Influencing factors for digital subtraction angiography and cone-beam computed tomography guided bead chemoembolization in resistant liver cancer

Abstract

BACKGROUND

Transcatheter arterial chemoembolization (TACE) failure or refractoriness in hepatocellular carcinoma (HCC) refers to patients who continue to experience tumor progression or recurrence after TACE. Drug-eluting bead (DEB) TACE guided by digital subtraction angiography (DSA) is a novel interventional technique. However, the efficacy of DEB-TACE varies among patients, making the analysis of the factors influencing treatment outcomes clinically important for optimizing therapeutic strategies and improving prognosis.

AIM

To explore the factors influencing the clinical efficacy of DSA-guided DEB-TACE in the treatment of TACE failure/refractoriness in patients with HCC.

METHODS

A retrospective analysis was conducted in 96 patients with HCC who were admitted to our hospital between January 2021 and December 2023, met the criteria for TACE failure or refractoriness, and underwent real-time DSA-guided DEB-TACE. Based on the modified response evaluation criteria in solid tumors criteria assessed at the 1-year follow-up, patients were classified into a favorable-outcome group (complete or partial response) and a poor-outcome group (stable or progressive disease). The clinical data of the two groups were compared, and multivariate logistic regression analysis was conducted to identify independent factors affecting treatment outcomes.

RESULTS

Among 96 patients with HCC and TACE failure/refractoriness, 64 had favorable outcomes, whereas 32 had poor outcomes. Univariate analysis revealed that the two groups exhibited statistically significant differences (P < 0.05) in lesion diameter ≥ 5 cm, multiple lesions, Child-Pugh class B, and preoperative alpha-fetoprotein (AFP) level ≥ 400 ng/mL. Multivariate logistic regression analysis identified lesion diameter, multiple lesions, Child-Pugh classification, and preoperative AFP levels as independent risk factors for poor outcomes in patients with HCC and TACE failure or refractoriness (P < 0.05).

CONCLUSION

The efficacy of DSA-guided DEB-TACE in patients with TACE-refractory HCC is closely linked to lesion diameter, multiplicity, Child-Pugh class, and preoperative AFP levels.

Key Words: Digital subtraction angiography-guided procedure; Drug-eluting bead transcatheter arterial chemoembolization; Transcatheter arterial chemoembolization failure/refractoriness; Hepatocellular carcinoma; Influencing factors

Core Tip: This study compared the clinical data of patients with favorable and poor outcomes after digital subtraction angiography-guided drug-eluting bead- transcatheter arterial chemoembolization (TACE) for TACE-refractory hepatocellular carcinoma. This study aimed to analyze factors influencing therapeutic efficacy and identify predictive indicators. This novel technique has been innovatively evaluated in cases of conventional TACE failure or refractoriness. The results identified lesion diameter, lesion multiplicity, Child-Pugh class, and preoperative alpha-fetoprotein levels as significant factors affecting the efficacy of digital subtraction angiography-guided drug-eluting bead-TACE.

INTRODUCTION

Hepatocellular carcinoma (HCC) is a malignant tumor originating from the liver cells and can be classified as primary or secondary liver cancer[1]. Its development is closely associated with chronic hepatitis B virus infection, aflatoxin exposure, liver cirrhosis, long-term heavy alcohol consumption, and other risk factors[2]. Early stages of HCC often present with subtle or asymptomatic clinical manifestations, with progression potentially manifesting as right upper quadrant pain, jaundice, ascites, weight loss, and other symptoms. In the advanced stages, it is frequently accompanied by liver failure and symptoms related to metastatic lesions, exerting a dual physical and psychological impact on patients, including anxiety, depression, and social isolation[3]. Transcatheter arterial chemoembolization (TACE) is a standard treatment for HCC that inhibits tumor growth by embolizing the blood supply arteries of the tumor, combined with the localized release of chemotherapeutic agents[4]. However, not all patients benefit from TACE, with a subset developing TACE failure or refractoriness, characterized by persistent tumor progression or recurrence. These patients have poor prognosis and limited therapeutic alternatives, posing significant clinical challenges. Digital subtraction angiography (DSA)-guided drug-eluting bead (DEB) TACE represents a promising alternative; however, its efficacy is influenced by the complex interplay of technical, tumor-related, and patient-specific factors[5].

