Abstract
Background
The efficacy of transarterial chemoembolization (TACE) in treating unresectable hepatocellular carcinoma (uHCC) complicated by arterioportal shunts (APS) was unsatisfactory. Developed systemic therapies can synergize with TACE, potentially reducing APS recanalization and enhancing patient benefits. The objective of this study was to evaluate and compare the therapeutic efficacy and safety of a combination therapy regimen that includes TACE, lenvatinib, and sintilimab (TACE-L-S) versus TACE monotherapy in uHCC patients with APS.
Methods
After reviewing hospital records, this retrospective study enrolled 96 patients: 51 in the TACE-L-S group and 45 in the TACE group. We utilized the Chi-squared test to analyze tumor response, changes in APS grades, APS recanalization rates, and adverse events (AEs) between the two groups. Kaplan-Meier analysis was employed to compare median progression-free survival (mPFS). Cox regression analyses were conducted to identify factors influencing mPFS, whereas logistic regression analyses were performed to assess factors influencing APS recanalization rates.
Results
The objective response rate (ORR) was 68.6% in the TACE-L-S group and 37.8% in the TACE group (P=0.002). The TACE-L-S group had better mPFS compared to the TACE group (168 vs. 111 days, P<0.001), influenced by the treatment option, hepatic vein invasion, and portal vein tumor thrombosis (PVTT) type. Following the first TACE procedure, APS grades were similar between the groups; however, at 3 months after the first TACE, the TACE-L-S group demonstrated better APS grades. APS recanalization rates also differed significantly between the groups (24.4% vs. 53.8%, P=0.006), influenced by the treatment option, preoperative APS grade, and PVTT type. AEs associated with TACE-L-S were tolerable.
Conclusions
For uHCC patients with APS, TACE-L-S may be a kind of effective and safe therapy.
Keywords: Hepatocellular carcinoma (HCC), arterioportal shunts (APS), transarterial chemoembolization (TACE), sintilimab, lenvatinib
Highlight box.
Key findings
• For unresectable hepatocellular carcinoma (uHCC) patients with arterioportal shunts (APS), transarterial chemoembolization (TACE) combined with lenvatinib plus sintilimab (TACE-L-S) could prolong survival time, reduce the possibility of APS recanalization compared with TACE alone, and its adverse reactions were safe and controllable.
What is known and what is new?
• For uHCC patients with APS, TACE-L-S could prolong survival time.
• TACE-L-S cloud reduces the possibility of APS recanalization.
What is the implication, and what should change now?
• If possible, for uHCC patients with APS, both TACE and systemic therapy should be used simultaneously. The prognosis of using TACE alone or systemic therapy alone is inferior to that of combination therapy.
Introduction
Hepatocellular carcinoma (HCC) ranks sixth in incidence and third in cancer-related mortality among all malignancies in China (1). In countries where systematic screening for liver cirrhosis is not conducted, 50% to 75% of patients are diagnosed with liver cancer at an advanced stage, resulting in a poor prognosis (2,3). Ten to 60 percent of patients with HCC have portal vein tumor thrombosis (PVTT) (3). PVTT is considered an independent risk factor for poor prognosis (4). Even more detrimental, PVTT can lead to the development of arterioportal shunts (APS), which increases the risk of tumor metastasis and severe complications, including esophageal varices and ascites, ultimately shortening the patients’ survival duration (5).
Currently, clinical guidelines recommend transarterial chemoembolization (TACE) as the standard therapy for patients with advanced HCC. During TACE treatment for HCC patients with APS, the lipiodol may inadvertently traverse the APS, impeding its effective deposition within the tumor, which can compromise its effectiveness (6). Therefore, using other embolization particles [such as polyvinyl alcohol (PVA) or gelatin sponge particles] to occlude or relieve APS is very important, as it can optimize the deposition of lipiodol, reduce complications caused by APS, and potentially bring better survival benefits to patients. However, embolism can potentially affect the blood supply of the liver from the portal vein, resulting in hepatic ischemia. Although TACE can immediately occlude or reduce APS, controlling rapidly progressing advanced HCC with TACE alone is challenging, and the recurrence rate of APS remains unsatisfactory.
