Liu S, Liu YH, Ni HB, Li JJ, Wu ZT, Wang LL, Ruan Y, Zhou XH. Transarterial chemoembolization plus lenvatinib with or without protein-1 inhibitor for hepatocellular carcinoma with portal vein tumor thrombus. World J Clin Oncol 2025; 16(6): 106798 [DOI: 10.5306/wjco.v16.i6.106798]
Corresponding Author of This Article
Xin-Hua Zhou, Chief Physician, Professor, Department of Hepatobiliary and Pancreatic Surgery, Li Huili Hospital Affiliated to Ningbo University, No. 1111 Jiangnan Road, Yinzhou District, Ningbo 315000, Zhejiang Province, China. zhouxinhua1002@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Shuai Liu, Yao-Hui Liu, Hong-Bo Ni, Jia-Jian Li, Ze-Tao Wu, Luo-Luo Wang, Yi Ruan, Xin-Hua Zhou, Department of Hepatobiliary and Pancreatic Surgery, Li Huili Hospital Affiliated to Ningbo University, Ningbo 315000, Zhejiang Province, China
Co-corresponding authors: Xin-Hua Zhou and Yi Ruan.
Author contributions: Liu S, Liu YH, Ruan Y and Zhou XH designed the research study; Liu YH, Ni HB, Li JJ and Wu ZT performed the research; Liu S and Li JJ analyzed the data and wrote the manuscript; Liu S and Wang LL analyzed the data; Ruan Y and Zhou XH acquired funding and provided supervision; all authors have read and approved the final manuscript.
Supported by Zhejiang Province Medicine and Health Science and Technology Project, No. 2023KY239; and Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project, No. 2024ZL949.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Li Huili Hospital Affiliated to Ningbo University (No. KY2024SL463-01).
Informed consent statement: All study participants, or their legal guardians, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Data sharing statement: Technical appendix, statistical code, and dataset are available from the corresponding author at zhouxinhua1002@163.com. Participants gave informed consent for data sharing consent was not obtained but the presented data are anonymized and the risk of identification is low.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xin-Hua Zhou, Chief Physician, Professor, Department of Hepatobiliary and Pancreatic Surgery, Li Huili Hospital Affiliated to Ningbo University, No. 1111 Jiangnan Road, Yinzhou District, Ningbo 315000, Zhejiang Province, China. zhouxinhua1002@163.com
Received: March 9, 2025 Revised: April 7, 2025 Accepted: April 29, 2025 Published online: June 24, 2025 Processing time: 104 Days and 17.3 Hours
Abstract
BACKGROUND
Hepatocellular carcinoma with portal vein tumor thrombus (HCC-PVTT) is a severe condition with poor prognosis. While transarterial chemoembolization (TACE) combined with lenvatinib (TACE-L) shows some promise, survival outcomes remain suboptimal. We hypothesize that TACE-L plus programmed cell death protein-1 inhibitors (TACE-L-P) may offer superior survival benefits compared to TACE-L in this patient population.
AIM
To compare efficacy and safety of TACE-L-P vs TACE-L in HCC-PVTT and identify prognostic factors.
METHODS
Data from HCC-PVTT patients treated with TACE-L-P or TTACE-L from January 2018 to December 2023 were collected and retrospectively analyzed. Propensity score matching (PSM) method with optimal matching was used to minimize confounding bias. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs) were compared between the two groups. Independent prognostic factors for OS and PFS were elucidated using the Cox proportional hazards model.
RESULTS
A total of 100 patients were included, with 42 patients in the TACE-L-P group and 68 patients in the TACE-L group. After PSM performing optimal matching, baseline characteristics were well balanced between the two groups, each comprising 42 patients. The median OS was significantly longer in the TACE-L-P group compared to the TACE-L group (17.2 months vs 12.6 months, P = 0.0207), as was the median PFS (10.6 months vs 7.1 months, P = 0.012). The ORR and disease control rate were both superior in the TACE-L-P group compared to the TACE-L group (66.7% vs 42.9%, P = 0.049; 78.6% vs 50.0%, P = 0.012). Multivariate analysis revealed that the independent prognostic factors for both OS and PFS were the treatment regimen and extrahepatic metastasis. The incidence of any-grade and grade 3 AEs was comparable between the TACE-L-P and TACE-L groups (84.5% vs 88.1%, P = 0.546), with no occurrences of grade 4/5 AEs or treatment-related mortality in either group.
CONCLUSION
Compared to TACE-L, the TACE-L-P regimen exhibits an acceptable safety profile and shows potential in improving survival outcomes, making it a promising therapeutic option for patients with HCC-PVTT.
Core Tip: This study evaluates the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus death protein-1 inhibitors (TACE-L-P) vs TACE combined with lenvatinib (TACE-L) in treating hepatocellular carcinoma with portal vein tumor thrombus (HCC-PVTT). The TACE-L-P regimen showed significantly improved overall survival, progression-free survival, and response rates compared to TACE-L. The safety profiles were comparable, with no severe treatment-related adverse events. These findings suggest that TACE-L-P may be a promising therapeutic option for HCC-PVTT patients.