Recently, with the development of DEB technology and DSA-guided super-selective catheterization techniques, DEB-TACE has enabled the sustained release of chemotherapeutic agents and precise embolization through the use of drug-loaded microspheres. This approach increases local drug concentration while reducing systemic toxicity, demonstrating improved disease control rates in patients with TACE failure/refractoriness[6]. Therefore, this study retrospectively analyzed the clinical data of 96 patients with HCC who had TACE failure or refractoriness who underwent DSA-guided DEB-TACE. This study aimed to explore the factors influencing the efficacy of DEB-TACE in this population and to provide evidence for optimizing clinical treatment strategies.

MATERIALS AND METHODS

Study subjects

This study retrospectively enrolled 96 patients with HCC and TACE failure or refractoriness who were admitted to our hospital between January 2021 and December 2023. The inclusion criteria were as follows: (1) All patients had previously undergone standardized TACE treatment (using epirubicin-lipiodol emulsion, supplemented with gelatin sponge particles when necessary) in accordance with the criteria outlined in the Standardization for Diagnosis and Treatment of HCC (2019 Edition)[7]; (2) TACE failure/refractoriness was defined based on the expert consensus on the TACE failure/refractoriness and its subsequent therapies in treating patients with HCC[8], specifically: Progression of the target intrahepatic lesion compared with observations in pre-treatment imaging, or the development of vascular invasion/extrahepatic metastasis, as assessed by contrast-enhanced computed tomography/magnetic resonance imaging within 1-3 months after the third or more consecutive standardized TACE procedures; and (3) liver function classified as Child-Pugh A or Child-Pugh B, ensuring tolerance to DSA-guided DEB-TACE treatment. The exclusion criteria were: (1) Severe coagulation dysfunction; (2) Other concurrent primary malignancies; (3) Severe liver or kidney failure, and (4) Incomplete clinical or follow-up data precluding efficacy analysis. The study protocol was approved by the Ethics Committee of Jiangsu Cancer Hospital.

Methods

Patient clinical data, including age, sex, Child-Pugh classification, body mass index, lesion diameter, etiology, presence of cirrhosis, and serological indicators, were collected.

Imaging examination: All patients with HCC were examined using a GE 64-slice 128-detector (GE HealthCare, IL, United States) computed tomography scanner. The patients were placed in the supine position with both arms raised above the head to minimize artifacts. The scanning range extended from the diaphragmatic dome to the inferior margin of the liver. A slice thickness of 2-5 mm was used to improve the detection rate of small lesions. An iodinated contrast agent was administered using a high-pressure injector at a flow rate of 3-5 mL/second. Dual-phase enhanced scanning (arterial and portal venous phases) was performed to capture the differences in the lesion blood supply with high resolution. Post-processing was conducted using a three-dimensional reconstruction software for multiplanar reconstruction, allowing precise measurement of lesion diameter and spatial mapping of multiple lesions.

DSA-guided DEB-TACE: Patients were placed in the supine position with their arms resting naturally on their sides and legs extended to ensure full exposure and stability of the operative area. This positioning facilitated the puncture of the groin region using the Seldinger technique and allowed multi-angle imaging with DSA equipment to clearly visualize the hepatic artery branches and tumor blood supply. During the procedure, restraint straps were appropriately applied to prevent movement, and a soft pillow was placed under the hip on the punctured side to reduce pressure and avoid nerve compression.

CalliSpheres^® beads (100-300 μm) were loaded with epirubicin hydrochloride (EPI). The EPI dose ranged from 50 mg to 75 mg based on the tumor size and vascularity. The recommended dose of EPI was mixed with a contrast agent and slowly injected into a microsphere vial using the “sandwich method”. The mixture was allowed to stand for 20-30 minutes, with gentle shaking every 5 minutes to ensure adequate drug adsorption. Catheterization was performed under local anesthesia via femoral artery puncture. Under DSA guidance, the catheter was superselectively advanced into the hepatic artery and its tumor-feeding branches. Angiography was performed to evaluate tumor vascularity, size, and number. The prepared drug-loaded microsphere suspension was slowly injected through the microcatheter under real-time DSA monitoring at a rate of 1-2 mL/minute until obvious flow reduction or the “vessel cutoff sign” was observed, at which point injection was stopped to prevent reflux.

All patients underwent a single DEB-TACE intervention. If follow-up assessments indicated the need for additional treatment, subsequent DEB-TACE or other therapies were administered 4-6 weeks after the initial procedure, although their efficacy was not included in the analysis. Postoperatively, the patients were maintained in the supine position with the punctured leg kept straight and immobilized for 12 hours to prevent bleeding or hematoma formation at the puncture site.

