Abstract
Objective
To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with bevacizumab arterial perfusion compared to TACE alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).
Methods
In this prospective, randomized, open-label, single-center study, 180 patients with HCC and PVTT were randomized (1:1) into a control group (TACE alone, n = 90) and an observation group (TACE plus bevacizumab, n = 90). Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included tumor response, changes in serum angiogenic factors (VEGF, PDGF), and tumor vascular density assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
Results
Baseline characteristics were well-matched. After a median follow-up of 24 months, the observation group showed significantly greater reductions in tumor diameter and number (P < 0.05). Post-treatment levels of VEGF and PDGF, and tumor vascular density, were significantly lower in the observation group (all P < 0.05). The median PFS was significantly longer in the observation group (10.5 months vs. 6.1 months; Hazard Ratio [HR], 0.58; P < 0.001), as was median OS (19.1 months vs. 13.0 months; HR, 0.62; P = 0.003). The incidence of grade ≥ 3 hypertension and thrombocytopenia was higher in the observation group (P < 0.05).
Conclusion
This study suggests that adding bevacizumab to TACE is associated with improved tumor control, inhibition of angiogenesis, and significantly prolonged survival in patients with HCC and PVTT, with a manageable safety profile.
Keywords: Hepatocellular carcinoma, Portal vein tumor thrombus, Transcatheter arterial chemoembolization, Bevacizumab, Dynamic contrast-enhanced MRI
Introduction
Hepatocellular carcinoma (HCC) persists as a formidable global health burden, ranking as the sixth most prevalent malignancy worldwide with disproportionate incidence in hepatitis B/C-endemic regions [1]. The clinical trajectory markedly deteriorates when tumor progression involves portal vein invasion, a condition known as portal vein tumor thrombus (PVTT). PVTT is a critical prognostic determinant associated with a dramatically increased mortality risk due to its potential for hematogenous dissemination and its compromise of hepatic vascular architecture [2, 3]. Despite advances, patients with PVTT have a dismal prognosis, with median survival often under a year with conventional treatments, highlighting a significant unmet clinical need [4].
Transcatheter arterial chemoembolization (TACE) has become a cornerstone of treatment for unresectable HCC [5], but its efficacy is limited in the setting of PVTT [6]. The therapeutic synergy between TACE and anti-angiogenic agents like bevacizumab offers a compelling strategy [5, 7]. The rationale is based on a dual-mechanism approach: TACE induces ischemic necrosis [8] but can also paradoxically trigger a pro-angiogenic rebound via hypoxia-inducible factor-1α (HIF-1α) and subsequent vascular endothelial growth factor (VEGF) upregulation [7, 9–11]. Bevacizumab, a monoclonal antibody against VEGF-A, directly counteracts this by neutralizing VEGF, thereby preventing tumor revascularization and enhancing the efficacy of embolization [12, 13]. This combined approach aims to simultaneously debulk the tumor locally while systemically controlling the angiogenic pathways that fuel its growth and spread.
While the theoretical promise is strong, robust clinical evidence from prospective studies is needed to establish the efficacy and safety of this combination, particularly regarding the optimal timing, patient selection, and impact on survival. This study was designed to prospectively evaluate the effects of TACE combined with bevacizumab arterial perfusion versus TACE alone on tumor load, angiogenesis, and survival outcomes in patients with HCC and PVTT.
Materials and methods
Study design and participants
In this prospective, randomized, open-label, single-center study, a total of 180 patients diagnosed with HCC with PVTT, admitted to The First Hospital of Hebei Medical University between June 2021 and December 2023, were enrolled. All diagnoses were confirmed through imaging and/or histopathological analysis. Patients were randomly assigned (1:1) using a computer-generated number table to a control group (TACE alone, n = 90) or an observation group (TACE plus bevacizumab, n = 90).
Inclusion criteria
Eligible patients were aged between 18 and 70 years, had confirmed HCC with radiological evidence of portal vein invasion (limited to Cheng’s type I or II) [14], preserved liver function (Child-Pugh class A or B) [15], an Eastern Cooperative Oncology Group (ECOG) [16] performance status of 0–1, absence of severe cardiac or renal dysfunction, and provided written informed consent.
Exclusion criteria
Patients were excluded if they had a history of other malignancies, prior liver transplantation, decompensated cirrhosis, active bleeding, severe comorbidities, were pregnant or lactating, or had known hypersensitivity to bevacizumab.
