This is a prospective, single-blinded, single-arm, open-label Phase II trial of trans-arterial radiation segmentectomy using Yttrium-90 glass microspheres (TheraSphere®) for Hepatocellular Carcinoma (HCC) participants with unresectable Barcelona clinic liver cancer (BCLC) stage A disease.

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (ORR) after radiation segmentectomy in participants with BCLC Stage A HCC and 1) a single solitary tumor measuring 2-5 centimeters (cm) and 2) 2 or 3 lesions each ≤ 3 cm.

II. To assess the safety of radiation segmentectomy.

SECONDARY OBJECTIVES:

I. To evaluate transplant-free survival.

II. To evaluate progression-free survival.

III. To evaluate the quality of life of participants.

IV. To evaluate the best imaging response. V. To determine the proportion of participants who remain active on the wait list for liver transplant and eventually are transplanted.

VI. The evaluate the number of participants that need additional treatment after TheraSphere® administration.

VII. Complete pathologic response (CPN) on liver explants among participants who underwent liver transplant.

Participants will undergo a single TheraSphere® administration and followed for quality-of-life outcomes and survival for up to 3 years after treatment. Participants will be censored at time of future transplant or if death occurs at any time after treatment.

Inclusion Criteria:

1. Participants must have histologically or imaging-confirmed confirmed HCC.

2. Group 1: Solitary tumor measuring 2-5 cm Or Group 2: 2-3 tumors each ≤ 3 cm in diameter.

3. No prior therapy to target tumor(s).

4. Not a candidate for surgical resection or thermal ablation after multidisciplinary assessment.

5. Age ≥22 years.

6. Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1.

7. Demonstrated adequate organ function as defined below:

   1. Total bilirubin ≤3.0 mg/dL, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
   2. aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) ≤5 X institutional upper limit of normal.
   3. alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤5 X institutional upper limit of normal.
   4. Creatinine Glomerular filtration rate (GFR) > 30 ml/min.

8. Child-Pugh score ≤ B7

9. Albumin-bilirubin (ALBI) score 1-2

10. Participants who have received systemic therapy for HCC will be excluded from the trial.

11. Ability to understand a written informed consent document, and the willingness to sign it.

12. Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

13. Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Exclusion Criteria:

1. Macrovascular tumor invasion or infiltrative appearance of hepatocellular carcinoma.
2. History of severe allergy to iodinated contrast agents despite appropriate premedication.
3. Is currently receiving any other anti-cancer agents and any previous therapy with a device that uses Y90 as the radioisotope.
4. Symptomatic heart failure or severe valvular insufficiency.
5. Symptomatic pulmonary hypertension or lung disease.
6. Symptomatic ascites.
7. Severe uncontrolled coagulopathy International Normalized Ratio (INR) ≥ 3.0 or Platelet ≤ 20,000.
8. Main vein thrombosis (portal vein, both bland and tumor thrombus). Note: Less than lobar portal vein thrombosis is allowable only if the thrombus is bland.
9. Pregnant women are excluded from this study because TheraSphere emits radiation with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with TheraSphere, breastfeeding should be discontinued if the mother is treated with TheraSphere.
10. Lung-shunt fraction (LSF) resulting in anticipated lung dose of >30 Gray (Gy).
11. History of sphincterotomy, biliary-enteric anastomosis, or other biliary tract instrumentation. Note: Prior cholecystectomy with or without bile duct exploration is permitted.
12. Tumor perfused by extrahepatic collateral arteries.
13. Prior partial hepatectomy.
14. Psychiatric illness, other significant medical illness, or social situation which, in the investigator's opinion, would limit compliance or ability to comply with study requirements.
15. History of or current extrahepatic cancer.
16. Pulmonary insufficiency (defined by an arterial oxygen pressure (Pa,O2) of < 60 mmHg, or oxygen saturation (Sa,O2) of < 90%).