Alpha-fetoprotein testing

Within 1 week before the procedure, 5 mL of venous blood was collected from each patient. Alpha-fetoprotein (AFP) levels were measured using a Roche Cobas e411 fully automated electrochemiluminescence immunoassay analyzer. Matching AFP diagnostic reagent kits were used according to the sandwich immunoassay principle, in which specific antibodies form complexes with AFP and are then bound to streptavidin-coated microparticles for magnetic separation. After washing away unbound substances, AFP concentrations were determined based on chemiluminescence signals. The results were automatically calculated from a standard curve using the instrument.

Child-Pugh classification

The Child-Pugh score quantifies liver function by evaluating five clinical measures[9]: Hepatic encephalopathy (none, 1 point; grade 1-2, 2 points; grade 3-4, 3 points); ascites (absent, 1 point; mild, 2 points; moderate to severe, 3 points); serum bilirubin (< 34 μmol/L, 1 point; 34-51 μmol/L, 2 points; > 51 μmol/L, 3 points); serum albumin (> 35 g/L, 1 point; 28-35 g/L, 2 points; < 28 g/L, 3 points); and prothrombin time (PT) or international normalized ratio (INR) (PT prolongation < 4 seconds or INR < 1.7, 1 point; PT prolongation 4-6 seconds or INR 1.7-2.3, 2 points; PT prolongation > 6 seconds or INR > 2.3, 3 points). The points from these five parameters were summed into a total score, which classified the liver function into three grades: Grade A (5-6 points, good liver function), grade B (7-9 points, moderately compromised liver function), and grade C (10-15 points, poor liver function). A higher grade indicated more severe liver dysfunction and was associated with a lower predicted survival rate.

One-year postoperative follow-up and efficacy evaluation

Treatment response was evaluated 1 year after surgery using the modified response evaluation criteria in solid tumors guidelines[10]. Based on this assessment, patients were categorized into two outcome groups: The favorable-outcome group, which consisted of patients with complete or partial response, and the poor-outcome group, which comprised patients with stable or progressive disease.

The modified response evaluation criteria in solid tumors criteria were defined as follows

Complete response was defined as the disappearance of all arterial enhancements within the target lesions. Partial response was defined as a minimum 30% reduction in total diameter of enhancing target lesions. Stable disease was defined as failure to meet the criteria for partial response or progressive disease. Progressive disease: A minimum 20% increase in the total diameter of enhancing target lesions and/or the emergence of new lesions (intrahepatic or extrahepatic) and/or evident progression of nontarget lesions (including portal vein tumor thrombus).

Statistical analysis

Data analysis was performed using SPSS software (version 20.0). Categorical data are expressed as n (%) and were compared using the χ² test. Measurement data are presented as mean ± SD and analyzed with the Student’s t test. Factors influencing the efficacy of DSA-guided DEB-TACE in patients with TACE-failure/refractory HCC were identified using logistic regression analysis. Statistical significance was set at P < 0.05.

RESULTS

Among the 96 patients with TACE failure or refractoriness-associated HCC, 64 exhibited favorable outcomes after DSA-guided DEB-TACE treatment and were classified into the favorable outcome group, while the remaining 32 patients were assigned to the poor outcome group.

Univariate analyses of the factors influencing DEB-TACE efficacy in patients with TACE failure or refractoriness and HCC are summarized in Table 1. The proportion of patients with a lesion diameter ≥ 5 cm was significantly higher in the poor-outcome group than in the favorable outcome group (59.38% vs 29.69%, P < 0.05). Similarly, the proportion of patients with multiple lesions was higher in the poor-outcome group than in the favorable outcome group (56.25% vs 26.56%, P < 0.05). The proportion of patients classified as Child-Pugh class B was 65.63% in the poor-outcome group and 23.44% in the favorable outcome group (P < 0.05). Preoperative AFP levels ≥ 400 ng/mL were observed in 56.25% and 28.13% of patients in the poor-outcome group and the favorable-outcome group, respectively (P < 0.05).

Table 1 Univariate analysis of factors influencing drug-eluting bead-transcatheter arterial chemoembolization efficacy in patients with transcatheter arterial chemoembolization failure/refractoriness and hepatocellular carcinoma, n (%).