Citation: Liu S, Liu YH, Ni HB, Li JJ, Wu ZT, Wang LL, Ruan Y, Zhou XH. Transarterial chemoembolization plus lenvatinib with or without protein-1 inhibitor for hepatocellular carcinoma with portal vein tumor thrombus. World J Clin Oncol 2025; 16(6): 106798
Hepatocellular carcinoma (HCC) is an aggressive and highly malignant liver cancer, accounting for approximately 80%-90% of primary liver cancers and being the third leading cause of cancer-related deaths globally[1]. With an overall 5-year survival rate of less than 18% in advanced stages and limited therapeutic options for advanced disease, HCC urgently requires the development of combined treatment strategies incorporating targeted therapies, immunotherapy, and locoregional approaches[2]. Due to its distinct biological characteristics and the unique anatomical structure of the liver, HCC exhibits a marked propensity for invasion of the portal venous system, which can result in the formation of portal vein tumor thrombus (PVTT)[3]. Nearly 45.6% of HCC patients are diagnosed with tumor thrombus in portal vein main trunk or its branches[4], with a median overall survival (OS) of only 2.7 months in the absence of intervention[5,6]. HCC-PVTT patients generally have a poor prognosis, and while tyrosine kinase inhibitors (TKIs) such as lenvatinib and sorafenib are recommended as first-line treatments for advanced HCC, the efficacy is still suboptimal[7]. Transarterial chemoembolization (TACE) allows direct delivery of chemotherapy agents to the tumor's feeding arteries, coupled with embolization to occlude its blood supply[8]. It can inhibit the progression of local lesions in HCC-PVTT patients with acceptable liver function and tumor burden, as recommended by the National Comprehensive Cancer Network and China Liver Cancer guidelines[9,10]. In addition, several studies indicate that combining TACE with anti-angiogenic agents, such as TKIs, may counteract hypoxia-induced angiogenesis after TACE and enhance survival benefits in patients with unresectable advanced HCC[11,12]. Nevertheless, current large-scale Phase III clinical trials, including the TACTICS and REFLECT trials[13,14], have systematically excluded HCC-PVTT patients, which means that the treatment outcomes for HCC-PVTT patients remain unclear.
On the other hand, a study shown that TKIs exert antitumor effects not only by inhibiting tumor cell proliferation and angiogenesis, but also by modulating the tumor immune microenvironment[15]. Theoretically, when combined with immune checkpoint inhibitors [programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors], they could exert a synergistic effect, enhancing antitumor immunity and potentially improving prognosis[16,17]. ORIENT-32 and KEYNOTE-5 have demonstrated that combination therapy with targeted agents and immunotherapy significantly prolongs both OS and progression-free survival (PFS) in patients with advanced HCC, thereby validating the synergistic effect[18,19]. Meanwhile, several studies have shown that TACE, as a local treatment strategy for advanced HCC, when combined with lenvatinib and PD-1 inhibitors, can improve the objective response rate (ORR) and OS in patients with unresectable advanced HCC compared to lenvatinib alone[20,21]. But it has not been widely explored in HCC-PVTT patients. Therefore, this study aims to compare the efficacy and safety of TACE combined with lenvatinib plus PD-1 inhibitors (TACE-L-P) vs combined with lenvatinib (TACE-L) in HCC-PVTT.
MATERIALS AND METHODS
Study design and patient selection
Data of consecutive patients with HCC-PVTT who received TACE-L-P or TACE-L at the single-center Li Huili Hospital, Ningbo Medical Center, between January 2018 and December 2023 were collected and analyzed. The classification of PVTT was based on Cheng's classification system[22].
Inclusion criteria: (1) Age between 18 years and 75 years; (2) Diagnosed with HCC-PVTT by imaging or pathology; (3) Child-Pugh class A or B; (4) Less than 5 lesions, with the total tumor volume not exceeding 60% of the liver volume; (5) Barcelona Clinic Liver Cancer (BCLC) stage B or C; and (6) Eastern Cooperative Oncology Group performance status score less than 2, with a life expectancy greater than 3 months.
Exclusion criteria: (1) Co-existing malignant tumors other than HCC; (2) Severe systemic diseases such as heart, lung, kidney, or coagulation disorders; (3) Prior systemic treatment, including chemotherapy, targeted therapy, or immunotherapy; (4) Central nervous system metastases (brain or spinal cord); (5) Severe portal vein or inferior vena cava obstruction, with no effective collateral circulation; and (6) History of organ transplantation.
Diagnostic criteria for HCC-PVTT: HCC must first be diagnosed. Imaging typically reveals a solid space-occupying lesion in the portal vein, with partial enhancement in the arterial phase and filling defects in the portal venous phase. It is crucial to distinguish this from thrombus, which is often associated with severe cirrhosis or a history of splenectomy or surgery involving the portal venous system. Thrombus does not enhance in the arterial phase, and may regress or improve with anticoagulation. The PVTT classification follows the Cheng classification system[23]: (1) Type I involves the segmental portal vein branches; (2) Type II involves the right or left portal vein; (3) Type III affects the main portal vein and its trunk; and (4) Type IV extends to the superior mesenteric vein. This classification aids in assessing disease severity and guiding treatment decisions.
The study was approved by the ethics committee and conducted in accordance with good clinical practice. Written informed consent was obtained from each patient, and the study adhered strictly to the ethical principles outlined in the Declaration of Helsinki[24], ensuring patient privacy and data security throughout the research process.
