 0.001), while BCLC stage C increased the risk of death (HR = 2.106, 95% CI: 1.412–3.146, P < 0.001). Regarding safety, the dual-drug group exhibited more pronounced hematological suppression, coagulopathy, and hepatic dysfunction (P < 0.05). Adverse events (hypertension, hand-foot syndrome, rash) were significantly more common in the TACE+dual-drug group (P < 0.01).
Conclusion
TACE combined with sintilimab and bevacizumab improves survival and tumor response over TACE-RFA but with increased systemic toxicity. Patient selection should balance efficacy and tolerability.
Keywords: Hepatocellular carcinoma, Transarterial chemoembolization, Radiofrequency ablation, Immune checkpoint inhibitors, Overall survival, Combination therapy
Introduction
Hepatocellular carcinoma (HCC) remains a major global health challenge, ranking as the third-leading cause of cancer-related mortality worldwide and accounting for approximately 8.3% of all cancer deaths [1, 2]. Patients with unresectable HCC—often diagnosed at advanced stages due to the disease’s insidious onset—lack curative surgical options, necessitating effective locoregional and systemic therapies. Transarterial chemoembolization (TACE) is a cornerstone treatment for intermediate-stage HCC, leveraging targeted ischemia and cytotoxic drug delivery to control tumor progression [3, 4]. However, its limitations in achieving complete tumor necrosis, particularly in larger lesions or those with compromised vascular supply, have driven the pursuit of combinatorial strategies to enhance therapeutic efficacy.
Two distinct multimodal paradigms have emerged to address these limitations. The first combines TACE with radiofrequency ablation (RFA), a synergistic approach wherein TACE reduces tumor vascularity and size, thereby potentiating RFA’s ablative capability. This combination has demonstrated superior survival outcomes compared to monotherapy, with significant improvements in 3-year overall survival (OS) and recurrence-free survival, particularly for tumors ≥ 5 cm [5–7]. The second paradigm integrates TACE with systemic agents, notably immune checkpoint inhibitors (e.g., sintilimab) and anti-angiogenic drugs (e.g., bevacizumab). This strategy exploits TACE’s ability to release tumor antigens and modulate the tumor microenvironment, potentially augmenting responses to immunotherapy and anti-angiogenic therapy [8–10]. Retrospective studies report promising outcomes for such combinations, including objective response rates (ORR) of 46.7–62.8% and median OS exceeding 22 months [8, 10].
Despite these advances, critical knowledge gaps persist. First, while both TACE-RFA and TACE-immunotherapy/anti-angiogenic regimens show efficacy [11–13], direct comparative evidence evaluating their relative efficacy, safety, and survival impact within a well-defined cohort of unresectable HCC patients remains scarce. Second, existing studies predominantly compare each combination against TACE alone, leaving clinicians without robust data to inform the choice between these increasingly utilized therapeutic pathways. Furthermore, comprehensive assessments encompassing not only traditional survival metrics but also detailed analyses of tumor response, longitudinal laboratory parameter changes, and distinct adverse event profiles are needed to clarify the risk-benefit ratio of each strategy.
Therefore, this retrospective cohort study aims to address this significant clinical question. We sought to directly compare the efficacy and safety of TACE combined with RFA versus TACE combined with sintilimab and bevacizumab in patients with unresectable HCC. Our analysis focuses on short-term tumor response, longitudinal changes in key laboratory indicators, the spectrum and severity of treatment-related adverse events, and crucially, survival outcomes. By providing this comparative data, our study endeavors to offer valuable insights to guide therapeutic decision-making for patients facing unresectable HCC.
Patients and methods
Participants
This retrospective cohort study included 207 patients with unresectable hepatocellular carcinoma who were treated with transarterial chemoembolization (TACE) combined with either radiofrequency ablation (RFA) or sintilimab and bevacizumab at our hospital from January 2021 to June 2022. Patients were divided into two groups according to the treatment they received: the TACE combined RFA group (hereinafter referred to as the TACE + RFA group, n = 93) and the TACE combined sintilimab and bevacizumab treatment group (hereinafter referred to as the TACE+dual-drug group, n = 114). Demographic information of the patients was collected through the case system.
Inclusion criteria: (1) Age between 18 and 80 years; (2) Histologically/cytologically confirmed hepatocellular carcinoma (HCC) or clinically diagnosed HCC meeting AASLD/EASL imaging diagnostic criteria, and assessed by a clinician to be unresectable liver cancer [14] ; (3) According to mRECIST criteria, presence of at least one measurable intrahepatic lesion; (4) For patients undergoing RFA treatment, tumor location must be ≥ 0.5 cm away from the porta hepatis and gallbladder, and ≥ 1 cm away from the common bile duct and intestines; (5) Liver function classified as Child-Pugh grade A or B (≤ 7 points); (6) Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2; (7) No prior immunotherapy or anti-angiogenic treatment or other local or systemic therapies (radiofrequency ablation, iodine-125 particle implantation, etc.).