Indicator	Favorable outcome group (n = 64)	Poor outcome group (n = 32)	χ2	P value
Sex			2.859	0.091
Male	52 (81.25)	21 (65.63)
Female	12 (18.75)	11 (34.38)
Age			0.208	0.649
< 60	43 (67.19)	20 (62.50)
≥ 60	21 (32.81)	12 (37.50)
BMI (kg/m2)			0.433	0.511
< 21	18 (28.13)	7 (21.88)
≥ 21	46 (71.88)	25 (78.13)
Lesion diameter (cm)			7.862	0.005
< 5	45 (70.31)	13 (40.63)
≥ 5	19 (29.69)	19 (59.38)
Etiology			2.041	0.360
Hepatitis B	46 (71.88)	27 (84.38)
Hepatitis C	13 (20.31)	3 (9.38)
Other disease	5 (7.81)	2 (6.25)
Multiple lesions			8.116	0.004
Yes	17 (26.56)	18 (56.25)
No	47 (73.44)	14 (43.75)
Hypertension			0.618	0.432
Yes	21 (32.81)	8 (25.00)
No	43 (67.19)	24 (75.00)
Portal vein invasion			0.025	0.874
Yes	19 (29.69)	9 (28.13)
No	45 (70.31)	23 (71.88)
Hepatocirrhosis			1.325	0.250
Yes	19 (29.69)	6 (18.75)
No	45 (70.31)	26 (81.25)
Child-Pugh classification			16.200	< 0.001
A	49 (76.56)	11 (34.37)
B	15 (23.44)	21 (65.63)
Preoperative AFP levels (ng/mL)			7.200	0.007
< 400	46 (71.88)	14 (43.75)
≥ 400	18 (28.13)	18 (56.25)

BMI: Body mass index; AFP: Alpha-fetoprotein.

The multivariate logistic regression analysis of the factors influencing DEB-TACE efficacy in patients with TACE failure/refractoriness and HCC is summarized in Table 2. Using treatment efficacy (favorable outcome = 0, poor outcome = 1) as the dependent variable, and lesion diameter (< 5 cm = 0, ≥ 5 cm = 1), presence of multiple lesions (no = 0, yes = 1), Child-Pugh classification (A = 0, B = 1), and preoperative AFP level (< 400 ng/mL = 0, ≥ 400 ng/mL = 1) as independent variables, a multivariate logistic regression analysis was performed. The results demonstrated that lesion diameter, multiple lesions, Child-Pugh classification, and preoperative AFP levels were significant factors influencing the treatment efficacy of DEB-TACE in patients with TACE failure/refractory HCC.

Table 2 Multivariate logistic regression analysis of factors influencing drug-eluting bead-transcatheter arterial chemoembolization efficacy in patients with transcatheter arterial chemoembolization failure/refractoriness and hepatocellular carcinoma.

Indicator	β	SE	Wald	OR	P value	95%CI
Lesion diameter	1.275	0.571	4.987	3.579	0.026	1.169-10.959
Multiple lesions	1.503	0.579	6.732	4.496	0.009	1.444-13.996
Child-Pugh classification	1.979	0.574	11.875	7.233	0.001	2.347-22.287
Preoperative AFP levels	1.581	0.578	7.473	4.859	0.006	1.564-15.096
Constant	-9.786	2.006	23.795		< 0.001

AFP: Alpha-fetoprotein; OR: Odds ratio; CI: Confidence interval.

DISCUSSION

Primary liver cancer, a highly prevalent malignant tumor of the digestive system, often presents with subtle and non-specific clinical symptoms in its early stages. Additionally, owing to the highly invasive nature of tumor cells and their rapid metastatic potential, approximately 70% of patients are already in advanced stages at the time of clinical diagnosis, losing the opportunity for curative surgical resection. With advancements in interventional techniques, TACE has become the first-line treatment for unresectable HCC. It primarily inhibits tumor progression by embolizing the arterial blood supply to the tumor and enabling the localized release of chemotherapeutic agents[11]. Although TACE can effectively reduce tumor burden and improve prognosis, clinical practice has shown that it often fails to completely eliminate residual tumor tissue around HCC lesions, resulting in a high postoperative recurrence rate[12]. DSA-guided DEB-TACE uses smaller drug-eluting microspheres to achieve deeper penetration of the tumor vasculature and sustained drug release, thereby improving local tumor control rates. However, the variability in clinical efficacy remains unclear[13]. Accordingly, this study explored the key factors influencing the efficacy of DEB-TACE, aiming to enable the early identification of high-risk patients, optimize treatment strategies, improve objective response rates, and prolong survival.