TACE procedure
All TACE procedures were performed by two experienced interventional radiologists. The femoral artery puncture site was located just below the right inguinal ligament, where the femoral pulse was distinctly palpable, and was anesthetized with 5 mL of 1% lidocaine. The procedure was performed using the Seldinger technique. After successful puncture, a guidewire and catheter sheath were introduced, followed by insertion of a 5F RH catheter into the hepatic artery for angiography, where a clustered contrast agent accumulation was observed at the lesion site. Under digital subtraction angiography guidance, a microcatheter was super-selectively advanced into the tumor's feeding artery. A mixture of 30 mg epirubicin, 20 mg oxaliplatin, and 3 mL iodine oil was emulsified and slowly injected through the microcatheter under fluoroscopy. Afterward, use polyvinyl alcohol embolic agent to embolize all the feeding vessels as much as possible. Finally, withdrew the microcatheter, catheter, and sheath, and compressed the puncture site with a sandbag. The endpoint of embolization was defined by the visible deposition of iodine oil and the cessation of blood flow in the tumor’s feeding artery[25].
If the initial TACE does not achieve the embolization endpoint or if subsequent computed tomography (CT) or magnetic resonance imaging (MRI) scans reveal tumor viability, a second or third TACE may be needed, provided the patient’s condition and liver function allow. If arteriovenous fistula is present, the fistula should be sealed with polyvinyl alcohol embolic agent before proceeding with TACE.
Lenvatinib and PD-1 inhibitor dosing regimen
Lenvatinib and PD-1 inhibitors were initiated systematically 7 days following TACE[26].
The dose of lenvatinib was 12 mg daily for patients weighing ≥ 60 kg and 8 mg daily for those weighing < 60 kg. PD-1 inhibitors include sintilimab, camrelizumab, and tislelizumab, each administered intravenously every 3 weeks at a dose of 200 mg per infusion. The common adverse reactions of PD-1 inhibitors include fatigue, rash, pruritus, diarrhea, and liver dysfunction. In the event of adverse reactions, the dosage should be reduced or discontinued according to the severity and the drug’s prescribing information, along with appropriate symptomatic treatment.
Follow-up
During the first year after initial treatment, follow-up was conducted every 4-6 weeks, including physical examinations, complete blood count, liver and renal function tests, tumor markers, abdominal enhanced CT or MRI, chest CT, and additional imaging studies as needed if metastasis or progression was detected, including positron emission tomography-CT when necessary.
During the follow-up period, if intolerable drug side effects or rapid disease progression occurred, the treatment regimen was adjusted, with the specific plan determined based on multidisciplinary discussion.
Outcome assessment
The primary outcomes were OS and PFS. OS was defined as the time from the initiation of treatment to death from any cause. PFS was defined as the time from the initiation of treatment to the first occurrence of tumor progression or death. Secondary outcomes included the ORR, disease control rate (DCR), and the incidence of adverse events (AEs). AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0[27]. Post-embolization syndrome, characterized by fever, abdominal pain, nausea, vomiting, leukocytosis, and transient liver enzyme abnormalities, may occur after TACE but typically resolves spontaneously within a short period, so it was not recorded. ORR was defined as the sum of the percentages of complete response (CR) and partial response (PR). DCR was defined as the sum of the percentages of CR, PR, and stable disease. DCR reflects the overall effect of treatment in controlling tumor progression. Tumor response on imaging was evaluated by two experienced radiologists 3–4 weeks after treatment according to the Modified Response Evaluation Criteria In Solid Tumors (mRECIST) version 5.0[28].
Statistical analysis
Using propensity score matching (PSM) reduces data bias and balances differences between variables. Compared to traditional multivariate regression methods, PSM is particularly effective in controlling confounding variables and selection bias in observational studies[29]. The propensity score for each patient to receive a specific treatment was calculated using a logistic regression model, incorporating multiple covariates and applying a 1:1 optimal matching method with a caliper set at 0.2. After matching, the balance of covariates was assessed using standardized mean differences (SMD), with a difference of less than 20% considered balanced. Categorical variables are presented as frequencies and percentages [n (%)], and group comparisons were made using the χ² test or Fisher’s exact test, depending on the data. Continuous variables are presented as means ± SD, and group comparisons were made using either the t-test or the Mann-Whitney U test, depending on the data distribution. Survival curve analysis was performed using the Kaplan-Meier method, and comparisons were made using the Log-rank test[30]. Univariate analysis was used to assess the significance of clinical features, and variables with P < 0.05 were included in the multivariate analysis. Multivariate Cox regression model was used to identify independent prognostic factors[31]. All statistical analyses were two-tailed, and P < 0.05 was considered statistically significant. The data were analyzed using R software (version 4.3.2).
RESULTS
Baseline characteristics
A total of 126 patients with HCC-PVTT were screened during the study period according to the predefined inclusion and exclusion criteria. Total 16 patients were excluded according to the study flow (Figure 1), leaving 110 patients were ultimately included, with 42 patients in the TACE-L-P group and 68 patients in the TACE-L group. There were significantly differences between the two groups in terms of extrahepatic metastasis, recurrent tumors, and serum albumin levels (P < 0.05). These variables showed significant differences were used as covariates for PSM with a 1:1 optimal matching method. After matching, 42 patients were included in each group, and the average SMD were all less than 0.2 (Supplementary Table 1). Baseline characteristics and clinical data were balanced between the two groups after PSM (P > 0.05) (Table 1). Baseline characteristics before and after PSM are essential for improving the validity of outcome comparisons, as shown in previous studies[32-34].