Exclusion criteria: (1) Predominantly extrahepatic metastasis or main portal vein tumor thrombus involving contralateral branches or inferior vena cava tumor thrombus; (2) Diffuse intrahepatic metastases; (3) Refractory ascites or renal failure; (4) Central nervous system metastases or other primary malignant tumors in different sites/organs; (5) Any contraindications to the drugs used in this study; (6) Recent history of gastrointestinal bleeding; (7) Pregnant or lactating women; (8) Missing clinical or follow-up data.
Given that this retrospective study utilizes anonymized patient data, it poses no potential risk to the involved patients, thereby negating the need for informed consent. Both this exemption and the research protocol have received approval from our hospital’s Ethics Review Committee, ensuring compliance with pertinent regulatory and ethical criteria.
Treatment methods
Combination treatment protocols
Patients in the TACE + RFA group received RFA treatment approximately 1–2 weeks after completing two cycles of TACE. The residual tumor was confirmed via enhanced CT or MRI before performing targeted ablation. This completed the planned combined local therapy. Subsequent management, including additional TACE sessions, was guided by tumor response and clinical judgment during follow-up. Patients in the TACE+dual-drug group were administered intravenous sintilimab combined with bevacizumab two weeks post-TACE. This systemic combination was planned for four cycles. Further therapy after these cycles, including continuation of sintilimab as maintenance or initiation of other systemic agents, was determined based on radiological response and tolerance.
Transarterial chemoembolization (TACE)
The entire TACE procedure was performed under DSA monitoring using the Seldinger technique, typically through a right femoral artery puncture for celiac trunk or superior mesenteric artery angiography. After identifying the tumor’s location, size, and number, a 4–5 F RH catheter (Cook, USA) was selectively inserted into the tumor-feeding artery, sometimes aided by a microcatheter (Terumo, Japan). Post-angiography confirmed vascular distribution, tumor blood supply, and any arteriovenous shunts. To minimize damage to normal liver tissue, chemotherapy drugs (5-fluorouracil [5-FU] 1000 mg/m², cisplatin 80 mg/m², mitomycin C 6 mg/m²) mixed with 5–30 ml lipiodol were injected into the arterial branches supplying the tumor. Gelatin sponge particles were used if necessary for additional embolization. Chemotherapy doses were adjusted based on liver function and peripheral blood counts. Post-embolization angiography confirmed the extent of vessel occlusion. Post-procedure management included pressure on the arterial puncture site and close monitoring of vital signs and complications, with symptomatic treatments as needed. Each TACE cycle lasted about four weeks, requiring a hospital stay of 7–10 days, extended if severe complications occurred.
Ultrasound-guided radiofrequency ablation (RFA)
RFA was performed under general anesthesia to alleviate patient anxiety and discomfort. Patients fasted for 4–6 h preoperatively to prevent vomiting and aspiration. Under ultrasound guidance, an RFA electrode needle (MedSphere, Shanghai) was percutaneously inserted into the target lesion. Based on tumor size and depth, the RFA generator settings (S-1500 model) were adjusted for power (up to 50 W, increasing by 10 W every 2 min) and temperature (90–110 °C). For tumors measuring 3–5 cm, 2–3 ablation points were required; larger tumors necessitated 4–8 points, ensuring a 0.5–1 cm margin beyond the tumor edge. Real-time ultrasound monitored liver tissue changes and checked for abdominal bleeding. Post-ablation, patients received intravenous sulfur hexafluoride microbubbles to assess ablation efficacy. Electrode needles were retracted while performing tract ablation to prevent bleeding and seeding. Post-RFA monitoring ensured no immediate bleeding complications, followed by transfer to the general ward. Typically, RFA was repeated every 2–3 weeks, with a hospital stay of 1–3 days, potentially extended for larger tumors or complications.
Targeted immunotherapy
Sintilimab (Innovent Biologics, Suzhou; NMPA approval No. S20180016; 10 mL: 100 mg) was administered intravenously at 200 mg every three weeks for four doses. Bevacizumab (Qilu Pharmaceutical; NMPA approval No. S20190040; 4 mL: 100 mg) was given at 5 mg/kg every three weeks for four doses.
Clinical data collection and follow-up
Clinical data were retrospectively collected from the hospital’s electronic medical record system, laboratory information system, and radiology database using standardized Excel spreadsheets. Any additional anti-tumor treatments administered during the follow-up period (such as subsequent TACE, other systemic therapies, or best supportive care) were also recorded. Baseline demographic and clinical characteristics included: age, body mass index (BMI), gender, history of alcohol consumption and smoking, Eastern Cooperative Oncology Group performance status (ECOG PS) score, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh grade, etiology (hepatitis B virus, hepatitis C virus, or non-viral), tumor size, tumor number, presence of vascular invasion, extrahepatic metastasis status, and number of TACE sessions. Longitudinal laboratory parameters and imaging data were systematically recorded at before treatment) and 3 months post-treatment initiation. The follow-up endpoint is June 2025 or death.
