The goal of this study is to evaluate whether prophylactic endoscopic variceal ligation (EVL) can prevent esophageal variceal bleeding in patients with hepatocellular carcinoma (HCC) receiving atezolizumab and bevacizumab (Atezo/Bev) therapy. The study will also assess the safety of prophylactic EVL in this population.

The main question it aims to answer is:

Does prophylactic EVL in high-risk varices reduce the incidence of variceal bleeding to a level similar to that of low-risk varices in HCC patients receiving Atezo/Bev?

Participants will:

1. Undergo prophylactic EVL before starting Atezo/Bev therapy (within 2 weeks ± 1 week before the first dose).
2. Start Atezo/Bev therapy 2 weeks (± 1 week) after EVL.
3. Have follow-up endoscopies (EGD) one week after the 3rd, 5th, and 7th doses of Atezo/Bev.

If varices improve, no additional intervention is needed. If varices persist or worsen, on-demand EVL will be performed, and Atezo/Bev will continue.

This study will help determine if prophylactic EVL should be a standard strategy for managing high-risk varices in HCC patients undergoing Atezo/Bev therapy.

1. Backgrounds Patients with hepatocellular carcinoma (HCC) undergoing treatment with atezolizumab plus bevacizumab (Atezo/Bev) are at a high risk of variceal bleeding. When bleeding occurs, it may necessitate treatment delays or permanent discontinuation of Atezo/Bev, potentially requiring a switch to alternative anticancer therapies that may be less effective. Additionally, variceal bleeding can result in hepatic decompensation, deteriorated liver function, and reduced quality of life.

   Prophylactic endoscopic variceal ligation (EVL) has been proposed as an approach to minimize the risk of variceal hemorrhage in patients with high-risk esophageal varices, as identified on screening endoscopy. By proactively treating high-risk varices before initiating Atezo/Bev, prophylactic EVL may optimize oncologic treatment continuity and overall patient outcomes.

2. Study aim

This Phase 2 study is designed to evaluate the efficacy and safety of prophylactic EVL in reducing variceal bleeding among HCC patients with high-risk esophageal varices undergoing Atezo/Bev therapy. In addition, this study aims to:

- Assess the impact of prophylactic EVL on patient survival and quality of life.

- Identify biomarkers associated with variceal bleeding risk and therapeutic response.

3. Study Design

1. Prophylactic EVL Procedure Prophylactic EVL will be performed within two weeks (± 1 week) before the initiation of Atezo/Bev therapy. The procedure will be conducted by board-certified gastroenterological endoscopists with expertise in therapeutic endoscopy.

   - EVL technique: Suctioning of esophageal varices until the red-out phenomenon occurs. Placement of a rubber band at the variceal base to induce thrombus formation, leading to subsequent necrosis and sloughing. The procedure begins at the distal esophageal varices and progresses spirally upward. Priority treatment will be given to varices with active bleeding or endoscopic signs of recent hemorrhage.

2. Follow-Up Endoscopy and Additional EVL Criteria Follow-up esophagogastroduodenoscopy (EGD) will be conducted one week after the 3rd dose of Atezo/Bev to assess variceal status.

   If any of the following criteria are met, additional EVL will not be performed, and Atezo/Bev therapy will continue two weeks later:

   • Varices have regressed to F1 or less
   • Red color signs have disappeared If these criteria are not met, an on-demand EVL session will be performed.

3. Further On-Demand EVL Strategy Additional on-demand EVL sessions will be considered after the 5th and 7th doses of Atezo/Bev, with EGD follow-up before each session.

The maximum number of EVL sessions will be limited to three during the study period.

Inclusion Criteria:

• Patients aged 19 years or older and under 80 years.
• Patients with liver function are classified as Child-Pugh Class A.
• Barcelona Clinic Liver Cancer stage C patients with no prior systemic anticancer therapy for hepatocellular carcinoma.
• Patients with an Eastern Cooperative Oncology Group performance score of 0-1.
• Adequate Hematologic and Liver Function:

A. Hemoglobin: ≥ 9.0 g/dL B. Absolute Neutrophil Count : ≥ 1,000/mm³ C. Platelet Count: ≥ 70,000/μL D. Prothrombin Time: ≥ 70% (or Prothrombin Time INR ≤ 1.2)

• Patients with upper gastrointestinal endoscopy performed within six months prior to the start of anticancer treatment.
• No plans for breastfeeding, and if of childbearing potential, using contraception or no plans for spouse's pregnancy or practicing contraception.
• Patients who have received an explanation of the treatment purpose and methods and have provided informed consent for the treatment.

Exclusion Criteria:

• Participants who have previously received systemic anticancer therapy for advanced hepatocellular carcinoma.
• Patients with intrahepatic tumor involvement of 50% or more.
• Patients with tumor thrombus in the main portal vein or both first-order branches (Vp4).
• Patients with a prior history of liver transplantation.
• with uncontrolled malignant tumors other than HCC at the time of enrollment (participation is allowed if disease-free survival exceeds two years).
• Patients with uncontrolled or serious underlying diseases requiring treatment.
• Patients with a history of esophageal or gastric variceal bleeding.
• Previous Variceal Treatments: Patients who have undergone any of the following treatments for variceal bleeding:

A. Endoscopic Variceal Obliteration (EVO) B. EVL C. Transjugular Intrahepatic Portosystemic Shunt (TIPS) D. Percutaneous Approach for Retrograde Transvenous Obliteration (PARTO) E. Surgical procedures

• Patients who have used anticoagulants or antiplatelet agents within one week prior to the study.
• Presence of grade 2 or higher isolated gastric varices or Red Color Signs confirmed by baseline endoscopy (EGD).
• Patients who are pregnant.
• Patients who are unable to understand or provide written informed consent.
• Patients deemed unsuitable for clinical study participation based on the investigator's judgment.