Treatment procedures
Control group (TACE Alone)
TACE was performed using the Seldinger technique. A microcatheter was selectively advanced into the tumor-feeding artery. An emulsion of doxorubicin (50 mg) and lipiodol (5–20 mL) was infused, followed by embolization with gelatin sponge particles (350–560 μm) until near-stasis of flow was achieved.
Observation group (TACE plus Bevacizumab)
Patients received bevacizumab (5 mg/kg) administered as an intra-arterial infusion through the catheter over 30 min. This was performed immediately before the TACE procedure, which was then carried out as described for the control group. Treatments were repeated every 6–8 weeks based on clinical and radiological evaluation.
Endpoints and assessments
The primary endpoints were overall survival (OS), defined as the time from randomization to death from any cause, and progression-free survival (PFS), defined as the time to disease progression or death. Secondary endpoints included tumor response assessed per Response Evaluation Criteria in Solid Tumors (RECIST 1.1), changes in serum angiogenic factors, tumor vascular density, and safety. Adverse events were graded using CTCAE v5.0. Patients were followed up until study completion or death, with a median follow-up duration of 24 months.
Imaging acquisition and analysis
Tumor size and number were assessed via magnetic resonance imaging (MRI) at baseline and 3 months post-treatment using a 1.5T scanner. Imaging parameters included T1-weighted, T2-weighted, and contrast-enhanced sequences. Contrast-enhanced sequences were acquired following an intravenous bolus injection of gadopentetate dimeglumine (Magnevist, Bayer) at a dose of 0.1 mmol/kg. All images were independently reviewed by two experienced radiologists (with 10 and 15 years of experience in liver imaging) who were blinded to the treatment allocation. Any discrepancies in measurement or assessment were resolved by consensus with a third senior radiologist.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)
Tumor vascular density was evaluated using DCE-MRI at baseline and 3 months post-treatment. Gadolinium-based contrast was injected intravenously at 2–3 mL/s. Dynamic scans were acquired over 5–10 min. Post-processing was performed using DynaCAD software (Invivo Corp.) to generate parametric maps, and regions of interest were drawn on the most enhanced tumor area to quantify vascular density.
Biomarker analysis
Serum levels of VEGF and platelet-derived growth factor (PDGF) were measured using enzyme-linked immunosorbent assay (ELISA) kits following the manufacturer’s protocols at baseline and 4 weeks after the first treatment.
Statistical analysis
Continuous variables were compared using Student’s t-tests. Categorical data were analyzed via Chi-square tests. OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. A two-tailed P < 0.05 was considered statistically significant. All analyses were performed using SPSS v21.0 (IBM Corp.).
Results
Patient characteristics
A total of 180 patients were enrolled. Demographic and clinical characteristics were well-balanced between the groups at baseline (all P > 0.05). In the control group, the mean age was 63.77 ± 5.22 years, and 40.0% had Child-Pugh A liver function. In the observation group, the mean age was 65.28 ± 3.49 years, and 44.4% had Child-Pugh A liver function. There were no significant intergroup differences in baseline characteristics (Table 1).
Table 1.
Baseline demographic and clinical characteristics
| Parameter | Control group (n = 90) | Observation group (n = 90) | P-value |
|---|---|---|---|
| Age (years), mean ± SD | 63.77 ± 5.22 | 65.28 ± 3.49 | 0.556 |
| Gender (Male/Female), n | 53 / 37 | 50 / 40 | 0.375 |
| BMI (kg/m²), mean ± SD | 23.68 ± 1.75 | 23.47 ± 2.05 | 0.226 |
| Child-Pugh Class (A/B), n (%) | 36 (40.0) / 54 (60.0) | 40 (44.4) / 50 (55.6) | 0.813 |
| Cheng’s PVTT Classification (I/II), n (%) | 58 (64.4) / 32 (35.6) | 62 (68.9) / 28 (31.1) | 0.531 |
| ECOG Performance Status (0/1), n (%) | 51 (56.7) / 39 (43.3) | 47 (52.2) / 43 (47.8) | 0.548 |
Comparison of tumor load and tumor response
Pretreatment MRI revealed no intergroup differences in tumor size or number (P > 0.05). Post-treatment, the observation group exhibited a significantly reduced tumor diameter (2.15 ± 0.30 cm vs. 3.26 ± 0.24 cm; P = 0.014) and fewer lesions (1.75 ± 0.88 vs. 3.16 ± 1.04; P = 0.003) compared to controls (Table 2). The objective response rate (ORR) was significantly higher in the observation group compared to the control group (47.8% [CR + PR] vs. 28.8%; P = 0.018), and the rate of progressive disease (PD) was significantly lower (7.8% vs. 21.1%; P = 0.007) (Table 3).