Evaluation methods
Laboratory parameters
Peripheral blood samples were collected at baseline (pre-treatment) and 3 months post-treatment initiation for comprehensive analysis: (1) Hematological and coagulation profiles: White blood cell count (WBC), hemoglobin (Hb), absolute neutrophil count (ANC), platelet count (PLT), prothrombin time (PT), and international normalized ratio (INR) were measured using automated analyzers (Sysmex XN-9000 for hematology; Sysmex CS-5100 for coagulation). (2) Liver and renal function: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), creatinine (Cr), and blood urea nitrogen (BUN) levels were quantified via enzymatic/colorimetric methods (Roche Cobas® 8000 analyzer). (3) Tumor markers: Serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 125 (CA125) were assessed using chemiluminescent immunoassays (Roche Cobas® 8000).
Short-term clinical efficacy evaluation
The effectiveness of the treatment in terms of tumor response was evaluated three months after the commencement of therapy through the use of contrast-enhanced CT or MRI scans, analyzed according to the RECIST 1.1 criteria [15]. Below are the detailed assessment guidelines: A Complete Response (CR) is identified by the complete absence of any arterial enhancement within all targeted lesions. Partial Response (PR) is characterized by a reduction of at least 30% in the aggregate diameters of targeted lesions observed during the arterial phase. The term Stable Disease (SD) applies when there is neither sufficient shrinkage to qualify for PR nor enough increase to fulfill the requirements for Progressive Disease (PD). PD is designated when there is an elevation of at least 20% in the total diameters of targeted lesions in the arterial phase or the emergence of new lesions. Additionally, both the Objective Response Rate (ORR), which combines CR and PR cases, and the Disease Control Rate (DCR), encompassing CR, PR, and SD cases, were computed.
Documentation of adverse events
Treatment-emergent adverse events were documented throughout the follow-up period and graded per the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [16]. Events included hypertension, hand-foot syndrome, skin rash, diarrhea, abdominal pain, fatigue, fever, decreased appetite, and vomiting.
Survival outcomes
Each patient is followed up until the end of the study or the occurrence of a death event, with outcomes recorded. Overall Survival (OS) and Progression-Free Survival (PFS) are documented.
Statistical analysis
All statistical analyses were performed using SPSS (version 22.0; IBM Corp., Armonk, NY, USA) and R software (version 4.3.1; R Foundation). Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and compared between the two treatment groups using independent samples t-tests. Non-normally distributed continuous data were analyzed with the Mann-Whitney U test. Categorical variables were presented as frequencies (%) and compared using Pearson’s χ² test or Fisher’s exact test for small cell counts. Survival outcomes were analyzed using time-to-event methods. Overall survival (OS) and progression-free survival (PFS) were calculated from treatment initiation to death/progression or last follow-up, visualized with Kaplan-Meier curves, and compared between groups using the log-rank test. To identify independent prognostic factors, multivariable Cox proportional hazards regression models were employed. Variables with potential clinical relevance or showing a trend in univariate analysis (P < 0.10) were included in the initial model, with backward stepwise selection used to derive the final model. The results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). A two-sided p-value < 0.05 defined statistical significance for all tests.
Results
Baseline demographic and clinical characteristics
The baseline demographic and clinical characteristics of the TACE + RFA group (n = 93) and the TACE+dual-drug group (n = 114) were comparable, with no statistically significant differences observed in age, BMI, gender distribution, history of alcohol consumption or smoking, ECOG PS score, BCLC stage, Child-Pugh grade, etiology, tumor size, tumor number, vascular invasion, extrahepatic metastasis status, or number of TACE sessions (all P > 0.05) (Table 1).
Table 1.
