This study is conducted to evaluate the efficacy and safety of lenvatinib plus iodine-125 seed brachytherapy (Len-I) compared with lenvatinib (Len) alone for patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE).

This is a single-center, prospective and randomized controlled trial to evaluate the efficacy and safety of Len-I versus Len alone for patients with TACE-refractory HCC.

187 patients with TACE-refractory HCC will be enrolled in this study. The patients will receive either Len-I or Len alone using an 2:1 randomization scheme.

Lenvatinib (body weight ≥ 60 kg, 12mg P.O. QD; body weight < 60 kg, 8mg P.O. QD) will be administered to the patients and last until disease progresses, intolerable toxicity, withdrawal of informed consent, loss of follow-up, death, or other circumstances that require termination of treatment, whichever occurs first. For patients in the Len-I arm, iodion-125 seeds will be implanted into the the target lesions (viable intrahepatic tumor and/or vascular tumor thrombus) under CT guidance according to the pre-operative planning within 7 days after lenvatinib administration. Iodion-125 seeds implantation can be repeated on demand during follow-up based on the evaluation of laboratory and imaging examination.

The primary end point of this study is overall survival (OS). The secondary endpoints are progression-free survival (PFS), time to progression (TTP), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs).

Inclusion Criteria:

• HCC confirmed by histopathology and/or cytology, or diagnosed clinically
• Diagnosis of HCC with TACE refractoriness according to the criteria proposed by Japan Society of Hepatology (2021)
• Patients who have Tumor recurrence after surgical resection or ablation are allowed to be included
• At least one measurable intrahepatic target lesion
• Child-Pugh class A/B
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 3 months

Exclusion Criteria:

• Extrahepatic metastasis
• Tumor thrombus involving main portal vein or both the first left and right branch of portal vein
• Vena cava invasion
• Patients who received prior systemic therapy, immunotherapy, hepatic arterial infusion chemotherapy (HAIC) or radiotherapy for HCC
• History of organ and cell transplantation
• History of bleeding from esophagogastric varices
• History of hepatic encephalopathy
• Hematologic examination: platelets <50×10^9/L
• Prothrombin time prolongation ≥ 4s
• Severe organ (heart, lung, kidney) dysfunction
• History of malignancy other than HCC