Factor Analysis of the Effect of Hepatitis B-Related Liver Cancer Treatment Efficacy

Introduction

Primary liver cancer, commonly referred to as hepatocellular carcinoma (HCC), ranks among the most prevalent and lethal malignancies worldwide. According to the Global Cancer Report of 2022, while the incidence of liver cancer is lower than that of breast, lung, stomach, and colorectal cancers, it has the second highest mortality rate globally.¹ In China, about 400,000 new cases are reported annually, accounting for nearly 50% of new cases worldwide, with a five-year survival rate of only 12.1–14.1%, significantly lower than that of other cancer types.² Hepatitis B virus (HBV) infection is the leading cause of primary liver cancer, particularly in Asian countries, where HBV-related cases comprise up to 60%.³ Despite advancements in early screening and therapeutic technologies that have improved the management of liver cancer, the disease often progresses insidiously with subtle early symptoms. Consequently, the majority of patients are diagnosed at intermediate or advanced stages, by which time the optimal window for surgical intervention is frequently missed. Surgical resection remains the first-line treatment for liver cancer; however, about 70% of patients are not candidates for curative surgery at the time of diagnosis.⁴ For patients with unresectable liver cancer, selecting effective local treatment strategies to enhance survival outcomes poses a considerable challenge. Transcatheter arterial chemoembolization (TACE), a commonly employed local treatment modality, is extensively used in such cases. TACE combines localized chemotherapy with vascular embolization by injecting microspheres containing chemotherapeutic agents and embolic substances into the tumor-feeding artery, thereby achieving a dual therapeutic effect and demonstrating promising efficacy.⁵

In recent years, drug-eluting bead transcatheter arterial chemoembolization (DEB-TACE), an advanced version of TACE, has become an important treatment modality for unresectable liver cancer patients owing to its relatively high drug adsorption capacity and slow, sustained drug release characteristics. DEB-TACE enables more precise delivery of chemotherapeutic agents while minimizing injury to healthy liver tissue, thereby enhancing both the safety and therapeutic efficacy of the intervention.⁶ Despite its proven clinical effectiveness, the determinants of DEB-TACE’s short-term efficacy remain insufficiently understood, particularly in patients with hepatitis B-related hepatocellular carcinoma. To address this gap, the present study retrospectively analyzed clinical data from 128 patients diagnosed with hepatitis B-associated primary liver cancer who underwent DEB-TACE. The objective was to identify the key factors influencing short-term treatment outcomes, thereby offering a theoretical foundation for clinical decision-making and supporting the development of individualized therapeutic strategies.

Materials and Methods

Study Design and Subjects

In this retrospective analysis, 128 patients with hepatitis B-related primary liver cancer who underwent DEB-TACE treatment at the General Hospital of Ningxia Medical University between September 2019 and March 2023 were included. All patients met the following inclusion criteria:⁷ (1) diagnosis of primary liver cancer confirmed by imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI); (2) history of HBV infection or positive HBV DNA test; (3) age above 18 years; (4) first-time diagnosis of primary liver cancer with TACE administered via catheter; (5) presence of measurable lesions; (6) CNLC stage IIb, IIIa, or IIIb, Child-Pugh class A or B, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; (7) eligibility for surgical or ablative treatments that were not undertaken due to advanced age, severe cirrhosis, or similar factors in CNLC stage I or IIa cases; (8) incomplete obstruction of the main portal vein or, if completely obstructed, presence of compensatory intrahepatic collateral circulation; (9) informed consent obtained from patients and their families; and (10) normal mental status with the ability to cooperate with treatment and follow-up procedures. Exclusion criteria were: (1) age over 80 years; (2) extensive liver cancer metastasis rendering TACE unfeasible; (3) severe coagulation disorders; (4) serious infections; (5) coexistence of other malignancies or multi-organ dysfunction; and (6) history of prior antitumor therapy. This retrospective cohort comprised 107 male and 21 female patients, with a mean age of 56.06 ±10.33 years. The study was approved by the Medical Ethics Committee of General Hospital of Ningxia Medical University (approval number: KYLL-2025-0039).

Observation Indicators

Comprehensive data were collected for all patients, encompassing tumor characteristics (including tumor diameter, number, distribution, alpha-fetoprotein levels, CNLC stage, BCLC stage, presence of lymph node metastasis, major vascular invasion, and liver cancer metastasis), comorbid conditions (such as cirrhosis, hypertension, diabetes, and coronary heart disease), postoperative embolism syndrome manifestations (including fever, nausea, vomiting, abdominal pain, and anorexia), as well as preoperative biochemical parameters (transaminases, bilirubin, albumin, creatinine, blood urea nitrogen, and cholinesterase). Additionally, routine blood tests, coagulation profiles, inflammatory markers, and HBV DNA levels were documented.