Baseline characteristics of patients undergoing TACE combined with RFA or sintilimab and bevacizumab
| Parameters | TACE + RFA group (n = 93) | TACE+dual-drug group (n = 114) | t/χ2 | P value |
|---|---|---|---|---|
| Age (years) | 54.14 ± 10.36 | 55.73 ± 9.92 | 1.125 | 0.262 |
| BMI (kg/m²) | 23.18 ± 3.46 | 22.87 ± 3.21 | 0.653 | 0.514 |
| Gender [n (%)] | 0.035 | 0.852 | ||
| - Male | 76 (81.72%) | 92 (80.7%) | ||
| - Female | 17 (18.28%) | 22 (19.3%) | ||
| History of Alcohol [n (%)] | 0.074 | 0.786 | ||
| - Yes | 48 (51.61%) | 61 (53.51%) | ||
| - No | 45 (48.39%) | 53 (46.49%) | ||
| History of Smoking [n (%)] | 0.003 | 0.957 | ||
| - Yes | 55 (59.14%) | 67 (58.77%) | ||
| - No | 38 (40.86%) | 47 (41.23%) | ||
| ECOG PS Score [n (%)] | 0.686 | 0.408 | ||
| − 0–1 points | 68 (73.12%) | 89 (78.07%) | ||
| − 2 points | 25 (26.88%) | 25 (21.93%) | ||
| BCLC Staging [n (%)] | 3.017 | 0.221 | ||
| - A | 28 (30.11%) | 23 (20.18%) | ||
| - B | 49 (52.69%) | 65 (57.02%) | ||
| - C | 16 (17.20%) | 26 (22.81%) | ||
| Child-Pugh grade [n (%)] | 0.894 | 0.344 | ||
| - Class A | 76 (81.72%) | 87 (76.32%) | ||
| - Class B | 17 (18.28%) | 27 (23.68%) | ||
| Etiology [n (%)] | 0.604 | 0.739 | ||
| - Hepatitis B virus | 80 (86.02%) | 94 (82.46%) | ||
| - Hepatitis C virus | 7 (7.53%) | 12 (10.53%) | ||
| - Without | 6 (6.45%) | 8 (7.02%) | ||
| Tumor Size [n (%)] | 1.819 | 0.177 | ||
| - ≤3 cm | 52 (55.91%) | 56 (46.49%) | ||
| - >3 cm | 41 (44.09%) | 61 (53.51%) | ||
| Tumor Number [n (%)] | 0.579 | 0.447 | ||
| - ≤3 | 72 (77.42%) | 83 (72.81%) | ||
| - >3 | 21 (22.58%) | 31 (27.19%) | ||
| Vascular Invasion [n (%)] | 1.833 | 0.176 | ||
| - Present | 26 (27.96%) | 42 (36.84%) | ||
| - Absent | 67 (72.04%) | 72 (63.16%) | ||
| Extrahepatic Metastasis [n (%)] | 0.283 | 0.595 | ||
| - Present | 13 (13.98%) | 19 (16.67%) | ||
| - Absent | 80 (86.02%) | 95 (83.33%) | ||
| TACE Sessions [n (%)] | 0.544 | 0.461 | ||
| - ≤3 | 68 (73.12%) | 78 (68.42%) | ||
| - >3 | 25 (26.88%) | 36 (31.58%) |
TACE + RFA Transarterial chemoembolization combined with either radiofrequency ablation, TACE+dual-drug Transarterial chemoembolization combined sintilimab and bevacizumab, BMI Body Mass Index, ECOG PS Eastern Cooperative Oncology Group performance status, BCLC Barcelona Clinic Liver Cancer
Changes in laboratory parameters at before treatment and 3 months post-treatment
Baseline hematological and coagulation parameters were comparable between the two groups (all P > 0.05, Table 2). At 3 months post-treatment, both groups exhibited significant declines in hemoglobin (Hb) and platelet (PLT) counts (P < 0.05); however, the TACE+dual-drug group showed significantly lower levels of WBC, Hb, ANC, and PLT compared to the TACE + RFA group (all P < 0.05). Furthermore, the TACE+dual-drug group demonstrated a significantly longer prothrombin time (PT) (13.58 ± 1.42 s vs. 13.14 ± 1.36 s, P = 0.024) and a higher international normalized ratio (INR) (1.27 ± 0.21 vs. 1.16 ± 0.19, P < 0.001). These findings suggest that the addition of sintilimab and bevacizumab to TACE therapy exerts a more pronounced impact on hematological and coagulation functions.
Table 2.
Analysis of differences in laboratory parameters between the two groups at before treatment and 3 months Post-treatment
| Parameters | Time | TACE + RFA group (n = 93) | TACE+dual-drug group (n = 114) | t | P value |
|---|---|---|---|---|---|
| Hematological and Coagulation Parameters | |||||
| WBC (×10⁹/L) | Before | 6.31 ± 1.83 | 6.29 ± 1.77 | 0.098 | 0.922 |
| 3 months | 5.88 ± 1.68 | 5.32 ± 1.84*** | 2.282 | 0.024 | |
| Hb (g/L) | Before | 133.18 ± 17.21 | 132.45 ± 16.73 | 0.309 | 0.758 |
| 3 months | 128.37 ± 15.64* | 121.45 ± 15.37*** | 3.196 | 0.002 | |
| ANC (×10⁹/L) | Before | 3.92 ± 1.31 | 3.86 ± 1.24 | 0.314 | 0.754 |
| 3 months | 3.74 ± 1.22 | 2.97 ± 1.08*** | 4.814 | < 0.001 | |
| PLT (×10⁹/L) | Before | 152.38 ± 44.27 | 148.73 ± 42.16 | 0.606 | 0.545 |
| 3 months | 136.42 ± 39.17* | 122.84 ± 36.71*** | 2.569 | 0.011 | |
| PT (s) | Before | 12.76 ± 1.31 | 12.83 ± 1.27 | 0.414 | 0.679 |
| 3 months | 13.14 ± 1.36 | 13.58 ± 1.42*** | 2.268 | 0.024 | |
| INR | Before | 1.11 ± 0.17 | 1.12 ± 0.18 | 0.500 | 0.618 |
| 3 months | 1.16 ± 0.19 | 1.27 ± 0.21*** | 3.986 | < 0.001 | |
| Hepatic and Renal Function | |||||
| ALT (U/L) | Before | 52.87 ± 21.64 | 54.32 ± 22.18 | 0.473 | 0.637 |
| 3 months | 61.23 ± 24.82* | 68.91 ± 26.37*** | 2.141 | 0.033 | |
