Prophylactic Endoscopic Variceal Ligation in Patients With High-risk Esophageal Varices Receiving Atezo/Bev for HCC
NCT ID: NCT06819566
Last Updated: 2025-07-24
Study Results
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Basic Information
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RECRUITING
PHASE2
44 participants
INTERVENTIONAL
2025-05-28
2029-03-31
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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EVL group
This group is single arm which undergo prophylactic endoscopic variceal ligation for high-risk esophageal varices
Endoscopic variceal ligation (EVL)
1. EVL for high-risk varices will be performed by experienced endoscopists, certified in gastroenterological endoscopy, within two weeks prior to the initiation of the Atezo/Bev.
2. A follow-up EGD will be conducted one week after the Atezo/Bev #3. If any of the following criteria are met, additional EVL will not be performed, and anticancer treatment will proceed two weeks later. Otherwise, an additional on-demand EVL session will be conducted:
* The esophageal varices have improved to F1 or less.
* The red color sign has disappeared.
3. On-demand EVL will be considered after 5th, and 7th consecutive doses of Atezo/Bev, with EGD follow-up performed to assess eligibility. The maximum number of EVL sessions is limited to three sessions.
Interventions
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Endoscopic variceal ligation (EVL)
1. EVL for high-risk varices will be performed by experienced endoscopists, certified in gastroenterological endoscopy, within two weeks prior to the initiation of the Atezo/Bev.
2. A follow-up EGD will be conducted one week after the Atezo/Bev #3. If any of the following criteria are met, additional EVL will not be performed, and anticancer treatment will proceed two weeks later. Otherwise, an additional on-demand EVL session will be conducted:
* The esophageal varices have improved to F1 or less.
* The red color sign has disappeared.
3. On-demand EVL will be considered after 5th, and 7th consecutive doses of Atezo/Bev, with EGD follow-up performed to assess eligibility. The maximum number of EVL sessions is limited to three sessions.
Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
19 Years
80 Years
ALL
No
Sponsors
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Seoul National University Hospital
OTHER
Hanyang University
OTHER
Samsung Medical Center
OTHER
National Cancer Center, Korea
OTHER_GOV
Seoul National University Bundang Hospital
OTHER
Asan Medical Center
OTHER
Responsible Party
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Ju Hyun Shim
Professor
Principal Investigators
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Jihyun An, MD, PhD
Role: STUDY_DIRECTOR
Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Republic of Korea
Locations
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Liver cancer center, Asan Medical Center
Seoul, Song-pa, South Korea
Countries
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Central Contacts
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Facility Contacts
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References
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Patel JN, Jiang C, Owzar K, Hertz DL, Wang J, Mulkey FA, Kelly WK, Halabi S, Furukawa Y, Lassiter C, Dorsey SG, Friedman PN, Small EJ, Carducci MA, Kelley MJ, Nakamura Y, Kubo M, Ratain MJ, Morris MJ, McLeod HL. Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance). Pharmacogenomics J. 2024 Mar 4;24(2):6. doi: 10.1038/s41397-024-00328-z.
Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. doi: 10.1016/j.jhep.2021.11.030. Epub 2021 Dec 11.
Larrey E, Campion B, Evain M, Sultanik P, Blaise L, Giudicelli H, Wagner M, Cluzel P, Rudler M, Ganne-Carrie N, Thabut D, Allaire M. A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC. Liver Int. 2022 Dec;42(12):2843-2854. doi: 10.1111/liv.15458. Epub 2022 Oct 26.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, Jou JH, Kulik LM, Agopian VG, Marrero JA, Mendiratta-Lala M, Brown DB, Rilling WS, Goyal L, Wei AC, Taddei TH. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023 Dec 1;78(6):1922-1965. doi: 10.1097/HEP.0000000000000466. Epub 2023 May 22. No abstract available.
Ben Khaled N, Moller M, Jochheim LS, Leyh C, Ehmer U, Bottcher K, Pinter M, Balcar L, Scheiner B, Weich A, Leicht HB, Zarka V, Ye L, Schneider J, Piseddu I, Ocal O, Rau M, Sinner F, Venerito M, Gairing SJ, Forster F, Mayerle J, De Toni EN, Geier A, Reiter FP. Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multicenter real-world study with focus on bleeding and thromboembolic events. JHEP Rep. 2024 Apr 8;6(6):101065. doi: 10.1016/j.jhepr.2024.101065. eCollection 2024 Jun.
Ha Y, Kim JH, Cheon J, Jeon GS, Kim C, Chon HJ. Risk of Variceal Bleeding in Patients With Advanced Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2421-2423.e2. doi: 10.1016/j.cgh.2022.07.035. Epub 2022 Aug 6. No abstract available.
Song YG, Yeom KM, Jung EA, Kim SG, Kim YS, Yoo JJ. Risk of Bleeding in Hepatocellular Carcinoma Patients Treated with Atezolizumab/Bevacizumab: A Systematic Review and Meta-Analysis. Liver Cancer. 2024 May 22;13(6):590-600. doi: 10.1159/000539423. eCollection 2024 Dec.
Jaiswal V, Jain E, Hitawala G, Loh H, Patel S, Thada P, Nandwana V, Pandey S, Quinonez J, Naz S, Stein JD, Cueva W. Bevacizumab and Sinus Venous Thrombosis: A Literature Review. Cureus. 2021 Nov 11;13(11):e19471. doi: 10.7759/cureus.19471. eCollection 2021 Nov.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
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2024-1524
Identifier Type: -
Identifier Source: org_study_id
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