The lesion diameter and the presence of multiple lesions are key factors influencing the efficacy of DSA-guided DEB-TACE in patients with HCC and TACE failure or refractoriness. The proportion of patients with a lesion diameter ≥ 5 cm and multiple lesions was higher in the poor outcome group than in the favorable outcome group. In patients with tumor diameter ≥ 5 cm, the complex blood supply and propensity for collateral vessel formation often led to incomplete embolization, substantially increasing the risk of residual tumor tissue. Makary et al[14] demonstrated that the complete necrosis rate in large lesions was considerably lower than that in small lesions, and was accompanied by a high 1-year postoperative recurrence rate. Furthermore, large tumors are often associated with a high expression of vascular endothelial growth factor, which promotes neovascularization and reduces embolization efficacy[15]. DEB-TACE uses small microspheres that enable deep vascular penetration. However, the objective response rate remains lower in large tumors than in smaller tumors. In patients with multiple lesions, a high tumor burden and potential intrahepatic micrometastases contribute to the more aggressive biological behavior of multifocal HCC. This increased the likelihood of satellite lesions or radiologically undetectable micrometastases. Even with precise DSA-guided targeting of all visible lesions, the incidence of new lesions remains high[16]. Additionally, multifocal disease often requires staged embolization, during which tumor progression may occur, leading to insufficient cumulative necrosis rates. Therefore, both lesion diameter and the presence of multiple lesions are clear factors influencing the efficacy of DSA-guided DEB-TACE in patients with TACE failure/refractoriness in HCC.

Multivariate logistic regression analysis also identified Child-Pugh classification and preoperative AFP levels as clear factors influencing the efficacy of DSA-guided DEB-TACE in patients with TACE failure/refractory HCC. The Child-Pugh classification directly reflects hepatic functional reserve. Patients classified as Child-Pugh B exhibit reduced metabolic and regenerative capacities, resulting in a twofold higher risk of postoperative liver function deterioration than grade A patients[17]. Impaired drug clearance in patients with Child-Pugh class B may lead to systemic toxicity. Additionally, patients with poorer liver function are more susceptible to aggravated post-embolization syndrome, which may limit opportunities for subsequent treatment.

AFP levels directly reflect the biological behavior and aggressiveness of tumors. Cheng et al[18] demonstrated that patients with AFP > 400 ng/mL exhibit more active tumor angiogenesis and elevated vascular endothelial growth factor expression, promoting the formation of collateral circulation and leading to incomplete embolization. This increased the risk of residual tumors after DEB-TACE by 3.2 times. Furthermore, high AFP expression is associated with cancer stem cell properties. It enhances tumor cell resistance to ischemia and chemotherapeutic drugs by inhibiting tumor suppressor genes such as phosphatase and tensin homolog and p53, thereby reducing the cytotoxic efficacy of chemotherapeutic agents released from drug-eluting microspheres[19]. Elevated AFP levels indicated an increased risk of microvascular invasion. Although imaging suggests complete necrosis, pathological examination may reveal residual cancer cells contributing to early recurrence after DSA-guided DEB-TACE[20]. This study has some limitations. First, the retrospective design may have introduced selection bias and limited causal inferences. Second, the sample size was relatively small (n = 96), particularly within the poor outcome subgroup (n = 32), which may have affected the statistical power and generalizability of the findings. Third, the follow-up period was limited to one year, which may not capture long-term efficacy and survival outcomes. Fourth, although several clinical and tumor-related predictors were identified, the study did not incorporate molecular or genomic data, which may play a crucial role in tumor behavior and treatment response. Therefore, future research should aim to conduct prospective, multicenter studies with larger sample sizes to validate our findings and enhance their robustness. Extending the follow-up duration will allow the assessment of long-term survival and late recurrence patterns. Moreover, integrating radiomic features, serum biomarkers, and genomic profiling (such as next-generation sequencing) into predictive models can significantly improve the stratification of patients and personalization of treatment strategies. Such integrative approaches may help identify which patients with TACE-refractory HCC are most likely to benefit from DSA-guided DEB-TACE, ultimately guiding more precise clinical decision-making.

CONCLUSION

The efficacy of DSA-guided DEB-TACE in patients with TACE failure or refractoriness is closely associated with lesion diameter, presence of multiple lesions, Child-Pugh classification, and preoperative AFP levels. In this study, treatment outcomes were influenced by a relatively small sample size and an insufficient comprehensive assessment of how molecular tumor characteristics. Future studies should aim to expand the sample size and conduct multicenter prospective cohort studies. Integrating genomic data with clinical indicators is essential for developing more accurate predictive models. These models are required to guide treatment strategies and improve patient outcomes.

ACKNOWLEDGEMENTS

We thank all medical staff who agreed to participate in this study.