| AST (U/L) | Before | 60.89 ± 24.96 | 62.14 ± 25.73 | 0.351 | 0.726 |
| 3 months | 67.15 ± 26.31 | 76.28 ± 28.46*** | 2.373 | 0.019 | |
| TBIL (µmol/L) | Before | 17.92 ± 6.47 | 18.76 ± 6.83 | 0.905 | 0.366 |
| 3 months | 20.17 ± 7.64* | 24.13 ± 8.92*** | 3.392 | < 0.001 | |
| ALB (g/L) | Before | 39.16 ± 4.38 | 38.42 ± 4.27 | 1.232 | 0.220 |
| 3 months | 37.24 ± 4.52** | 35.18 ± 4.63*** | 3.223 | 0.001 | |
| Cr (µmol/L) | Before | 74.89 ± 17.83 | 76.32 ± 18.47 | 0.563 | 0.574 |
| 3 months | 77.42 ± 19.28 | 81.16 ± 20.34 | 1.347 | 0.180 | |
| BUN (mmol/L) | Before | 5.76 ± 1.68 | 5.82 ± 1.73 | 0.228 | 0.820 |
| 3 months | 6.08 ± 1.84 | 6.37 ± 1.92* | 1.091 | 0.277 | |
| Tumor Markers | |||||
| AFP (ng/mL) | Before | 498.42 ± 172.18 | 512.36 ± 168.75 | 0.586 | 0.559 |
| 3 months | 343.17 ± 108.24*** | 307.53 ± 102.69*** | 2.424 | 0.016 | |
| CA125 (U/mL) | Before | 56.28 ± 21.87 | 58.73 ± 22.16 | 0.796 | 0.427 |
| 3 months | 48.42 ± 14.63** | 44.18 ± 11.47*** | 2.283 | 0.024 | |
| CEA (U/mL) | Before | 7.63 ± 3.28 | 7.82 ± 3.46 | 0.408 | 0.684 |
| 3 months | 6.89 ± 3.12 | 6.17 ± 2.84*** | 1.743 | 0.083 | |
TACE + RFA Transarterial chemoembolization combined with either radiofrequency ablation, TACE+dual-drug Transarterial chemoembolization combined sintilimab and bevacizumab, WBC White Blood Cell, Hb Hemoglobin, ANC Absolute Neutrophil Count, PLT Platelet, PT Prothrombin Time, INR International Normalized Ratio, ALT Alanine Aminotransferase, AST Aspartate Aminotransferase, TBIL Total Bilirubin, ALB Albumin, Cr Creatinine, BUN Blood Urea Nitrogen, AFP Alpha-fetoprotein, CEA Carcinoembryonic Antigen, CA125 Cancer Antigen 125
*P < 0.05, **P < 0.01, ***P < 0.001: Compared to before treatment
Regarding hepatic and renal functions, no significant differences were observed between groups at baseline (P > 0.05). By 3 months post-treatment, both groups demonstrated elevated ALT, AST, and TBIL levels alongside decreased albumin (ALB). However, the TACE+dual-drug group experienced more significant hepatic impairment, characterized by higher ALT (68.91 ± 26.37 U/L vs. 61.23 ± 24.82 U/L, P = 0.033), TBIL levels (P < 0.001), and a more substantial reduction in ALB (P = 0.001) compared to the TACE + RFA group. Conversely, renal function parameters, including Cr and BUN, remained stable in both groups post-treatment (P > 0.05), indicating that both therapeutic regimens have a limited impact on kidney function.
Analysis of tumor marker evolution revealed that baseline AFP, CA125, and CEA levels were similar between the two groups (P > 0.05). Three months following treatment, both groups achieved significant reductions in AFP and CA125 levels, with the TACE+dual-drug group demonstrating more pronounced decreases (AFP: 307.53 ± 102.69 ng/mL vs. 343.17 ± 108.24 ng/mL, P = 0.016; CA125: P = 0.024). Notably, CEA levels significantly declined only in the TACE+dual-drug group (P < 0.001), whereas the reduction in the TACE + RFA group did not reach statistical significance (P = 0.083). Collectively, these results suggest that TACE combined with sintilimab and bevacizumab provides superior efficacy in suppressing tumor markers compared to TACE combined with RFA.
Comparison of short-term treatment response at 3 months
In the comparison of short-term treatment response at 3 months according to RECIST 1.1 criteria, notable differences were observed between the TACE + RFA group and the TACE+dual-drug group. The objective response rate (ORR), which includes complete response (CR) and partial response (PR), was significantly higher in the TACE+dual-drug group (44 patients, 38.60%) compared to the TACE + RFA group (23 patients, 24.73%, χ²=4.498, P = 0.034) (Table 3). Specifically, CR was observed in 8 patients (7.02%) in the TACE+dual-drug group and 5 patients (5.38%) in the TACE + RFA group, while PR was seen in 36 patients (31.58%) and 18 patients (19.35%) respectively. However, the disease control rate (DCR), encompassing CR, PR, and stable disease (SD), did not show a significant difference between the two groups (TACE + RFA: 69 patients, 74.19%; TACE+dual-drug: 87 patients, 76.32%, χ²=0.124, P = 0.724). SD was recorded in 43 patients (37.72%) in the TACE+dual-drug group and 46 patients (49.46%) in the TACE + RFA group. Additionally, progressive disease (PD) was noted in 24 patients (25.81%) in the TACE + RFA group and 27 patients (23.68%) in the TACE+dual-drug group.