In the past decade, systemic therapies for HCC have undergone rapid development, which includes tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors. Lenvatinib has demonstrated the ability to suppress tumor vessel growth and improve median overall survival (OS) in HCC patients, making it a recommended first-line treatment for unresectable HCC (uHCC) (7). PD-1 inhibitors can counter immune evasion strategies used by tumor cells. Various studies have shown that combining TKIs with PD-1 inhibitors leads to better outcomes for uHCC patients (8-10). As the second domestically produced PD-1 inhibitor in China, sintilimab was approved for marketing in 2019 and has been recommended as a first-line treatment for uHCC, with widespread use in China. The combined treatment regimen of TACE, lenvatinib, and sintilimab (TACE-L-S) has been proven effective in numerous studies and is widely used in the treatment of uHCC in China (11,12).
We believe that the deficiencies of TACE for patients with uHCC accompanied by APS can be compensated for by systemic therapies. When used in combination, they can synergistically control the progression of HCC, occlude or relieve APS, reduce the recurrence rate of APS, and thus bring survival benefits to patients. Currently, there are scant studies reporting on the comparative efficacy of TACE-L-S versus TACE for uHCC patients with APS. Consequently, in this study, we conducted a retrospective analysis to compare the efficacy and safety of TACE-L-S versus TACE in treating uHCC patients with APS. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-167/rc).
Methods
Patient criteria
Our study adhered to the ethical standards outlined in the Helsinki Declaration and its subsequent amendments. The study underwent a thorough examination and was approved by the ethics committee at Ningbo No. 2 Hospital (No. PJ-NBEY-KY-2024-187-01). Since this was a retrospective study, informed consent was unnecessary. Data collection and analysis were conducted anonymously to protect the privacy and confidentiality of participants. The inclusion criteria were: (I) aged 18–75 years; (II) HCC with pathological examination; (III) diagnosis of PVTT by magnetic resonance imaging (MRI) or computed tomography (CT) imaging and APS by hepatic angiography; (IV) treated by TACE-L-S or TACE alone from May 1, 2016 to November 31, 2022; (V) APS assessment through hepatic angiography approximately 3 months after the first TACE procedure. Exclusion criteria were: (I) ECOG score >1; (II) Child-Pugh grade C; (III) undergoing different anticancer therapies; (IV) presence of other types of cancer; (V) lack of complete medical information. The patients who had undergone TACE-L-S belonged to the TACE-L-S group, and those who had undergone TACE alone belonged to the TACE group.
Treatment
Before initiating the treatment, an enhanced MRI or an enhanced CT scan was conducted within the preceding week, with all requisite laboratory tests being accomplished within a period of three days. All patients received 200 mg of sintilimab intravenously, administered at a three-week interval. Furthermore, patients were prescribed lenvatinib for oral administration, with a dose of 8 or 12 mg based on whether the weight exceeded 60 kg.
During the TACE procedure, hepatic angiography was used to find the tumor-feeding arteries as well as the pathways of APS. The embolism procedure was carried out as described below: (I) if the microcatheter was unable to navigate past the area of APS, the chemoembolization was performed in the feeding artery, allowing for the simultaneous embolization of both the tumor and the APS; (II) if the microcatheter was able to navigate past the area of APS, the tumor’s feeding artery was initially embolized with a mixture of lipiodol and 20 mg of epirubicin. Afterward, the microcatheter was withdrawn to the APS region to embolize APS with PVA, gelfoam particles, or a spring coil. If enhanced CT or MRI scans showed that the tumor still demonstrated enhancement, TACE procedures were conducted at intervals of 1 to 2 months.
