A Study Evaluating the Safety and Efficacy of Selective Internal Radiation Therapy (SIRT) Using SIR-Spheres® Y-90 Resin Microspheres to Bridge or Downstage Patients With Hepatocellular Carcinoma (HCC) to Liver Transplant or Resection and Elicit Pathologic Necrosis.

Subjects must meet all of the following criteria to be eligible for study participation (Inclusion Criteria):

1. Willing, able, and mentally competent to provide written informed consent
2. Age 18 years or older at the time of informed consent
3. All tumors must be measurable by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) according to localized mRECIST
4. Diagnosis of HCC with Liver Imaging Reporting and Data System (LIRADS) 5 or by histology that is amenable to treatment with Y-90 radioembolization by radiation segmentectomy
5. Patients must be treatment-naïve or have developed a new lesion following one of the prior locoregional treatments listed below, including TACE failure, as defined by the investigator:
6. Liver resection with negative pathologic margins, no vascular invasion, and no recurrence at resection margins for at least 6 months post-treatment and no new lesions within 6 months of liver resection
7. Ablation of a single ≤3 cm lesion with no recurrence of the treated lesion for at least 6 months post-treatment
8. Trans-arterial chemoembolization (TACE) failure or refractoriness (e.g., inadequate response or progression following TACE), per investigator assessment
9. Inclusion into the Bridging or Downstaging Cohort:

• Bridging Cohort:
• Unresectable HCC within Milan criteria for liver transplant at baseline (Mazzafero et al, 1996) [17]
• Solitary tumor ≤5 cm or up to 3 lesions each ≤3 cm
• No EHD
• No vascular involvement
• Downstaging Cohort:
• Unresectable HCC within UNOS downstaging criteria for liver transplant at baseline (Natarajan et al, 2023) [21]
• Solitary HCC 5-8 cm, or 2-3 tumors each ≤5 cm w/sum ≤8 cm or 4- 5 tumors each ≤3 cm w/sum ≤8 cm
• No Extrahepatic Disease (EHD)
• No vascular involvement

1. Child-Pugh score of A5, A6, or B7 at baseline
2. Eastern Cooperative Oncology Group (ECOG) performance score of ≤1 at baseline
3. Adequate blood count, liver enzymes, and renal function at baseline:
4. No absolute contraindications to arterial access
5. Albumin-bilirubin grade 1 or 2
6. International Normalized Ratio (INR) ≤2.0
7. Glomerular filtration Rate (GFR) >45
8. Negative serum pregnancy test at baseline

Subjects must not meet any of the following exclusion criteria:

1. Eligible for curative treatment by resection or not considered optimal candidates for curative ablation, in the opinion of the investigator, based on tumor location, multifocality, underlying liver disease, anticipated risk of recurrence, or institutional practice patterns.
2. Prior systemic anti-cancer therapy (including immunotherapy and/or targeted therapy), radiotherapy or use of other investigational agents for the treatment of HCC
3. Intrahepatic arteriovenous shunting (arteriovenous shunting resulting from a biopsy is allowed but must be embolized during the pre-treatment mapping procedure)
4. History of biliary-enteric anastomosis (e.g., hepaticojejunostomy) or active biliary infection (e.g., ongoing cholangitis) at the time of screening. Subjects with prior biliary intervention (e.g., Endoscopic Retrograde Cholangiopancreatography (ERCP), sphincterotomy, biliary stent placement) or suspected compromise of the Ampulla of Vater may be enrolled at the Investigator's discretion provided there is no evidence of active biliary infection and prophylactic antibiotic coverage is administered per institutional standard of care before and after Y-90 radioembolization.
5. Planned localized cancer treatment to the liver, other than the study treatment, throughout the duration of the study
6. Planned systemic cancer treatment throughout the duration of the study
7. Portal vein tumor thrombosis (macrovascular invasion). Bland (non-tumoral) portal vein thrombosis is allowed if portal venous flow is preserved and there is no evidence of clinically significant portal hypertension complications that would increase risk of hepatic decompensation.
8. Patients with EHD
9. Patients with contraindications to angiography or selective visceral catheterization
10. Evidence of extrahepatic collateral supply to the tumor
11. Evidence of potential delivery of mean radiation dose >30 Gy to the lungs (single treatment)
12. Evidence of any detectable 99mTc-MAA scintigraphy or cone-beam computed tomographic (CB-CT) evidence of any deposition outside of the liver in the gastrointestinal tract after application of established angiographic techniques to stop or mitigate such flow (e.g., placing catheter distal to gastric vessels or coiling)
13. 99mTc-MAA hepatic arterial perfusion scintigraphy showing poor tumor and/or portal vein thrombosis targeting that would lead to a dose that does not meet the liver dosing criteria.
14. Prior liver resection is permitted, provided the patient meets all other criteria and has recurrent HCC eligible for transplant consideration. Prior liver transplant remains exclusionary.
15. Female patients who are pregnant, breastfeeding, or pre-menopausal and unwilling to use an effective method of contraception through the 1-year followup; males unwilling to use an effective method of contraception for 30 days post-procedure
16. Evidence of portal hypertension with uncontrolled or refractory ascites despite optimal medical management or any active or uncontrolled variceal bleeding at the time of screening
17. Concurrently enrolled in another study unless it is an observational, noninterventional study
18. History of other cancer requiring active treatment within the past 3 years, with the exception of adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, in the opinion of the investigator.
19. Patients with drug or alcohol dependency (within 6 months prior to study entry) in the opinion of the investigator
20. Inability to safely receive contrast, narcotics, or sedatives required to complete treatment
21. Any condition that, in the opinion of the investigator, would interfere with safe delivery of the study treatment or the interpretation of study results
22. Alpha-fetoprotein (AFP) >10000 ng/mL at baseline