Table 3.
Short-term tumor response at 3 months according to RECIST 1.1 [n (%)]
| Parameters | TACE + RFA group (n = 93) | TACE+dual-drug group (n = 114) | χ2 | P value |
|---|---|---|---|---|
| ORR | 23 (24.73%) | 44 (38.60%) | 4.498 | 0.034 |
| DCR | 69 (74.19%) | 87 (76.32%) | 0.124 | 0.724 |
| - CR | 5 (5.38%) | 8 (7.02%) | ||
| - PR | 18 (19.35%) | 36 (31.58%) | ||
| - SD | 46 (49.46%) | 43 (37.72%) | ||
| - PD | 24 (25.81%) | 27 (23.68%) |
TACE + RFA Transarterial chemoembolization combined with either radiofrequency ablation, TACE+dual-drug Transarterial chemoembolization combined sintilimab and bevacizumab, ORR Objective response rate, DCR Disease control rate, CR Complete Response, PR Partial Response, SD Stable Disease, PD Progressive Disease
Comparison of treatment-related adverse events during follow-up
In the comparison of treatment-related adverse events graded by CTCAE v5.0, the TACE+dual-drug group exhibited a significantly higher incidence of specific adverse events (Fig. 1). Adverse events of any grade were common in both groups. The spectrum differed notably: the TACE+dual-drug group had significantly higher rates of cardiovascular (hypertension: 32.5% vs. 6.5%, P < 0.001), dermatological (rash: 15.8% vs. 3.2%, P = 0.003; hand-foot syndrome: 12.3% vs. 2.2%, P = 0.007). Conversely, post-procedural fever was more frequent in the TACE + RFA group (22.6% vs. 10.5%, P = 0.018). Gastrointestinal events (diarrhea, abdominal pain, vomiting), fatigue, and decreased appetite did not differ significantly between groups (all P > 0.05).
Fig. 1.
Spectrum of treatment-emergent adverse events. TACE + RFA: transarterial chemoembolization combined with either radiofrequency ablation; TACE+dual-drug: transarterial chemoembolization combined sintilimab and bevacizumab. #P < 0.05; ##P < 0.01; ###P < 0.001
Survival outcomes analysis
Using the Log-rank method to analyze the survival curves between the two groups, significant differences were observed in both OS and PFS. Specifically, patients in the TACE+dual-drug group exhibited a significantly longer OS (27.24 ± 4.14 months) compared to those in the TACE + RFA group (24.17 ± 4.67 months), with a statistical significance of t = 5.014 and P < 0.001 (TACE + RFA vs. TACE+dual-drug) (Fig. 2). Similarly, the TACE+dual-drug group showed a markedly improved PFS (10.42 ± 2.86 months) over the TACE + RFA group (8.13 ± 2.37 months), where the difference was also statistically significant (t = 6.182, P < 0.001) (Fig. 3).
Fig. 2.
Overall survival curves between the two groups. A Kaplan-Meier survival analysis; B number at risk table
Fig. 3.
Progression-free survival curves between the two groups. A Kaplan-Meier survival analysis; (B) number at risk table
Multivariable Cox regression analysis for survival outcomes
To identify factors independently associated with survival outcomes, multivariable Cox regression analyses were performed. Variables considered included treatment group (TACE + RFA as reference), age, gender, BCLC stage (A/B vs. C), tumor size (> 3 cm vs. ≤3 cm), presence of vascular invasion, and extrahepatic metastasis. For OS, the final model identified the treatment group and BCLC stage as independent significant factors (Table 4). Compared to the TACE + RFA group, the TACE+dual-drug group was associated with a significantly reduced risk of death (HR = 0.520, 95% CI: 0.370–0.731, P < 0.001). BCLC stage C was associated with a significantly increased risk of death compared to stages A/B (HR = 2.106, 95% CI: 1.412–3.146, P < 0.001).
Table 4.