Evaluation criteria
APS is diagnosed when the portal vein or its tributaries opacify during the arterial phase of hepatic arteriography. Based on the timing of their appearance, APS are categorized into three grades: (I) severe: during visualization of the main hepatic artery and its branch, the portal vein becomes visible, indicating that tumor staining is absent or in its early stages; (II) moderate: during middle to late phases of tumor staining, primary vein or its branch become visible; (III) mild: while small branch of portal vein is visible on angiography, the morphology of the shunt is not discernible (13).
Based on the mRECIST criteria (14), the lesions were categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).
The main goals were to evaluate mPFS, tumor response, changes in APS grade, and the prognostic factors of progression-free survival (PFS) and APS recanalization. PFS was measured from the first treatment until the onset of PD, decrease, or conclusion of the follow-up period. Our objective also included assessing adverse events (AEs) as secondary endpoints.
We engaged two radiologists with over 15 years of experience in image diagnosis to evaluate the patients’ imaging data. In cases where the two radiologists assigned different ratings, they would discuss and reach a consensus on the final rating, thereby minimizing bias.
Data extraction
Participants were followed up every 30 to 90 days after the first TACE procedure. At every follow-up session, blood tests were carried out for hematological parameters, and an enhanced MRI was carried out to evaluate the tumor response. The cutoff date for follow-up was set as November 31, 2024. During the follow-up period, we did not interfere with the selection or modification of treatment options.
Statistical analysis
Using data from 36 patients (20 in the TACE-L-S group and 16 in the TACE group), we conducted a pilot study to analyze the APS recanalization rates of the two groups. The recanalization rates for the two groups were 25% and 62.5%. So, we used PASS software to calculate the sample size, with a power set at 0.90, an alpha level at 0.05, an APS recanalization rate of 0.25 for the TACE-L-S group, and an APS recanalization rate of 0.60 for the TACE group. The calculation resulted in N1=N2=37. A sample size of more than 37 in both groups ensures adequate statistical power.
Categorical variables were compared through the χ2 test. Continuous variables were analyzed using the Student’s t-test. The mPFS was estimated by the Kaplan-Meier method. We analyzed clinical features via Cox analysis. Variables with a P value less than 0.10 in the univariate analysis were selected for inclusion in the multivariate analysis. Univariate (P<0.1) and multivariate (P<0.05) logistic regression analyses were employed to investigate the prognostic factors that influence APS recanalization. Differences were considered statistically significant at P<0.05.
Results
Patient’s characteristics
One hundred and thirty-eight uHCC patients with APS met the inclusion criteria, but 42 individuals were disqualified according to the exclusion criteria (Figure 1). As a result, the research comprised 96 individuals, with 51 belonging to the TACE-L-S group and 45 to the TACE group. There was no significant statistical difference in the baseline characteristics presented in Table 1. The follow-up time ranged from 33 to 417 days. The overall mean follow-up time was 135±57.64 days.
Figure 1.
Selection criteria. APS, arterioportal shunts; ECOG PS, Eastern Cooperative Oncology Group performance status; uHCC, unresectable hepatocellular carcinoma; TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
Table 1. Baseline characteristics of the patients.