Table 2.
Tumor burden comparison before and after treatment
| Parameter | Control group (n = 90) | Observation group (n = 90) | P-value |
|---|---|---|---|
| Tumor Size (cm), mean ± SD | |||
| Before treatment | 4.36 ± 0.57 | 4.30 ± 0.60 | 0.583 |
| After treatment | 3.26 ± 0.24 | 2.15 ± 0.30 | 0.014 |
| Tumor Number, mean ± SD | |||
| Before treatment | 3.44 ± 1.27 | 3.52 ± 1.35 | 0.332 |
| After treatment | 3.16 ± 1.04 | 1.75 ± 0.88 | 0.003 |
Table 3.
Tumor response rates per RECIST 1.1
| Response category | Control group (n = 90), n (%) | Observation group (n = 90), n (%) | P-value |
|---|---|---|---|
| Complete Response (CR) | 4 (4.4) | 8 (8.9) | 0.132 |
| Partial Response (PR) | 22 (24.4) | 35 (38.9) | 0.018 |
| Stable Disease (SD) | 45 (50.0) | 40 (44.4) | 0.442 |
| Progressive Disease (PD) | 19 (21.1) | 7 (7.8) | 0.007 |
ELISA detection of angiogenic factors
Pretreatment VEGF and PDGF levels were comparable between groups (P > 0.05). Post-treatment, the observation group demonstrated marked reductions in both VEGF (118.6 ± 12.5 pg/mL vs. 159.4 ± 14.7 pg/mL; P < 0.001) and PDGF (110.5 ± 12.3 pg/mL vs. 145.8 ± 14.2 pg/mL; P < 0.001) relative to controls (Table 4; Fig. 1).
Table 4.
Serum angiogenesis biomarkers before and after treatment
| Biomarker (pg/mL) | Control group (n = 90) | Observation group (n = 90) | P-value |
|---|---|---|---|
| VEGF, mean ± SD | |||
| Before treatment | 178.5 ± 21.3 | 185.2 ± 19.8 | 0.091 |
| After treatment | 159.4 ± 14.7 | 118.6 ± 12.5 | < 0.001 |
| PDGF, mean ± SD | |||
| Before treatment | 148.9 ± 24.5 | 154.1 ± 25.1 | 0.204 |
| After treatment | 145.8 ± 14.2 | 110.5 ± 12.3 | < 0.001 |
Fig. 1.
ELISA analysis of serum angiogenic factors. Bar charts showing serum concentrations (pg/mL) of VEGF and PDGF at baseline and post-treatment. Data are presented as mean ± SD. *Indicates P < 0.05
Comparison of neovascularization density
DCE-MRI analysis showed comparable baseline vascular density (P > 0.05). Post-treatment, vascular density in the observation group was significantly lower than in controls (83.31 ± 15.55 vessels/cm² vs. 118.55 ± 13.49 vessels/cm²; P = 0.014) (Fig. 2).
Fig. 2.
DCE-MRI Quantification of tumor vascular density. Bar charts showing mean tumor vascular density (vessels/cm²) at baseline and post-treatment. Data are presented as mean ± SD. *Indicates P < 0.05
Safety and adverse events
The overall incidence of grade ≥ 3 adverse events was higher in the observation group. The rates of grade ≥ 3 hypertension (13.3% vs. 5.6%; P = 0.048) and thrombocytopenia (10.0% vs. 3.3%; P = 0.035) were significantly higher in the observation group compared to the control group. There was no significant difference in the rates of fatigue or hepatic dysfunction (Table 5). No treatment-related deaths occurred in either group.
Table 5.