Multivariable Cox regression analysis for overall survival
| Variables | Category | HR (95% CI) | P value |
|---|---|---|---|
| Treatment Group | TACE+dual-drug vs. TACE + RFA | 0.520 (0.370–0.731) | < 0.001 |
| BCLC Stage | C vs. A/B | 2.106 (1.412–3.146) | < 0.001 |
| Tumor Size | > 3 cm vs. ≤3 cm | 1.204 (0.868–1.671) | 0.265 |
| Vascular Invasion | Present vs. Absent | 1.318 (0.923–1.881) | 0.129 |
| Extrahepatic Metastasis | Present vs. Absent | 1.432 (0.940–2.182) | 0.094 |
HR Hazard Ratio, CI Confidence Interval, TACE + RFA Transarterial chemoembolization combined with radiofrequency ablation, TACE+dual-drug Transarterial chemoembolization combined with sintilimab and bevacizumab, BCLC Barcelona Clinic Liver Cancer
Discussion
This retrospective cohort study directly compares two multimodal approaches for unresectable HCC: TACE combined with RFA versus TACE combined with sintilimab and bevacizumab. Our findings reveal a distinct therapeutic trade-off. While the dual-drug regimen demonstrated superior survival (OS, PFS) and ORR, it incurred significantly greater systemic toxicity, evidenced by adverse events (hypertension, hand-foot syndrome, rash) and pronounced alterations in laboratory parameters (hematological suppression, coagulopathy, hepatic dysfunction). Conversely, TACE + RFA offered a more favorable short-term safety profile but yielded inferior survival outcomes. Understanding the mechanisms underlying these divergent efficacy and toxicity profiles is crucial for clinical decision-making and future research.
Mechanistic basis for differential efficacy and tumor response
Superior survival and response rates observed with TACE/sintilimab/bevacizumab likely stem from synergistic immunomodulatory and anti-angiogenic effects amplifying TACE-induced tumor cell death. Recent studies confirm TACE promotes immunogenic cell death, releasing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) like HMGB1 and ATP. This creates a pro-inflammatory microenvironment conducive to antigen presentation and T-cell priming, effectively acting as an in situ vaccine [17, 18]. Sintilimab, an anti-PD-1 antibody, augments this by blocking inhibitory checkpoints on T cells, reversing exhaustion and enabling a potent cytotoxic T lymphocyte (CTL) response against exposed TAAs [19]. Crucially, this TACE-induced immunogenic effect is often counteracted by compensatory immunosuppression, primarily driven by hypoxia-triggered upregulation of vascular endothelial growth factor (VEGF). The study by Haist et al. [20] demonstrates that elevated VEGF fosters an immunosuppressive tumor microenvironment (TME) by promoting regulatory T cell (Treg) expansion, myeloid-derived suppressor cell (MDSC) infiltration, and abnormal, dysfunctional vasculature that hinders T-cell trafficking and function. Bevacizumab directly targets this escape mechanism. By neutralizing VEGF, it promotes vascular normalization (improving perfusion and reducing interstitial pressure), reduces immunosuppressive cell populations, and may enhance dendritic cell maturation [21]. This creates a virtuous cycle: TACE provides antigens, sintilimab unleashes T cells, and bevacizumab removes barriers (immunosuppression, abnormal vasculature) to effective T-cell infiltration and function [22, 23]. This systemic immunologic synergy extends beyond the locoregional effects of TACE, potentially controlling micrometastatic disease and translating into the significant survival advantage and the more profound reductions in systemic tumor markers (AFP, CA125) observed in our dual-drug group. This aligns with the improved OS (> 22.3 months) reported by Yang et al. [8] and Shen et al. [24] for similar TACE/ICI/anti-VEGF combinations, and conceptually supports the impressive results seen with TACE plus lenvatinib/pembrolizumab.
In contrast, the efficacy of TACE + RFA primarily relies on spatial synergy within the targeted lesion. TACE-induced ischemia and lipiodol deposition can reduce tumor vascularity and size, potentially diminishing the “heat-sink” effect (cooling by blood flow) and improving thermal conduction during subsequent RFA [25]. This allows for a larger, more complete ablation zone, particularly beneficial for tumors > 3 cm. However, RFA’s mechanism is fundamentally local and cytodestructive, relying on thermal coagulation necrosis. While localized tumor control can be excellent, RFA lacks the capacity to induce a sustained systemic immune response or effectively target distant microscopic disease [25, 26]. This mechanistic limitation likely underpins the lower ORR and shorter PFS/OS observed in our TACE + RFA group compared to the dual-drug approach.
Mechanisms underlying differential toxicity and laboratory alterations
The distinct toxicity profile and significant laboratory alterations observed with the dual-drug regimen are mechanistically predictable and reflect the systemic biological activity of its components. The pronounced hematological suppression (significant decreases in Hb, ANC, PLT) likely results from the cumulative myelosuppressive effects of TACE chemotherapy (5-FU, cisplatin) potentiated by the systemic agents [27]. Bevacizumab’s inhibition of VEGF signaling is particularly relevant, as VEGF is essential for maintaining the integrity and function of the bone marrow hematopoietic niche, including sinusoidal endothelial cells critical for stem/progenitor cell support. Disruption of this niche can impair hematopoiesis [28]. While sintilimab’s primary target is immune cells, immune-mediated effects on hematopoietic precursors or contributing bone marrow inflammation are plausible [29, 30]. The observed coagulopathy (prolonged PT, elevated INR) specifically in the dual-drug group points towards a greater impact on hepatic synthetic function or coagulation factor activity, potentially linked to bevacizumab-induced endothelial dysfunction affecting factor production/release or sintilimab-related immune effects on the liver.