| Characteristics | TACE-L-S group (n=51) | TACE group (n=45) | P |
|---|---|---|---|
| Sex | 0.68 | ||
| Male | 39 (76.5) | 36 (80.0) | |
| Female | 12 (23.5) | 9 (20.0) | |
| Age (years) | 61.6±9.3 | 61.3±8.2 | 0.63 |
| ECOG PS | 0.65 | ||
| 0 | 17 (33.3) | 17 (37.8) | |
| 1 | 34 (66.7) | 28 (62.2) | |
| Child-Pugh class | 0.38 | ||
| A | 26 (51.0) | 27 (60.0) | |
| B | 25 (49.0) | 18 (40.0) | |
| AFP | 0.46 | ||
| ≤300 ng/mL | 20 (39.2) | 21 (46.7) | |
| >300 ng/mL | 31 (60.8) | 24 (53.3) | |
| Number of tumors | 0.22 | ||
| ≤3 | 23 (45.1) | 26 (57.8) | |
| >3 | 28 (54.9) | 19 (42.2) | |
| Largest tumor size (mm) | 95.3±33.7 | 94.1±31.0 | 0.42 |
| PVTT | 0.69 | ||
| Vp2 | 22 (43.1) | 23 (51.1) | |
| Vp3 | 17 (33.4) | 14 (31.1) | |
| Vp4 | 12 (23.5) | 8 (17.8) | |
| Hepatic vein invasion | 0.18 | ||
| Yes | 19 (37.3) | 11 (24.4) | |
| No | 32 (62.7) | 34 (75.6) | |
| Extrahepatic metastasis | 0.57 | ||
| Yes | 10 (19.6) | 11 (24.4) | |
| No | 41 (80.4) | 34 (75.6) | |
| Grades of APS | 0.53 | ||
| Mild | 13 (25.5) | 10 (22.2) | |
| Moderate | 25 (49.0) | 27 (60.0) | |
| Severe | 13 (25.5) | 8 (17.8) | |
| Liver cirrhosis | 0.2 | ||
| Yes | 38 (74.5) | 28 (62.2) | |
| No | 13 (25.5) | 17 (37.8) |
Data were presented as n (%) or mean ± standard deviation. AFP, a-fetoprotein; APS, arterioportal shunts; ECOG PS, Eastern Cooperative Oncology Group performance status; PVTT, portal vein tumor thrombosis; TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
Tumor response
The tumor responses in the TACE-L-S group were as follows: CR: 3 (5.9%), PR: 32 (62.7%), SD: 12 (23.5%), PD: 4 (7.8%), while the tumor responses in the TACE group were as follows: CR: 0, PR: 17 (37.8%), SD: 23 (51.1%), and PD: 5 (11.1%) (Table 2). There was a statistical difference in tumor response between the two groups (P=0.01). The ORR was 68.6% and 37.8% in the TACE-L-S group and the TACE group (P=0.002).
Table 2. Tumor response.
| Tumor response | TACE-L-S | TACE | P |
|---|---|---|---|
| CR | 3 (5.9) | 0 | 0.01 |
| PR | 32 (62.7) | 17 (37.8) | |
| SD | 12 (23.5) | 23 (51.1) | |
| PD | 4 (7.8) | 5 (11.1) | |
| ORR (CR + PR) | 35 (68.6) | 17 (37.8) | 0.002 |
| DCR (CR + PR + SD) | 47 (92.2) | 40 (88.9) | 0.58 |
Data were presented as n (%). CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
PFS and its risk factors
All patients developed PD during the follow-up period. The median PFS in the TACE-L-S group was 168 days [95% confidence interval (CI): 142.0–194.0], and that in the TACE group was 111 days (95% CI: 99.2–122.8). There was a statistically significant difference between the two groups (P<0.001, Figure 2).
Figure 2.
Kaplan-Meier curves of progression-free survival. TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
The univariate Cox analysis revealed that the P values for treatment option, hepatic vein invasion, and PVTT type were less than 0.10. Hepatic vein invasion (yes/no, HR: 1.76, P=0.02), PVTT type (Vp4/Vp2, HR: 2.50, P=0.002) and treatment option (TACE-L-S/TACE, HR: 0.25, P<0.001) were identified as preoperative prognostic factors for PFS after multivariate Cox analysis (Table 3).
Table 3. Univariate and multivariate Cox analyses of risk factors for PFS.