Grade ≥ 3 adverse events
| Adverse event | Control group (n = 90), n (%) | Observation group (n = 90), n (%) | P-value |
|---|---|---|---|
| Hypertension | 5 (5.6) | 12 (13.3) | 0.048 |
| Thrombocytopenia | 3 (3.3) | 9 (10.0) | 0.035 |
| Fatigue | 8 (8.9) | 10 (11.1) | 0.623 |
| Hepatic Dysfunction | 6 (6.7) | 7 (7.8) | 0.772 |
Comparison of patient survival
The observation group showed significantly prolonged survival outcomes. The median PFS was 10.5 months (95% CI, 9.0–11.8) in the observation group versus 6.1 months (95% CI, 5.3–6.9) in the control group (Hazard Ratio [HR], 0.58; 95% CI, 0.44–0.77; P < 0.001). The median OS was 19.1 months (95% CI, 17.2–21.0) in the observation group compared to 13.0 months (95% CI, 11.7–14.3) in the control group (HR, 0.62; 95% CI, 0.46–0.83; P = 0.003) (Table 6; Fig. 3).
Table 6.
Progression-Free and overall survival
| Outcome | Control group (n = 90) | Observation group (n = 90) | Hazard ratio (95% CI) | P-value |
|---|---|---|---|---|
| Progression-Free Survival, median months (95% CI) | 6.1 (5.3–6.9) | 10.5 (9.0–11.8) | 0.58 (0.44–0.77) | < 0.001 |
| Overall Survival, median months (95% CI) | 13.0 (11.7–14.3) | 19.1 (17.2–21.0) | 0.62 (0.46–0.83) | 0.003 |
CI, confidence interval; P-values calculated using the log-rank test
Fig. 3.
Kaplan-Meier Survival Curves. (A) Overall Survival (OS) and (B) Progression-Free Survival (PFS) in the observation (TACE + bevacizumab) and control (TACE alone) groups. Hazard ratios (HR), 95% confidence intervals (CI), and P-values from log-rank tests are shown
Discussion
This prospective, randomized study demonstrates that combining TACE with intra-arterial bevacizumab offers significant clinical benefits over TACE alone for patients with HCC and PVTT. The combination therapy was associated with superior tumor response, marked inhibition of angiogenic pathways, and a clinically meaningful improvement in both PFS and OS.
The strength of our study lies in its randomized design and multimodal assessment, linking radiological response with underlying biological changes. The significant post-treatment reduction in serum VEGF and PDGF levels, corroborated by decreased tumor vascular density on DCE-MRI, provides direct evidence of bevacizumab’s anti-angiogenic activity counteracting the TACE-induced hypoxic response. These findings are consistent with previous reports and support the mechanistic synergy of this combination [11, 17].
The observed survival benefit is particularly noteworthy. A median OS of 19.1 months in the bevacizumab arm represents a substantial improvement over the 13.0 months seen with TACE alone and compares favorably to outcomes reported for this high-risk population [18]. This suggests that for select patients with preserved liver function, this combination could be a valuable treatment strategy. The safety profile was manageable, with an increased but expected incidence of bevacizumab-related toxicities like hypertension, consistent with large-scale clinical trials [12].
This study has limitations, including its single-center design, which may limit generalizability. Additionally, we did not perform statistical adjustments for multiple comparisons on the secondary endpoints, which should be considered exploratory.
In conclusion, this single-center randomized study suggests that the addition of bevacizumab to TACE is associated with reduced tumor burden, significant inhibition of angiogenesis, and prolonged survival in patients with HCC and PVTT. These findings support the therapeutic potential of this combination strategy, warranting further validation in larger, multicenter trials.
Author contributions
DY and HW contributed to the conception and design of the study. DY and HW contributed to the acquisition of data. YZ contributed to the analysis of data. DY and HW wrote the manuscript. BY revised the manuscript. All authors approved the final version of the manuscript.
Funding
This study was funded by the Medical Science Research Project of Hebei (No. 20231018).
Data availability
The datasets used during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study protocol was approved by the Institutional Review Board (IRB) of The First Hospital of Hebei Medical University. All participants provided written informed consent.
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.
Dawei Yang and Haifang Wang contributed equally to this work.