Surgical Procedure

All surgeries were performed in the digital subtraction angiography room. Preoperative liver cancer patients were evaluated for tumor status through upper abdominal CT or MRI based on the Guidelines for the diagnosis and treatment of primary liver cancer.⁸ Following anesthesia, standard disinfection procedures were conducted, and the femoral artery was punctured using the Seldinger technique, after which a 5F sheath was introduced. Under X-ray fluoroscopic guidance, a catheter was super-selectively advanced to the celiac trunk artery for angiography to identify the tumor’s arterial blood supply and any accessory hepatic arteries. Subsequently, a microcatheter was used to embolize the tumor’s feeding arteries.⁹ In the DEB-TACE group, DC^® drug-eluting microspheres (BioCompatibles, UK) with diameters of 100–300 μm or 300–500 μm served as both drug carriers and embolic agents. These microspheres were loaded with idarubicin hydrochloride (10 mg, Nanjing Pharmaceutical Co., Ltd., batch number: 2404071) and mixed with a high-concentration contrast agent at ratios of 1:1, 1:1.1, or 1:1.2. The resulting mixture of embolic agent and chemotherapeutic drug was then pulse-injected into the tumor’s feeding vessels via the microcatheter. The embolization endpoint was the complete disappearance of tumor staining on angiography. After surgery, the microcatheter was removed, the wound was compressed, hemostasis was achieved, and the wound was bandaged.

Follow-up, Observation, and Evaluation Indicators

Follow-up was conducted over the telephone or by reviewing the outpatient reexamination medical records of the patients to understand the recurrence and survival status of the patients. One month postoperatively, patients were followed up at intervals of 2–3 months, with patient death defined as the endpoint of follow-up; all surviving patients were followed until March 2023.

The patients underwent enhanced CT or MRI of the abdomen every 1–3 months after the surgery to assess treatment efficacy. The efficacy was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST): (1) Progression-free survival (PFS): the time from randomization (or start of treatment in single-arm trials) to tumor progression or death due to any other cause (whichever occurs first). (2) Overall survival (OS): the time from randomization (or start of treatment in single-arm trials) to death due to any cause.¹⁰

Statistical Analysis

All statistical analyses were performed using SPSS version 25.0. Continuous variables were expressed as mean ±standard deviation (), and comparisons between groups were conducted using either the independent samples t-test or the Mann–Whitney U-test, depending on data distribution. Categorical variables were compared using the Chi-square test. Survival curves were constructed using the Kaplan-Meier method, and the Log rank test was employed to assess the influence of various clinical characteristics on the OS and PFS. The proportional hazards assumption for the Cox regression model was evaluated using the Schoenfeld residual test (global test p-value = 0.25), and Kaplan-Meier curves were observed to not intersect, supporting model validity. Linearity between continuous variables and the log hazard was confirmed through Martingale residual plots. Accordingly, Cox proportional hazards regression analysis was applied. Statistical significance was defined as a two-sided P-value of less than 0.05.

Results

Multiple Tumors and Vascular Invasion Reduce Patient Prognosis

In this study, 128 patients diagnosed with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) were included, comprising 107 males (83.5%) and 21 females (16.5%), with a mean age of 56.06 ±10.33 years. Tumor characteristics revealed that 57 patients (44.5%) had tumors measuring ≤5 cm, while 71 patients (55.5%) had tumors >5 cm in diameter; 54 patients (42.2%) presented with a single tumor, and 74 patients (57.8%) had multiple tumors. All patients received DEB-TACE treatment and were followed up for a period ranging from 4 to 39 months. Analysis of the impact of tumor characteristics on survival prognosis demonstrated statistically significant differences (P < 0.05) in OS and PFS based on several factors: tumor size >5 cm, the presence of multiple tumors (>2), the coexistence of multiple tumors with the largest exceeding 5 cm, portal vein invasion, CNLC stage, BCLC stage, alpha-fetoprotein (AFP) levels, lymph node metastasis, and extrahepatic metastasis (Table 1). Patients classified as CNLC stage III and BCLC stage C exhibited significantly shorter OS compared to those at earlier stages (P < 0.05), underscoring the advanced stage as a critical indicator of poor prognosis. Additionally, elevated AFP levels (>400 ng/mL) were linked to increased tumor aggressiveness, potentially reflecting a more active biological behavior of the malignancy. The median PFS of patients with lymph node and extrahepatic metastases was reduced by about 50%, highlighting distant metastasis as a pivotal risk factor for treatment failure.