| Variables | Univariate | Multivariate | |||
|---|---|---|---|---|---|
| P | HR (95% CI) | P | HR (95% CI) | ||
| Treatment option | |||||
| TACE | 1.00 (reference) | 1.00 (reference) | |||
| TACE-L-S | <0.001 | 0.36 (0.23–0.56) | <0.001 | 0.25 (0.16–0.41) | |
| Age | |||||
| >60 years | 1.00 (reference) | – | – | ||
| ≤60 years | 0.46 | 1.17 (0.77–1.76) | – | – | |
| Sex | |||||
| Female | 1.00 (reference) | – | – | ||
| Male | 0.65 | 1.12 (0.69–1.82) | – | – | |
| Child-Pugh | |||||
| A | 1.00 (reference) | – | – | ||
| B | 0.93 | 0.98 (0.65–1.47) | – | – | |
| AFP | |||||
| <300 ng/mL | 1.00 (reference) | – | – | ||
| ≥300 ng/mL | 0.37 | 1.21 (0.80–1.83) | – | – | |
| Number of tumors | |||||
| <3 | 1.00 (reference) | – | – | ||
| ≥3 | 0.20 | 0.77 (0.51–1.16) | – | – | |
| Tumor diameter | |||||
| >10 cm | 1.00 (reference) | – | – | ||
| ≤10 cm | 0.66 | 0.91 (0.60–1.38) | – | – | |
| PVTT type | |||||
| Vp2 | 1.00 (reference) | 1.00 (reference) | |||
| Vp3 | 0.49 | 1.18 (0.74–1.88) | 0.09 | 1.54 (0.95–2.49) | |
| Vp4 | 0.02 | 1.89 (1.10–3.25) | 0.002 | 2.50 (1.39–4.51) | |
| Hepatic vein invasion | |||||
| No | 1.00 (reference) | 1.00 (reference) | |||
| Yes | 0.06 | 1.52 (0.98–2.37) | 0.02 | 1.76 (1.09–2.84) | |
| Extrahepatic metastasis | |||||
| No | 1.00 (reference) | – | – | ||
| Yes | 0.22 | 1.36 (0.83–2.21) | – | – | |
| Preoperative APS grade | |||||
| Mild | 1.00 (reference) | – | – | ||
| Moderate | 0.15 | 1.46 (0.88–2.43) | – | – | |
| Severe | 0.14 | 1.57 (0.86–2.89) | – | – | |
| ECOG PS | |||||
| 0 | 1.00 (reference) | – | – | ||
| 1 | 0.68 | 1.09 (0.72–1.67) | – | – | |
| Liver cirrhosis | |||||
| No | 1.00 (reference) | – | – | ||
| Yes | 0.32 | 0.80 (0.51–1.24) | – | – | |
AFP, a-fetoprotein; APS, arterioportal shunts; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PFS, progression-free survival; PVTT, portal vein tumor thrombosis; TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
Change in APS grade
After embolization in the initial TACE procedure, the improvement rate of APS was 96.9% (93/96). Among these 93 patients, APS completely disappeared in 84 patients (45 in TACE-L-S and 39 in TACE) and alleviated in 9 patients. We reassessed APS grades 3 months after the initial TACE and found that the APS grades 3 months after the initial TACE of the TACE-L-S group were superior to those of the TACE group (Table 4), and the APS recanalization rate of the TACE-L-S group was better (24.4% vs. 53.8%, P=0.006).
Table 4. Chance in APS grades.
| Time | APS grade | TACE-L-S | TACE | P |
|---|---|---|---|---|
| Before first TACE | Mild | 13 (25.5) | 10 (22.2) | 0.53 |
| Moderate | 25 (49.0) | 27 (60.0) | ||
| Severe | 13 (25.5) | 8 (17.8) | ||
| After embolization in first TACE | None | 45 (88.2) | 39 (86.7) | 0.76 |
| Mild | 4 (7.8) | 5 (11.1) | ||
| Moderate | 1 (2.0) | 1 (2.2) | ||
| Severe | 1 (2.0) | 0 | ||
| Three months after first TACE | None | 36 (70.6) | 18 (40.0) | 0.02 |
| Mild | 5 (9.8) | 12 (26.7) | ||
| Moderate | 8 (15.7) | 11 (24.4) | ||
| Severe | 2 (3.9) | 4 (8.9) | ||
| APS recanalization | 11 (24.4) | 21 (53.8) | 0.006 |
Data were presented as n (%). APS, arterioportal shunts; TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
Risk factors influencing APS recanalization
We employed logistic regression analysis to analyze factors influencing APS recanalization. After univariate (P<0.1) and multivariate (P<0.05) logistic analysis, treatment option (TACE-L-S/TACE, HR: 0.22, P=0.005), PVTT type (Vp3/Vp2, HR: 4.11, P=0.02) and PVTT type (Vp4/Vp2, HR: 4.80, P=0.04), preoperative APS grade (moderate/mild, HR: 5.29, P=0.02) and preoperative APS grade (severe/mild, HR: 7.27, P=0.02) were identified as independent risk factors for APS recanalization showed in Table 5.