Figure 1 Flow diagram of hepatocellular carcinoma with portal vein tumor thrombus patients treated with transarterial arterial chemoembolization combined with lenvatinib plus death protein-1 inhibitors or transarterial arterial chemoembolization combined with lenvatinib therapy.
ECOG: Eastern Cooperative Oncology Group; HCC-PVTT: Hepatocellular carcinoma with portal vein tumor thrombus; PSM: Propensity score matching; TACE: Transarterial arterial chemoembolization; TACE-L-P: Transarterial arterial chemoembolization combined with lenvatinib plus death protein-1 inhibitors; TACE-L: Transarterial arterial chemoembolization combined with lenvatinib.
Table 1 Baseline characteristics and clinical data of hepatocellular carcinoma with portal vein tumor thrombus patients before and after propensity score matching, n (%).
Variables
Before PSM
After PSM
TACE-L-P group (n = 42)
TACE-L group (n = 68)
P value
TACE-L group (n = 42)
Adjusted P value
Patient characteristics
Sex (male)
34 (81.0)
51 (75.0)
0.624
32 (76.2)
0.790
Age (years)
53.0 ± 14.1
52.8 ± 15.1
0.963
51.02 ± 13.4
0.513
Hepatitis B surface antigen (positive)
32 (76.2)
48 (70.6)
0.674
27 (64.3)
0.340
Liver cirrhosis (yes)
23 (54.8)
30 (44.1)
0.374
20 (47.6)
0.662
Recurrent tumor (yes)
12 (28.6)
8 (11.8)
0.049
7 (16.7)
0.296
Imaging parameters
Largest tumor size (cm)
13.6 ± 5.1
12.5 ± 4.9
0.294
12.7 ± 4.8
0.402
Barcelona Clinic Liver Cancer Tumor staging
B
15 (35.7)
33 (48.5)
0.263
18 (42.9)
0.655
C
27 (64.3)
35 (51.5)
24 (57.1)
Portal vein tumor thrombus classification
VP 1-2
10 (23.8)
10 (14.7)
0.343
7 (16.7)
0.587
VP 3-4
32 (76.2)
58 (85.3)
35 (83.3)
Biochemical parameters
Hemoglobin (g/L)
120.9 ± 18.4
123.1 ± 22.8
0.579
122.9 ± 21.6
0.652
Serum albumin (g/L)
34.2 ± 5.58
36.2 ± 5.2
0.040
34.9 ± 5.2
0.492
Alpha-fetoprotein ≥ 400 ng/mL (yes)
33 (78.6)
49 (72.1)
0.592
33 (78.6)
1.000
Child–Pugh classification
A
20 (47.6)
37 (57.4)
0.620
26 (61.9)
0.273
B
22 (52.4)
31 (45.6)
16 (38.1)
Total bilirubin > 17.1 μmol/L (yes)
5 (11.9)
13 (19.1)
0.467
6 (16.3)
> 0.999
Alanine aminotransferase > 50 (U/L)
8 (19.0)
18 (26.5)
0.509
11 (26.2)
0.602
Aspartate aminotransferase > 40 (U/L)
7 (16.7)
17 (25.0)
0.430
11 (26.2)
0.425
Creatinine > 97 (μmol/L)
7 (16.7)
19 (27.9)
0.262
13 (31.0)
0.200
Histopathological parameters
Extrahepatic invasion (yes)
22 (52.4)
21 (30.8)
0.041
20 (47.6)
0.827
Tumor type
Nodular
10 (23.8)
11 (16.7)
0.459
9 (21.4)
> 0.999
Infiltrative
32 (76.2)
57 (83.8)
33 (78.6)
The data after matching showed that patients in TACE-L-P group received a total of 135 TACE treatments, with a median of 3 treatments (range 2-8), while patients in TACE-L group received 98 TACE treatments, with a median of 2 treatments (range 1-7). The average duration of lenvatinib use was 8.7 months ± 4.4 months in the TACE-L-P group, compared to 6.7 months ± 2.8 months in the TACE-L group (P = 0.01). The use of PD-1 inhibitors in TACE-L-P group was as follows: (1) 28 patients (66.7%) received sintilimab; (2) 8 patients (19.0%) received camrelizumab; and (3) 6 patients (14.3%) received tislelizumab.
Survival time
The follow-up period ranged from 4.1 months to 32.3 months, with a median follow-up time of 15.6 months. At the end of the follow-up, 56 patients (66.7%) had died, including 25 patients (59.5%) in the TACE-L-P group and 21 patients (73.8%) in the TACE-L group. Among the deceased patients, 21 (84.0%) in the TACE-L-P group died due to disease progression, and 4 (16.0%) died from other causes. In the TACE-L group, 27 patients (87.1%) died due to disease progression, and 4 (12.9%) died from other causes. The median OS in the TACE-L-P group was 17.2 months (95%CI: 16.0-27.4), while the median OS in the TACE-L group was 12.6 months (95%CI: 10.3-19.5), and the difference between the two groups was statistically significant (Log-rank χ² = 5.354, P = 0.0207) (Figure 2A). The survival rates at different time points showed that the 1-year, 2-year, and 3-year OS rates for the TACE-L-P group were 80.6%, 29.2%, and 9.7%, respectively, while for the TACE-L group, they were 51.7%, 20.8%, and 10.4%, respectively.