Table 1 The Effect of Patient Tumor Characteristics on the Prognosis and Survival of Patients

Complications, Postembolization Syndrome, Preoperative Biochemistry, and Routine Blood Tests Influence the Prognosis and Survival of Patients

Regarding liver function and accompanying diseases, the Child-Pugh classification, combined with cirrhosis, diabetes, coronary heart disease, hypertension, and post-TACE syndromes, such as nausea, vomiting, fever, poor appetite, and abdominal pain, did not significantly affect the PFS or OS of patients (P > 0.05) (Table 2).

Table 2 Effect of Liver Function and Complications on the Prognosis and Survival of Patients

The results of preoperative blood biochemistry analysis revealed that patients with abnormal aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), white blood cell (WBC), neutrophil absolute value (NEUT#), and procalcitonin (PCT) levels had significantly shorter OS than patients with normal levels of the above indicators (P < 0.05). Patients with abnormal levels of cholinesterase (ChE) and C-reactive protein (CRP) had significantly shorter OS and PFS than patients with normal levels of the above indicators (P < 0.05). These results suggested that AST, ChE, TBIL, ALB, WBC, NEUT#, PCT, ChE, and CRP may be important factors influencing OS. Further binary logistic regression analysis indicated that patients with higher platelet counts (PLTs) had longer OS (P < 0.05) (Tables 3 and 4).

Table 3 Effect of Preoperative Biochemical and Routine Blood Tests on Patient Prognosis and Survival

Table 4 Binary Logistic Regression Analysis of the Effect on Survival Outcomes

Cox Regression Analysis

Based on the results of multivariate Cox regression analysis, we further identified the independent prognostic factors affecting the OS and PFS of patients. The results indicated that patient age, Child-Pugh score, BCLC stage, TBIL, indirect bilirubin, ChE, PT, PLT, CRP, PCT, AFP, and postoperative fever were significant predictors of OS, with abnormalities in these parameters being strongly associated with a reduced OS duration (P < 0.05). In contrast, other variables, including sex, the presence of comorbid conditions, and HBV DNA status, did not demonstrate a statistically significant impact on patient prognosis in this study (Table 5).

Table 5 Cox Regression Analysis of Factors Affecting Overall Survival Time

Survival Curve Analysis

Further analysis using Kaplan-Meier survival curves demonstrated that AFP, ALB, AST, ChE, presence of extrahepatic metastasis, hepatic vein invasion, leukocyte count, lymph node metastasis, PCT, TBIL, tumor size, solitary tumor status, and portal vein invasion were all significantly associated with OS (P < 0.05). Specifically, patients who were AFP-negative, exhibited normal levels of AST, WBC, ALB, TBIL, and PCT, had a solitary tumor, and lacked extrahepatic metastasis, hepatic vein invasion, and portal vein invasion, demonstrated significantly prolonged OS compared to those with abnormalities in these parameters (Figure 1).

Figure 1 K-M curves influencing the survival time of patients after D-TACE ((A) Multilobular tumor; (B) Tumor size; (C) AFP; (D) AST; (E) Portal vein invasion; (F) Lymph node metastasis; (G) Extrahepatic metastasis; (H) Total bilirubin; (I) Procalcitonin; (J) Albumin; (K) Cholinesterase; (L) Leukocyte).

Complications and Safety Analysis

No patients experienced serious complications following surgery, and the treatment was generally well-tolerated. A small number of patients developed mild liver function impairment, fever, nausea, or localized pain postoperatively; however, these symptoms were effectively managed and resolved within a short duration. The findings indicate that D-TACE demonstrates a high safety profile in patients with unresectable HBV-related liver cancer.

Discussion

Transcatheter arterial chemoembolization (TACE) is the preferred nonsurgical palliative treatment method for primary liver cancer in clinical practice. The mechanism of action involves obstructing the tumor’s blood supply while delivering chemotherapeutic agents to kill or inhibit tumor cells; however, this approach does not directly or completely eradicate tumor cells.¹¹ Drug-eluting microspheres represent a novel class of embolic materials, offering advantages such as non-degradability, the ability to maintain high local drug concentrations within the tumor, and reduced systemic drug exposure. Several studies have demonstrated that, in patients with unresectable HCC, drug-eluting microspheres provide superior short-term efficacy and safety compared to conventional TACE.¹² Nevertheless, this method incurs higher costs than traditional TACE. Therefore, it is essential for clinicians to adopt a rational surgical strategy based on a comprehensive assessment of the patient’s overall condition, tumor characteristics, and financial considerations.

