Proton Beam Radiotherapy Followed by Tecentriq and Avastin for Primary Liver Cancer With Vp2-4 Portal Vein Invasion

This study is investigator initiated, single-institution, prospective, phase 2 open-label study to determine the efficacy and safety of combination therapy of atezolizumab/bevacizumab and proton beam therapy to portal vein tumor thrombosis with or without main primary tumor in patients with stage 3 or higher hepatocellular carcinoma (HCC) with Vp2-4 portal vein invasion who had not undergone systemic therapy for HCC. The primary endpoint of this study is progression-free survival and secondary endpoints are overall survival (OS), time to progression (TTP), objective response rate, disease control rate (DCR), and time to local disease progression (LTP).

Inclusion Criteria:Patients with HCC meeting all of following criteria;Histologically or radiologically confirmed hepatocellular carcinoma based on the guidelines of the Korean Liver Cancer Association-National Cancer Center 2022Age >= 20Vp2-4 portal vein tumor thrombosis diagnosed by dynamic enhanced computed tomography (CT) or maganetic resonance images (MRI) with below finding 1) an intraluminal filling defect adjacent to the primary tumor in Vp2-4 portal vein 2) an enhancement of the filling defect on arterial phase and a washout on portal/delayed phases.Signed written informed consentat least one or more measurable intrahepatic viable HCC lesionsChild-Pugh class A within 2 weeks from screening for study registrationEastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 within 2 weeks from screening for study registrationLife expectancy of at least 16 weeksadequate bone marrow and liver function within 2 weeks from screening for study registrationHemoglobin ≥ 9.0 g/dLAbsolute neutrophil count (ANC) ≥ 1,000/mm3Platelet count ≥ 50,000/μLTotal bilirubin < 2.5 mg/dLSerum albumin >2.8 g/dLAlanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × upper limit of normal (ULN)Prothrombin time in INR ≤ 1.8 × ULNSerum creatinine ≤ 1.5 mg/dLWomen of childbearing potential and men must agree to use highly efficient contraception since signing of the informed consent form until at least 6 months (women) and 7 months (men) after the last study drug administrationIf other selection conditions are satisfied and the exclusion criteria are not met, registration is possible even in case of N1 or M1.Registration is possible even in the case of hepatic vein tumor infiltration if other selection conditions are satisfied and the exclusion criteria are not metno limitation according to the size and number of tumors in the liver.Exclusion Criteria:Patients with HCC meeting all of following criteria;previous history of systemic treatment for HCC (If systemic treatment for HCC has been performed at least once, it will not be enrolled in this study.) However, registration is permitted if the previous systemic treatment is for adjuvant purposes or treatment for other cancers. Also allowed if previous HCC treatment is local treatment. However, cases with a history of previous upper abdominal radiotherapy (including proton therapy and heavy particle therapy) are excluded.any type of anticancer agent (including investigational) within 2 weeks before enrollmentHaving active brain metastasis or leptomeningeal metastasis need surgery or steroid therapyModerate to severe or intractable ascitesA history or presence of hepatic encephalopathyPresence of active bacterial infectionUntreated active chronic hepatitis B or active hepatitis CHistory of portal hypertension with bleeding within the past 6 monthsPrior liver transplantUncontrolled severe medical comorbidityunhealed wounduncontrolled electrolyte imbalanceNon-interruptible therapeutic use of anticoagulants or thrombolyticsHistory of uncontrolled or autoimmune disease, or immunocompromisedinterstitial lung diseaseOther malignant disease (a history of treated malignancy -other than HCC- is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding two years)Mentally retarded/medically incapable of consent