The significantly greater hepatic biochemical derangements (elevations in ALT, AST, TBIL; decrease in ALB) in the dual-drug group highlight an increased hepatic burden. TACE inherently causes ischemic injury to peritumoral liver parenchyma. Bevacizumab adds vascular toxicity risks (e.g., sinusoidal injury). Critically, sintilimab carries a well-established risk of immune-mediated hepatitis (IMH), where activated T cells directly attack hepatocytes [31, 32]. This immune-mediated injury, superimposed on TACE-induced ischemia and the underlying chronic liver disease prevalent in HCC patients, provides a compelling explanation for the more pronounced transaminitis and synthetic dysfunction. The relative stability of renal markers (e.g., Cr, BUN) suggests renal sparing in this cohort, though bevacizumab’s known risks (proteinuria, hypertension-induced renal injury) necessitate ongoing vigilance.
The specific adverse event profile observed in our study may be indicative of the underlying mechanisms at play. Bevacizumab’s inhibition of VEGF signaling has been associated with hypertension, potentially due to reduced nitric oxide production and capillary rarefaction [33]. Similarly, hand-foot syndrome and rash are commonly reported immune-related adverse events (irAEs) linked to PD-1 inhibitors such as sintilimab, which could reflect T-cell activation against skin antigens. These safety observations align with the adverse event profiles documented in trials involving comparable regimens [33, 34]. The increased incidence of post-procedural fever noted in the RFA group might suggest a localized inflammatory response resulting from thermal necrosis.
Clinical implications and future directions
Our findings underscore a critical therapeutic trade-off in managing unresectable HCC. The TACE/sintilimab/bevacizumab combination offers superior survival and tumor response but demands careful patient selection and proactive management of systemic toxicities. Prioritizing this dual-drug approach seems most justified for patients with good performance status (ECOG 0–1), preserved organ function (especially hepatic and renal), and the capacity for close monitoring and management of hypertension, hematologic suppression, and potential irAEs. Vigilant monitoring (CBC, LFTs, coagulation profiles, blood pressure) is essential. Conversely, TACE-RFA might be more suitable for lesions that are anatomically suited for ablation or in cases where systemic therapy is contraindicated due to conditions like active autoimmunity, uncontrolled hypertension, or high bleeding risk. Furthermore, multivariable Cox regression analysis confirmed that the TACE+dual-drug regimen was an independent prognostic factor for both improved OS, even after adjusting for BCLC stage and other baseline characteristics. This strengthens the conclusion regarding the survival benefit associated with this combination strategy.
Several limitations warrant acknowledgment, including the retrospective design, potential selection bias despite balanced baselines, the high prevalence of HBV-related etiology in our cohort, which may limit the generalizability of our findings to populations with different predominant etiologies (e.g., HCV or NASH) where tumor biology and treatment responses might differ, relatively short follow-up for definitive survival conclusions (though the survival difference was significant), and the single-center nature limiting generalizability. Future prospective or well-matched retrospective studies using propensity score methods are encouraged to validate our findings. Furthermore, the specific contributions of sintilimab versus bevacizumab within the dual-drug regimen cannot be disentangled in this study design. Moving forward, prospective randomized controlled trials directly comparing these strategies are paramount to confirm our findings, establish causality, and evaluate long-term outcomes. Biomarker-driven patient selection is crucial. Exploring predictive biomarkers (e.g., PD-L1 expression, tumor mutational burden, angiogenic signatures, circulating immune cell profiles) could help identify patients most likely to benefit from the dual-drug approach or those better suited for locoregional strategies. Optimizing therapeutic sequencing or dose/schedule modifications may help mitigate toxicity while preserving efficacy. Finally, comparisons with emerging combinations, such as TACE plus novel bispecific antibodies or next-generation TKIs, represent promising avenues for further improving the therapeutic landscape for unresectable HCC.
Conclusion
In conclusion, our study provides valuable insights into the comparative effectiveness and safety of TACE combined with either RFA or a dual-drug regimen of sintilimab and bevacizumab in treating unresectable HCC. While the dual-drug approach shows promise in terms of survival benefits, it requires careful consideration of patient-specific factors and proactive management of adverse events. Further research is needed to optimize treatment protocols and identify the most suitable candidates for each therapeutic strategy.
Acknowledgments
AI Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
Authors’ contributions
Tingting Li, Hongyi Zhao: Conceptualization, methodology, writing original draft preparation. Chengbin Dong, Yang Song: Investigation, software, statistical analysis. Miaomiao Li: Reviewing and editing, funding acquisition, supervision. All authors read and approved the final manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
All data in this study is available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study follows the Helsinki Declaration and the relevant provisions of the International Ethical Guidelines. All research procedures have been approved by the Beijing Shijitan Hospital Affiliated to Capital Medical University Ethics Committee (Approval number: IIT2024-106-002). Informed consent was waived for this retrospective study due to the exclusive use of de-identified patient data, which posed no potential harm or impact on patient care.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data in this study is available from the corresponding author on reasonable request.