In this study, we investigated the factors influencing PFS and OS in patients with primary liver cancer undergoing DEB-TACE treatment for the first time, including various factors, such as the general conditions of patients, underlying comorbidities, tumor characteristics, and preoperative clinical indicators. The results indicated that sex and the presence of underlying comorbidities did not have a significant impact on the PFS or OS of patients undergoing DEB-TACE. In contrast, tumor characteristics such as CNLC stage, tumor diameter, number of lesions, presence of vascular invasion, lymph node metastasis, and extrahepatic metastasis were found to significantly influence OS, consistent with findings from previous studies.^11,13 Among clinical indicators, factors including AFP, AST, ChE, TBIL, ALB, WBC, NEUT, PCT, and CRP emerged as potential determinants of OS. Multifactor Cox regression analysis further identified age, Child-Pugh score, BCLC stage, TBIL, IBIL, ChE, prothrombin time (PT), platelet count (PLT), CRP, PCT, AFP, and postoperative fever as independent risk factors for OS.¹¹ While tumor volume and stage are well-established prognostic factors in liver cancer, the role of inflammation in tumor progression has been relatively underexplored. The tumor microenvironment is rich in inflammatory factors and immune cells that contribute to the initiation and progression of malignant tumors. In recent years, there has been a growing body of research and literature supporting the prognostic significance of inflammatory markers in liver cancer and other malignancies.¹⁴ The binary logistic regression analysis, multifactor Cox regression analysis, and Kaplan-Meier method employed in this study indicated that common inflammatory factors, such as WBCs, neutrophils, PCT, and CRP, are closely related to the PFS and OS of primary liver cancer patients undergoing DEB-TACE and can serve as preoperative predictive indicators along with tumor characteristics, the Child-Pugh score, tumor stage, etc.

Previous studies have primarily focused on evaluating the efficacy and safety of various treatment modalities for patients with primary liver cancer. With ongoing advancements in medical technology, the emphasis has increasingly shifted toward precision and personalized oncologic therapies, necessitating more thorough preoperative assessments tailored to individual patients. Global clinical research has demonstrated that the postoperative survival of patients with primary liver cancer is influenced by a combination of clinicopathological factors, sociodemographic characteristics, medical history, and imaging findings.^{2,5,7,10,15–17} In recent years, considerable progress has been made in constructing predictive models using machine learning, which have been extensively applied in areas such as disease diagnosis, onset prediction, treatment efficacy evaluation, survival analysis, and recurrence prediction.^11–13,18 Despite these advancements, the prognostic evaluation framework for primary liver cancer remains underdeveloped, primarily due to the disease’s complexity, poor curability, frequent postoperative complications, generally unfavorable prognoses, and high recurrence and metastasis rates. In particular, research focusing on predictive models for TACE is limited. Current models rely on only a few prognostic indicators, such as tumor size, tumor count, degree of differentiation, lymph node involvement, AJCC stage, and alpha-fetoprotein levels.

Limitations

This was a single-center retrospective study with a relatively small sample size and did not consider machine learning algorithms to construct the final predictive model.

All patients in this study had primary liver cancer based on hepatitis B, and a certain selection bias might have occurred in the population.

Due to the fact that liver reserve function tests have only recently been initiated locally, the results of this study lack indicators pertaining to liver reserve function.

The prognostic model developed in this study was constructed using clinical index variables and did not include molecular typing parameters, such as gene mutations or characteristics of the immune microenvironment.¹⁹ Although the model demonstrated a certain degree of predictive efficacy, incorporating established molecular features—such as TP53 mutations and PD-L1 expression—may enhance the precision of prognostic stratification.^11–13,18 Future research may improve model accuracy and clinical utility by integrating multi-omics data, thereby enabling a more comprehensive and individualized prediction framework.

Conclusion

This study included commonly used clinical indicators closely associated with the occurrence and progression of primary liver cancer, such as routine blood tests, biochemical parameters, and coagulation profiles, which are standard inflammatory markers, along with tumor-related indicators, including tumor diameter, number, stage classification, and the presence of distant and lymph node metastases. The study confirmed the clinical utility of these variables in predicting PFS and OS in patients undergoing DEB-TACE.