Figure 2 Kaplan-Meier analyses.
A: Overall survival; B: Progression-free survival according to treatment groups after propensity score matching. EH: Emergency hepatectomy; PSM: Propensity score matching; SH: Staged hepatectomy; TACE-L: Transarterial chemoembolization combined with lenvatinib; TACE-L-P: Transarterial arterial chemoembolization combined with lenvatinib plus death protein-1 inhibitors.
The median PFS in the TACE-L-P group was 10.6 months (95%CI: 8.4-15.1), while the median PFS in the TACE-L group was 7.1 months (95%CI: 6.5-8.1), and the difference was statistically significant (Log-rank χ² = 6.251, P = 0.012) (Figure 2B).
Tumor response
According to the mRECIST criteria, the ORR in TACE-L-P group was higher than TACE-L group (66.7% vs 42.9%, P = 0.049), and the DCR was also higher in the TACE-L-P group (78.6% vs 50.0%, P = 0.012) (Figure 3A). Additionally, within the TACE-L-P group, the ORR (53.6% vs 64.3%, P = 0.740) and DCR (67.9% vs 71.4%, P = 0.957) were similar between patients receiving Sintilimab and those receiving Camrelizumab/Tislelizumab (Figure 3B).
Figure 3 Comparison of objective response rate and disease control rate.
A: Comparison of objective response rate (ORR) and disease control rate (DCR) between transarterial arterial chemoembolization combined with lenvatinib plus death protein-1 inhibitors (TACE-L-P) and transarterial chemoembolization combined with lenvatinib groups based on Modified Response Evaluation Criteria In Solid Tumors criteria after propensity score matching; B: Comparison of ORR and DCR within the TACE-L-P group stratified by programmed death ligand-1 inhibitors (Sintilimab vs Camrelizumab/Tislelizumab). CR: Complete response; DCR: Disease control rate; HCC-PVTT: Hepatocellular carcinoma with portal vein tumor thrombus; ORR: Objective response rate; PD: Death protein; PD-L1: Programmed death ligand-1; PR: Partial response; SD: Stable disease; TACE-L: Transarterial chemoembolization combined with lenvatinib; TACE-L-P: Transarterial arterial chemoembolization combined with lenvatinib plus death protein-1 inhibitors.
Prognostic factor analysis
Univariate analysis for OS revealed that treatment regimen [hazard ratio (HR) = 0.501, 95%CI: 0.305–0.874, P = 0.012], alpha-fetoprotein (HR = 1.320, 95%CI: 1.102–2.265, P = 0.019), and extrahepatic metastasis (HR = 0.750, 95%CI: 0.551–1.054, P = 0.043) were associated with prognosis. After multivariate analysis, treatment regimen (HR = 0.581, 95%CI: 0.352–0.941, P = 0.023) and extrahepatic metastasis (HR = 0.720, 95%CI: 0.511–1.020, P = 0.045) were identified as independent prognostic factors (Figure 3).
For PFS, univariate analysis showed that treatment regimen (HR = 0.548, 95%CI: 0.319–0.941, P = 0.029), BCLC tumor staging (HR = 1.721, 95%CI: 0.994–2.981, P = 0.043), and extrahepatic metastasis (HR = 0.978, 95%CI: 0.576–1.660, P = 0.043) were significant prognostic factors. After multivariate analysis, treatment regimen (HR = 0.490, 95%CI: 0.300–0.790, P = 0.014) and extrahepatic metastasis (HR = 0.612, 95%CI: 0.435–0.844, P = 0.035) were identified as independent prognostic factors (Figure 4A).
Figure 4 Univariate and multivariate analysis.
A: Overall survival after propensity score matching; B: Univariate and multivariate analysis of progression-free survival after propensity score matching. AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HbsAg: Hepatitis B surface antigen; HR: Hazard ratio; TACE-L: Transarterial chemoembolization combined with lenvatinib; TACE-L-P: Transarterial arterial chemoembolization combined with lenvatinib plus death protein-1 inhibitors; TBIL: Total bilirubin.
Safety
A total of 71 cases (84.5%) of treatment-related AEs were observed, with 15 cases (18.3%) experiencing grade 3 AEs. No grade 4/5 AEs or treatment-related deaths were reported. All AEs were alleviated or resolved after symptomatic treatment, dose reduction, or discontinuation. The most common TACE-related AEs were abdominal pain (19.0%), followed by fever (7.1%), inguinal hematoma (6.0%), nausea and vomiting (4.8%), and bile duct injury (1.2%). The most common drug-related AEs were diarrhea (23.8%), followed by thrombocytopenia (20.2%), decreased appetite (10.7%), fatigue (14.3%) and leukopenia (10.7%). The incidence of AEs of any grade and grade 3 AEs was similar between the two groups (any grade: 81.0% vs 88.1%, P = 0.546; grade 3: 21.4% vs 14.3%, P = 0.568), as shown in Table 2.