References
- 1.Sung H, Ferlay J, Siegel RL. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
- 2.Brown ZJ, Hewitt DB, Pawlik TM. Combination therapies plus transarterial chemoembolization in hepatocellular carcinoma: a snapshot of clinical trial progress. Expert Opin Investig Drugs. 2022;31(4):379–91. 10.1080/13543784.2022.2008355. [DOI] [PubMed] [Google Scholar]
- 3.Zhou XH, Li JR, Zheng TH, Chen H, Cai C, Ye SL, Gao B, Xue TC. Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy. Clin Exp Metastasis. 2023;40(1):5–32. 10.1007/s10585-022-10188-1. [DOI] [PubMed] [Google Scholar]
- 4.Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, Kelley RK, Galle PR, Mazzaferro V, Salem R, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76(3):681–93. 10.1016/j.jhep.2021.11.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Manjunatha N, Ganduri V, Rajasekaran K, Duraiyarasan S, Adefuye M. Transarterial chemoembolization and unresectable hepatocellular carcinoma: A narrative review. Cureus. 2022;14(8):e28439. 10.7759/cureus.28439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Yu WB, Rao A, Vu V, Xu L, Rao JY, Wu JX. Management of centrally located hepatocellular carcinoma: update 2016. World J Hepatol. 2017;9(13):627–34. 10.4254/wjh.v9.i13.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Li J, Bai Y, Xiong F. Atezolizumab plus bevacizumab combined with or without transarterial chemoembolization in the treatment of advanced hepatocellular carcinoma: A Single-Center retrospective study. J Hepatocell Carcinoma. 2025;12:973–84. 10.2147/jhc.s515453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Liu ZY, Kan XF, Zhang LJ, Makamure J, Li Q, Zhao D, Zhou GF, Feng GS, Zheng CS, Liang B. Transarterial chemoembolization combined with apatinib for treatment of advanced hepatocellular carcinoma: analysis of survival and prognostic factors. Curr Med Sci. 2022;42(5):1015–21. 10.1007/s11596-022-2620-6. [DOI] [PubMed] [Google Scholar]
- 9.Shim JH, Park JW, Kim JH, An M, Kong SY, Nam BH, Choi JI, Kim HB, Lee WJ, Kim CM. Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci. 2008;99(10):2037–44. 10.1111/j.1349-7006.2008.00909.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Chang Y, Jeong SW, Young Jang J, Jae Kim Y. Recent updates of transarterial chemoembolilzation in hepatocellular carcinoma. Int J Mol Sci. 2020;21(21). 10.3390/ijms21218165. [DOI] [PMC free article] [PubMed]
- 11.Zhao C, Xiang Z, Li M, Wang H. Transarterial chemoembolization combined with Atezolizumab plus bevacizumab or lenvatinib for unresectable hepatocellular carcinoma: A propensity score matched study. J Hepatocell Carcinoma. 2023;10:1195–206. 10.2147/jhc.s418256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905. 10.1056/NEJMoa1915745. [DOI] [PubMed] [Google Scholar]
- 13.Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Sci (New York NY). 2005;307(5706):58–62. 10.1126/science.1104819. [DOI] [PubMed] [Google Scholar]
- 14.Shi J, Lai EC, Li N, Guo WX, Xue J, Lau WY, Wu MC, Cheng SQ. Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus. Ann Surg Oncol. 2010;17(8):2073–80. 10.1245/s10434-010-0940-4. [DOI] [PubMed] [Google Scholar]
- 15.Wu HX, Ding XY, Xu YW, Yu MH, Li XM, Deng N, Chen JL. Transcatheter arterial chemoembolization combined with PD-1 inhibitors and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus. World J Gastroenterol. 2024;30(8):843–54. 10.3748/wjg.v30.i8.843. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Azam F, Latif MF, Farooq A, Tirmazy SH, AlShahrani S, Bashir S, Bukhari N. Performance status assessment by using ECOG (Eastern cooperative oncology Group) score for cancer patients by oncology healthcare professionals. Case Rep Oncol. 2019;12(3):728–36. 10.1159/000503095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ueda S, Hori S, Hori A, Makitani K, Wan K, Sonomura T. Retrospective study of the efficacy and safety of chemoembolization with Drug-Eluting microspheres combined with Intra-Arterial infusion of bevacizumab for unresectable hepatocellular carcinoma. J Hepatocell Carcinoma. 2022;9:973–85. 10.2147/jhc.s380439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.He MK, Liang RB, Zhao Y, Xu YJ, Chen HW, Zhou YM, Lai ZC, Xu L, Wei W, Zhang YJ, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Therapeutic Adv Med Oncol. 2021;13:17588359211002720. 10.1177/17588359211002720. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used during the current study are available from the corresponding author on reasonable request.