Table 5. Univariate and multivariate logistic analyses of risk factors for APS recanalization.
| Variables | Univariate | Multivariate | |||
|---|---|---|---|---|---|
| P | OR (95% CI) | P | OR (95% CI) | ||
| Treatment option | |||||
| TACE | 1.00 (reference) | 1.00 (reference) | |||
| TACE-L-S | 0.007 | 0.28 (0.11–0.70) | 0.005 | 0.22 (0.08–0.63) | |
| Age | |||||
| >60 years | 1.00 (reference) | – | – | ||
| ≤60 years | 0.73 | 1.17 (0.48–2.82) | – | – | |
| Sex | |||||
| Female | 1.00 (reference) | – | – | ||
| Male | 0.53 | 0.71 (0.25–2.05) | – | – | |
| Child-Pugh | |||||
| A | 1.00 (reference) | – | – | ||
| B | 0.16 | 0.52 (0.21–1.30) | – | – | |
| AFP | |||||
| <300 ng/mL | 1.00 (reference) | – | – | ||
| ≥300 ng/mL | 0.20 | 0.56 (0.23–1.37) | – | – | |
| Number of tumors | |||||
| <3 | 1.00 (reference) | – | – | ||
| ≥3 | 0.92 | 0.95 (0.39–2.30) | – | – | |
| Tumor diameter | |||||
| >10 cm | 1.00 (reference) | – | – | ||
| ≤10 cm | 0.27 | 0.60 (0.24–1.47) | – | – | |
| PVTT type | |||||
| Vp2 | 1.00 (reference) | 1.00 (reference) | |||
| Vp3 | 0.08 | 2.44 (0.89–6.72) | 0.02 | 4.11 (1.22–13.80) | |
| Vp4 | 0.04 | 3.76 (1.06–13.28) | 0.04 | 4.80 (1.11–20.67) | |
| Hepatic vein invasion | |||||
| No | 1.00 (reference) | – | – | ||
| Yes | 0.47 | 1.42 (0.55–3.69) | – | – | |
| Extrahepatic metastasis | |||||
| No | 1.00 (reference) | – | – | ||
| Yes | 0.40 | 1.59 (0.54–4.67) | – | – | |
| Preoperative APS grade | |||||
| Mild | 1.00 (reference) | 1.00 (reference) | |||
| Moderate | 0.03 | 3.84 (1.13–13.02) | 0.02 | 5.29 (1.29–21.79) | |
| Severe | 0.04 | 4.75 (1.06–21.36) | 0.02 | 7.27 (1.36–38.84) | |
| ECOG PS | |||||
| 0 | 1.00 (reference) | – | – | ||
| 1 | 0.24 | 1.74 (0.69–4.41) | – | – | |
AFP, a-fetoprotein; APS, arterioportal shunts; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; OR, odds ratio; PVTT, portal vein tumor thrombosis; TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
AEs
Upon analyzing the adverse reactions, it was found that the incidences of hand-foot syndrome, hypertension, thyroid dysfunction and rash in the TACE-L-S group were higher than those in the TACE group, which were associated with Lenvatinib and sintilimab (Table 6). On the other hand, AEs associated with TACE were similar between the two groups, such as fatigue, anorexia and nausea and hyperbilirubinemia (Table 6). All AEs were tolerable and were alleviated after symptomatic treatment or modification of drug dosage.
