Building Evidence for Ablative Internal Radiation Therapy in Localized HCC Beyond the Up-To-7 Criteria

At four major centers in Korea, patients with hepatocellular carcinoma (HCC) that exceed the up-to-7 criteria yet remain locally confined will undergo ablative radioembolization using Yttrium-90 glass microspheres, guided by a standardized dosimetry method. Their treatment response, survival outcomes, and adverse events will be monitored for two years following the procedure.

This prospective, multi-center, open-label, single-arm, phase II clinical trial aims to evaluate the efficacy and safety of ablative radioembolization in patients with hepatocellular carcinoma (HCC) that exceeds the up-to-seven (UT7) criteria but is confined to up to five geographically adjacent Couinaud segments. The primary endpoint is the objective response rate, assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST).

All patients will receive ablative radioembolization using Yttrium-90 glass microspheres with a personalized dosimetry approach targeting a tumor dose of 700 Gy (±50%). In cases of high tumor burden, a second radioembolization within 180 days of the initial procedure will be permitted at the operators' discretion, provided the cumulative lung dose remains below 50 Gy. Follow-up evaluations, including laboratory tests and dynamic imaging, will be performed at 4 weeks post-treatment and every 3 months thereafter for a total of 2 years. Efficacy data-including tumor response and survival-will be collected, with tumor responses evaluated by both site investigators and a blinded independent central review. Adverse events will be documented and graded according to the Common Terminology Criteria for Adverse Events v5.0. In addition, the incidence of radioembolization-induced liver disease and radiation pneumonitis will be monitored for 6 months following the procedure.

Eligibility Criteria:
Inclusion criteria

* Adult aged 19 and over
* HCC diagnosed by histology or non-invasive criteria of the American Association for the Study of Liver Disease
* Unresectable HCC beyond the UT7 criteria: the sum of the diameter of the largest tumor (cm) and the number of tumors \> 7
* Localized HCC: all tumors are in the one to five geographically adjacent Couinaud segments
* No current or previous HCC in the untreated liver (i.e., future liver remnant \[FLR\])
* FLR volume \> 30% of total non-tumorous liver volume
* Child-Pugh class A
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
* No major organ dysfunction according to blood test performed within two months of study enrollment:

  * Leukocytes ≥ 2,000/µL and ≤ 15,000/µL
  * Hemoglobin ≥ 8.0 g/dL (transfusion allowed to meet this criterion)
  * Total bilirubin ≤ 2.0 mg/dL
  * Platelet ≥ 40,000/µL
  * International normalized ratio (INR) ≤ 2.0 for patients not taking anticoagulants
  * Aspartate transaminase (AST) ≤ 200 IU/L (i.e., ≤ 5X upper normal limit)
  * Alanine transaminase (ALT) ≤ 200 IU/L (i.e., ≤ 5X upper normal limit)
  * Creatinine ≤ 2.5 mg/dL
* Patients with a life expectancy of more than 3 months
* For women of childbearing age, a negative serum pregnancy test
* Patients who have adequately understood the clinical trial and consented in writing

Exclusion Criteria:

* HCC with vascular invasion and/or bile duct invasion on dynamic computed tomography (CT) or magnetic resonance imaging (MRI)
* HCC with extrahepatic spread on chest CT and abdominal CT or MRI
* Multinodular disseminated HCC: largest tumor size \< 6 cm, or number of tumors \> 10
* Patients who are not suitable for ablative radioembolization as indicated by pre-treatment mapping with 99mTc-macroaggregated albumin (MAA):

  * Cases where the estimated lung dose exceeds 30 Gy when 350 Gy of tumor absorbed dose is administered to the tumor based on the multicompartment Medical Internal Radiation Dose (MIRD) model
  * Cases with severe hepatic artery-portal vein shunting that might lead to irradiation of the non-tumorous liver segments
  * Cases where the operator determines that there is substantial adhesion with the surrounding organs such as the bowel, making ablative radioembolization infeasible
* Cases where the operator judges that the occurrence of even mild radiation pneumonitis could be fatal, based on marked emphysema or interstitial lung disease findings on chest CT
* Patients who have had active cancer within the last two years prior to the study enrollment
* History of severe allergy of intolerance to contrast agents
* Contraindication to angiography or selective visceral catheterization