In terms of treatment management, lenvatinib-related AEs primarily affected treatment continuity and dose adjustments. In the TACE-L-P group, 10 patients (23.8%) had treatment interruptions and 17 patients (40.5%) required dose reduction. In the TACE-L group, the respective numbers were 8 patients (19.5%) and 15 patients (35.7%). No patients in either group discontinued medication due to AEs. Additionally, in the TACE-L-P group, 6 patients (14.2%) interrupted PD-L1 inhibitor therapy due to AEs, 5 patients (11.9%) had a dose reduction, 1 patient (2.3%) simultaneously interrupted both lenvatinib and PD-L1 inhibitor therapy due to AEs, and 2 patients (4.8%) had dose reductions for both drugs (Figure 4B).
DISCUSSION
A retrospective study by Kuzuya et al[35] in 2020 first demonstrated that in first-line treatment regimens for HCC-PVTT (Vp3/4 type), lenvatinib outperforms sorafenib in terms of OS (median OS: Not reached vs 187 days, P = 0.0040) and ORR (53.8% vs 14.3%, P = 0.0193), and is the only significant and independent predictor for better OS and time to progression. Building on this finding, it is hypothesized that combining TACE-L may lead to better survival outcomes. A systematic review and meta-analysis by Deng et al[36] showed that compared to TACE combined with sorafenib, TACE-L demonstrated stronger results in terms of ORR (60.7% vs 38.9%) and time to progression (HR = 0.61, 95%CI: 0.43–0.86), although no significant differences were found in DCR (96.4% vs 96.3%) and OS (HR = 0.70, 95%CI: 0.46–1.05).
In addition, some studies suggest that lenvatinib, as a multi-target tyrosine kinase inhibitor, can weaken the immune-suppressive effects mediated by key signaling pathways such as vascular endothelial growth factor by inhibiting them. It also induces vascular normalization within the tumor, thereby promoting T cell infiltration in the tumor microenvironment to enhance the efficacy of anti-PD-1 therapy[37-39]. Recent studies have highlighted the role of the tumor microenvironment in modulating immune cell function, for example, a study by Liu et al[40] identified novel exhausted T cell CD8+ markers in breast cancer, which may serve as a valuable indicator of tumor progression and response to immunotherapy. These findings align with broader The Cancer Genome Atlas (TCGA)-based biomarker discovery efforts. Those laboratory have systematically characterized immune-related gene sets across multiple cancer types[41-44], revealing conserved molecular signatures of immune evasion[45-48]. Such pan-cancer analyses highlight potential therapeutic targets that may also influence HCC immunogenicity and response to PD-1 inhibitors[40,49-51]. Moreover, recent advancements in liquid biopsy techniques, such as circulating tumor DNA detection, have proven useful in cancer diagnostics and monitoring[52]. Additionally, emerging sequencing technologies have enhanced the sensitivity and specificity of DNA analysis[53], while methylation signatures are increasingly utilized for tumor detection[54]. Notably, while TCGA-based studies have identified prognostic biomarkers through bulk transcriptomic analysis[55-59], these datasets often lack treatment response annotations and may be confounded by technical biases[60,61]. Our clinical findings thus complement such discoveries by directly linking therapeutic outcomes to patient characteristics, emphasizing the need to validate bioinformatic predictions in cohort studies. On the other hand, TACE can reduce the blood supply to tumors, induce extensive local necrosis of tumor cells, and release a large amount of tumor-specific antigens, thereby enhancing the anti-tumor immune effects of PD-1 inhibitors[62]. Based on these synergistic effects, an increasing number of studies have explored the efficacy of TACE combined with lenvatinib and PD-1 inhibitors in the treatment of advanced HCC, achieving promising outcomes and offering new hope for HCC treatment[20,21,63].
Our study demonstrates that the TACE-L-P regimen significantly improved survival outcomes in HCC-PVTT patients, with higher ORR and DCR, and extended median OS from 12.6 months to 17.2 months, and median PFS from 7.1 months to 10.6 months. These findings are consistent with previous studies that have evaluated the efficacy of TACE combined with lenvatinib and PD-1 inhibitors in patients with advanced unresectable HCC, which reported ORRs ranging from 46.7% to 72.7%[21,64-66]. In this study, the ORR in the TACE-L-P group was 50.4%. Higher ORR is a crucial predictor for tumor downstaging and conversion to surgical treatment. For patients successfully converted to surgery, the treatment not only reduces tumor burden but also minimizes the treatment-related AEs associated with prolonged systemic therapy. Nine patients in the TACE-L-P group underwent surgical treatment, resulting in a conversion rate of 21.4%, which was higher than the 11.9% conversion rate observed in the TACE-L group. However, the overall conversion rate was lower than that reported in a previous study by Yuan et al[67], where the post-downstaging salvage hepatectomy rate was 46.3% and the pathological complete response rate was 31.6%. The lower conversion rate may be due to the larger tumor size and higher proportion of multifocal lesions in our study, which likely increased the difficulty of conversion surgery. In addition, the multivariate analysis indicates that extrahepatic metastasis is a significant factor affecting OS and PFS, which is consistent with previous research[64,66].
No unforeseeable AEs occurred in this study, and all AEs were manageable. The incidence of AEs of any grade was similar between the two groups, with the main AEs being diarrhea, thrombocytopenia, and decreased appetite. No treatment-related deaths were observed, and the rates of dose reduction and treatment interruption were similar between the groups, with no cases of treatment discontinuation. These findings indicate that PD-L1 inhibitors do not increase the risk of treatment-related complications and exhibit a favorable safety profile, which is consistent with previous studies[67-69]. In addition, the three different PD-L1 inhibitors used in this study did not show significant differences in efficacy. However, considering the immune modulation mechanisms and individual factors such as the patient’s immune status, tumor burden, and genetic mutations[19,70,71], the potential efficacy differences between inhibitors and their impact on treatment outcomes warrant further investigation.