Table 6. Treatment-related adverse events in two groups.
| AEs | TACE-L-S (n=51) | TACE (n=45) | P | ||||
|---|---|---|---|---|---|---|---|
| Any grade | Grade 3–4 | Any grade | Grade 3–4 | Any grade | |||
| Diarrhea | 10 (19.6) | 2 (3.9) | 3 (6.7) | 0 | 0.06 | ||
| Hand-foot syndrome | 20 (39.2) | 3 (5.9) | 0 | 0 | – | ||
| Hypertension | 14 (27.5) | 2 (3.9) | 2 (4.4) | 0 | 0.003 | ||
| Fatigue | 27 (54.9) | 5 (9.8) | 20 (44.4) | 3 (6.7) | 0.64 | ||
| Anorexia and nausea | 25 (49.0) | 0 | 18 (40.0) | 0 | 0.38 | ||
| Rash | 11 (21.6) | 1 (2.0) | 0 | 0 | – | ||
| Leukopenia | 9 (17.6) | 2 (3.9) | 7 (15.6) | 0 | 0.79 | ||
| Thyroid dysfunction | 12 (23.5) | 1 (2.0) | 1 (2.2) | 0 | 0.002 | ||
| Hyperbilirubinemia | 23 (45.1) | 2 (3.9) | 14 (31.1) | 1 (2.2) | 0.19 | ||
| Thrombocytopenia | 7 (13.7) | 0 | 5 (11.1) | 0 | 0.70 | ||
Data were presented as n (%). AEs, adverse events; TACE, transarterial chemoembolization; TACE-L-S, TACE combined with lenvatinib plus sintilimab.
Discussion
APS represents a characteristic complication associated with PVTT and is recognized as a standalone indicator of unfavorable prognosis in HCC (15). APS causes blood to be directly injected from the hepatic artery into the portal vein, increasing the incidences of tumor metastasis and portal hypertension, and resulting in poor prognosis (5). As a first-line treatment for uHCC, TACE has potential problems when used for uHCC in patients with APS. Because the lipiodol may inadvertently penetrate through the APS, impeding its effective deposition within the tumor, treatment efficacy could be compromised. Therefore, embolizing the APS during the TACE procedure is crucial. However, TACE treatment alone is often difficult to achieve satisfactory therapeutic effects, and the APS recanalization rate is also relatively high. These deficiencies can be compensated for by systemic treatment. We believe that TACE-L-S can bring greater benefits to uHCC patients with APS.
In our study, we embolized APS using PVA, gelfoam particles or spring coil. The choice of embolization material was mainly based on APS grade. For severe APS, spring coils were used for embolization, with gelatin particles employed as necessary. After the embolization during the first TACE, approximately 90% of APS in the two groups completely disappeared. There was no statistical difference between the two groups. It was suggested that TACE could successfully embolize APS with a very high technical success rate. Xia et al. used gelatin sponge, PVA particles, and an ethanol-soaked gelatin sponge for the embolization of APS (16). APS disappears completely in 95.2% of patients in the study, which was similar to ours.
Progression in APS grade during treatment leads to a shortening of patients’ survival periods, which is an important factor affecting therapeutic efficacy. In our study, we reassessed APS grades 3 months after the initial TACE. Progression in APS grade following the first TACE occurred in 21 patients in the TACE group and 11 patients in the TACE-L-S group. The APS recanalization rate in the TACE-L-S group was higher than that in the TACE group (24.4% vs. 53.8%, P=0.006). This result suggested that systemic treatment could inhibit the progression of APS and significantly reduce APS recanalization, which is consistent with our expectations. Unfortunately, there were rarely similar studies analyzing APS recanalization or progression, and we had not found relevant evidence.
