Overview
Advanced hepatocellular carcinoma (HCC) remains a major therapeutic challenge. Although targeted therapy combined with immune checkpoint inhibitors has improved clinical outcomes, the objective response rate and conversion surgery rate remain suboptimal. Irreversible electroporation (IRE) is a non-thermal ablation technique that can induce tumor cell death while preserving surrounding vascular and biliary structures. Emerging evidence suggests that IRE may enhance anti-tumor immunity and synergize with systemic therapy.
This prospective, single-center, open-label study aims to evaluate the efficacy and safety of IRE combined with lenvatinib and sintilimab in patients with advanced HCC. Eligible patients with unresectable CNLC stage IIa, IIb, or IIIa disease will receive standard targeted therapy and immunotherapy with or without IRE according to treatment allocation. The primary endpoints are objective response rate (ORR) and conversion surgery rate. Secondary endpoints include time to response (TTR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs).
The study is expected to provide evidence regarding the role of IRE in enhancing tumor response and increasing the likelihood of curative-intent surgical resection in patients with advanced HCC.
Description
- Background
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. For patients with advanced-stage disease, systemic therapy based on tyrosine kinase inhibitors and immune checkpoint inhibitors has become the standard of care. However, only a proportion of patients achieve meaningful tumor regression, and the rate of successful conversion to surgical resection remains limited.
Irreversible electroporation (IRE) is a novel non-thermal local ablative technique that induces apoptosis through permanent disruption of cellular membranes. Unlike thermal ablation modalities, IRE preserves major blood vessels and bile ducts, making it particularly suitable for tumors adjacent to critical structures. Furthermore, preclinical and clinical studies have suggested that IRE may induce immunogenic cell death and augment anti-tumor immune responses. 2. Study Objectives
The primary objective of this study is to evaluate whether the addition of IRE to targeted therapy and immunotherapy improves tumor response and conversion surgery rate in patients with advanced HCC.
The secondary objective is to assess survival outcomes and treatment-related safety. 3. Study Design
This is a prospective, single-center, open-label interventional study. Patients with advanced HCC meeting the eligibility criteria will receive either:
IRE combined with lenvatinib and sintilimab; or Lenvatinib and sintilimab alone.
Tumor response will be evaluated according to RECIST version 1.1 and mRECIST criteria. Patients will undergo regular imaging assessments and multidisciplinary evaluation to determine eligibility for curative-intent surgical resection.
Eligibility
Inclusion Criteria:
- Age 18 to 75 years.
- Clinically or pathologically confirmed hepatocellular carcinoma (HCC).
- Unresectable HCC corresponding to CNLC stage IIa, IIb, or IIIa, without extrahepatic metastasis.
- At least one measurable lesion according to RECIST version 1.1.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
- Child-Pugh class A or B liver function.
- Adequate organ function, including an absolute neutrophil count ≥1.5 × 10⁹/L; platelet count ≥75 × 10⁹/L; hemoglobin ≥80 g/L; serum creatinine ≤1.5 × the upper limit of normal (ULN) or creatinine clearance ≥50 mL/min; total bilirubin ≤3 × ULN; and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × ULN.
- Suitable for treatment with lenvatinib and sintilimab according to institutional standards.
- Able to understand and sign written informed consent.
Exclusion Criteria:
- Presence of extrahepatic metastasis.
- Previous treatment with irreversible electroporation.
- Prior systemic therapy that precludes treatment with lenvatinib or sintilimab.
- Diffuse infiltrative HCC not suitable for IRE evaluation.
- Uncontrolled ascites, hepatic encephalopathy, or active gastrointestinal bleeding.
- Active severe infection requiring systemic treatment.
- Active tuberculosis.
- Uncontrolled hepatitis B virus replication despite antiviral therapy.
- Clinically significant cardiovascular disease, including uncontrolled hypertension, recent myocardial infarction, unstable angina, or severe arrhythmia.
- Concurrent malignancy requiring active treatment.
- Pregnancy or breastfeeding.
- Any condition that, in the investigator's judgment, would interfere with study participation or interpretation of the study results.