Although many previous studies have reported the efficacy and safety of this triple therapy, the enrolled advanced HCC patient populations were highly heterogeneous, including those with distant metastasis, multiple intrahepatic lesions, and other complex pathological conditions. The strength of the present study lies in its focus on the high-risk group of HCC-PVTT patients, making the results more clinically relevant and valuable for guiding treatment. It is noteworthy that PVTT may obstruct portal vein blood flow and worsen liver function. However, the process of PVTT formation is relatively slow, and the liver gradually develops collateral circulation, allowing it to still partially receive blood supply, thereby attenuating the acute impact of portal vein obstruction on liver function[72]. In HCC-PVTT patients, the hepatic artery is the primary source of blood supply to the tumor tissue. TACE treatment leverages this physiological characteristic by injecting embolic agents and chemotherapeutic drugs into the hepatic artery, blocking the main blood supply to the tumor and inducing tumor necrosis. This approach not only prevents further obstruction of portal vein blood flow and exacerbation of liver dysfunction but also provides an ideal local therapeutic support for subsequent combination targeted therapy and immunotherapy.
This study has certain limitations. First, as a retrospective study, the treatment regimen was determined by the attending physician and the patient based on individual circumstances, making it difficult to completely eliminate the potential interference of confounding factors. Although PSM was used to balance baseline characteristics, inherent selection bias and data imbalances in retrospective design could not be entirely avoided. The use of different types of PD-L1 inhibitors may affect the consistency of efficacy and the interpretation of safety. Finally, the results of this study are based on a Chinese population predominantly infected with HBV, and may not be universally applicable to populations in Western countries where HCV infection or alcohol consumption is the primary etiology. On the other hand, while public genomic resources like TCGA have advanced cancer research, their limitations—such as lack of treatment response data and underrepresentation of advanced tumors[61,73]—highlight the unique value of our real-world cohort focusing on HCC-PVTT patients receiving TACE-L-P therapy.
In general, the TACE-L-P regimen significantly improved survival outcomes in patients with HCC-PVTT, which is consistent with findings from previous studies evaluating combination therapies in advanced HCC or HCC-PVTT patients[36,67,68]. These findings suggest that combining TACE with lenvatinib plus PD-1 inhibitors may offer a more effective treatment approach for this high-risk group, as immunotherapy has been shown to enhance antitumor responses by overcoming immune evasion in HCC[74]. Future studies using patient-derived xenograft models could further validate the TACE-L-P regimen’s efficacy. Additionally, the safety profile of the TACE-L-P regimen was favorable, with manageable AEs and no treatment-related deaths, indicating that the TACE-L-P regimen can be safely administered without significantly increasing treatment-related complications.
CONCLUSION
Compared to TACE-L, the TACE-L-P regimen exhibits an acceptable safety profile and shows potential in improving survival outcomes, making it a promising therapeutic option for patients with HCC-PVTT.
ACKNOWLEDGEMENTS
We sincerely thank the interventional radiology team at Li Huili Hospital Affiliated to Ningbo University for their expert technical support. We are grateful to Xiao-Dong Chen for clinical advice on portal vein tumor thrombus management and Nurse Wang Lina's team for patient care. Special thanks to all participating patients for their trust and cooperation.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade A
Creativity or Innovation: Grade A
Scientific Significance: Grade A
P-Reviewer: Zhang L S-Editor: Luo ML L-Editor: A P-Editor: Zhao YQ
Zhang XP, Zhou TF, Feng JK, Sun ZY, Zhen ZJ, Zhou D, Zhang F, Hu YR, Zhong CQ, Chen ZH, Chai ZT, Wang K, Shi J, Guo WX, Wu MC, Lau WY, Cheng SQ. Association of Preoperative Coagulability With Incidence and Extent of Portal Vein Tumor Thrombus and Survival Outcomes in Hepatocellular Carcinoma After Hepatectomy: A Large-Scale, Multicenter Study.Front Oncol. 2021;11:697073.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in RCA: 3][Reference Citation Analysis (0)]
Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, Izumi N, Yamasaki T, Nojiri S, Hino K, Tsumura H, Kuzuya T, Isoda N, Moriguchi M, Aino H, Ido A, Kawabe N, Nakao K, Wada Y, Ogasawara S, Yoshimura K, Okusaka T, Furuse J, Kokudo N, Okita K, Johnson PJ, Arai Y. Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma.Liver Cancer. 2022;11:354-367.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 41][Cited by in RCA: 86][Article Influence: 28.7][Reference Citation Analysis (0)]
Kudo M, Finn RS, Galle PR, Zhu AX, Ducreux M, Cheng AL, Ikeda M, Tsuchiya K, Aoki KI, Jia J, Lencioni R. IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study.Liver Cancer. 2023;12:238-250.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 4][Cited by in RCA: 32][Article Influence: 16.0][Reference Citation Analysis (0)]
Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, Li Q, Lu Y, Chen Y, Guo Y, Chen Z, Liu B, Jia W, Wu J, Wang J, Shao G, Zhang B, Shan Y, Meng Z, Wu J, Gu S, Yang W, Liu C, Shi X, Gao Z, Yin T, Cui J, Huang M, Xing B, Mao Y, Teng G, Qin Y, Wang J, Xia F, Yin G, Yang Y, Chen M, Wang Y, Zhou H, Fan J; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.Lancet Oncol. 2021;22:977-990.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 253][Cited by in RCA: 644][Article Influence: 161.0][Reference Citation Analysis (1)]
Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, Zhang C, Lunceford JK, Joe A, Cheng J, Webber AL, Ibrahim N, Plimack ER, Ott PA, Seiwert TY, Ribas A, McClanahan TK, Tomassini JE, Loboda A, Kaufman D. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.Science. 2018;362.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1035][Cited by in RCA: 1631][Article Influence: 233.0][Reference Citation Analysis (0)]
Li B, Qiu J, Zheng Y, Shi Y, Zou R, He W, Yuan Y, Zhang Y, Wang C, Qiu Z, Li K, Zhong C, Yuan Y. Conversion to Resectability Using Transarterial Chemoembolization Combined With Hepatic Arterial Infusion Chemotherapy for Initially Unresectable Hepatocellular Carcinoma.Ann Surg Open. 2021;2:e057.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 11][Cited by in RCA: 44][Article Influence: 11.0][Reference Citation Analysis (0)]
Shuqun C, Mengchao W, Han C, Feng S, Jiahe Y, Guanghui D, Wenming C, Peijun W, Yuxiang Z. Tumor thrombus types influence the prognosis of hepatocellular carcinoma with the tumor thrombi in the portal vein.Hepatogastroenterology. 2007;54:499-502.
[PubMed] [DOI]
Gaba RC, Lokken RP, Hickey RM, Lipnik AJ, Lewandowski RJ, Salem R, Brown DB, Walker TG, Silberzweig JE, Baerlocher MO, Echenique AM, Midia M, Mitchell JW, Padia SA, Ganguli S, Ward TJ, Weinstein JL, Nikolic B, Dariushnia SR; Society of Interventional Radiology Standards of Practice Committee. Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy.J Vasc Interv Radiol. 2017;28:1210-1223.e3.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 69][Cited by in RCA: 103][Article Influence: 12.9][Reference Citation Analysis (0)]
Liu J, Wei S, Yang L, Yu J, Yan D, Yi P. Efficacy and safety of transarterial chemoembolization plus lenvatinib with or without programmed death-1 inhibitors in the treatment of unresectable hepatocellular carcinoma: a systematic review and meta-analysis.J Cancer Res Clin Oncol. 2023;149:14451-14461.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 6][Reference Citation Analysis (0)]
Liu L, Suo T, Shen Y, Geng C, Song Z, Liu F, Wang J, Xie Y, Zhang Y, Tang T, Zhang L, Wang W. Clinicians versus patients subjective adverse events assessment: based on patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).Qual Life Res. 2020;29:3009-3015.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 9][Cited by in RCA: 25][Article Influence: 5.0][Reference Citation Analysis (0)]
Abraham A, Hoyos Idrobo A. Improving Bias Correction Standards by Quantifying its Effects on Treatment Outcomes. 2024 Preprint.
ArXiv.
[PubMed] [DOI] [Full Text]
Wilkinson J, Mamas MA, Kontopantelis E. How do dataset characteristics affect the performance of propensity score methods and regression for controlling confounding in observational studies?
ArXiv.
[PubMed] [DOI] [Full Text]
Yamauchi M, Ono A, Amioka K, Fujii Y, Nakahara H, Teraoka Y, Uchikawa S, Fujino H, Nakahara T, Murakami E, Okamoto W, Miki D, Kawaoka T, Tsuge M, Imamura M, Hayes CN, Ohishi W, Kishi T, Kimura M, Suzuki N, Arihiro K, Aikata H, Chayama K, Oka S. Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma.Commun Med (Lond). 2023;3:152.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in RCA: 16][Reference Citation Analysis (0)]
Ohyama H, Hirotsu Y, Amemiya K, Mikata R, Amano H, Hirose S, Oyama T, Iimuro Y, Kojima Y, Mochizuki H, Kato N, Omata M. Development of a molecular barcode detection system for pancreaticobiliary malignancies and comparison with next-generation sequencing.Cancer Genet. 2024;280-281:6-12.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 9][Reference Citation Analysis (0)]
Liu H, Tang T. A bioinformatic study of IGFBPs in glioma regarding their diagnostic, prognostic, and therapeutic prediction value.Am J Transl Res. 2023;15:2140-2155.
[PubMed] [DOI]
Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.N Engl J Med. 2020;382:1894-1905.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 2542][Cited by in RCA: 4555][Article Influence: 911.0][Reference Citation Analysis (2)]
Chen Y, Jia L, Li Y, Cui W, Wang J, Zhang C, Bian C, Wang Z, Lin D, Luo T. Clinical Effectiveness and Safety of Transarterial Chemoembolization: Hepatic Artery Infusion Chemotherapy Plus Tyrosine Kinase Inhibitors With or Without Programmed Cell Death Protein-1 Inhibitors for Unresectable Hepatocellular Carcinoma-A Retrospective Study.Ann Surg Oncol. 2024;31:7860-7869.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1][Cited by in RCA: 5][Article Influence: 5.0][Reference Citation Analysis (0)]