After statistical analysis, preoperative APS grade, PVTT type, and treatment option were identified as independent prognostic factors for APS recanalization. The occurrence of APS has a close relationship with PVTT. The portal vein obstruction resulting from PVTT triggers the opening of widespread anastomotic channels between the hepatic artery and portal vein within normal liver tissue, ultimately contributing to the progression of APS (17). Xia et al. treated 42 similar patients with TACE and 125I seed implantation and found that PVTT type was also an independent prognostic factor for APS recanalization (16). Therefore, severe PVTT is more likely to lead to the recurrence of APS. After the disappearance of severe APS following embolism, its recanalization rate was as high as 60% in our study. Poor tumor progression and PVTT type may lead to a worse APS grade, thereby favoring APS recanalization.
It is a worldwide consensus that combination therapy involving TACE, TKIs, and PD-1 inhibitors is superior to TACE to treat advanced HCC. Systemic therapy can further decrease the likelihood of APS recanalization for uHCC patients with APS, thereby preventing APS-related complications and contributing to improved patient survival outcomes. In our study, the ORR and mPFS of the TACE-L-S group were better than those of the TACE group. This result aligned with the aforementioned theory. Therefore, it is unquestionable that the treatment option has been identified as an independent prognostic factor for PFS. Other independent prognostic factors included hepatic vein invasion and PVTT type. Lin et al. used HAIC-P-L (hepatic artery infusion chemotherapy in combination with lenvatinib and sintilimab) and TACE-L-S to treat uHCC patients with APS and identified PVTT type (HR: 1.98, 95% CI: 1.46–2.70, P<0.001) as an independent prognostic factor for PFS as well (18). Zou et al. used TACE-L-S to treat 160 uHCC patients with PVTT and identified PVTT type (HR: 1.911; 95% CI: 1.377–2.572, P=0.03) as an independent prognostic factor for PFS as well (19). Similar studies have reached the same conclusion: PVTT type is an independent prognostic factor affecting PFS.
Although the AEs in the TACE-L-S group were significantly more numerous than those in the TACE group, all AEs were tolerable and alleviated after symptomatic treatment or dose adjustment. Numerous studies on the combination therapy of TACE, TKIs, and PD-1 inhibitors for the treatment of advanced HCC have reached the same conclusion (20-22). The AEs of this treatment are similar in uHCC patients with or without APS. As we all know, TACE-L-S is widely used in China for patients with uHCC for severe years, and its AEs are acceptable. Therefore, we think AEs of TACE-L-S are acceptable for uHCC patients with APS. The benefit of PFS does not necessarily translate into a benefit in OS, but the likelihood of such an occurrence is not insignificant. What is more concerning is that HCC-related symptoms, such as pain, jaundice, and ascites, are all related to the tumor’s growth and compression or invasion of the liver capsule, bile ducts, and blood vessels. The extension of PFS can delay the occurrence of such symptoms and improve the quality of life of patients. Due to cultural differences, these two advantages are sufficient to make Chinese patients willing to accept more tolerable AEs. In addition, the embolism of APS may lead to hepatic ischemia, thereby resulting in impaired liver function, with early manifestations including hyperbilirubinemia. Patients with cirrhosis may face even worse consequences due to the embolism of APS. Fortunately, in our study, hyperbilirubinemia in both cirrhotic and non-cirrhotic patients was transient and returned to normal within a few days after liver protection treatment, and its occurrence probability was similar to that of uHCC patients without APS in other studies (20-22). In summary, we believe that TACE-L-S has sufficient safety.
This study had limitations. First, the selection of treatment in our study was non-random, which may introduce bias. Second, the follow-up time was short, making it difficult to analyze OS. Third, the sample size of this study is limited. Therefore, further randomized controlled trials should be conducted to validate these results.
Conclusions
For uHCC patients with APS, TACE-L-S may be an effective and safe therapy that can prevent tumor progression, occlude APS, reduce the occurrence of APS recanalization, and increase survival benefits.
Supplementary
The article’s supplementary files as
Acknowledgments
We would like to thank our family for their support, which enabled us to complete this research.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study underwent a thorough examination and was approved by the ethics committee at Ningbo No. 2 Hospital (No. PJ-NBEY-KY-2024-187-01). Individual consent is not required due to the retrospective nature of this study.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-167/rc
Funding: None.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-167/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-167/dss
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