The standard treatment of unresectable hepatocellular carcinoma (HCC) is transarterial chemoembolization (TACE) or sorafenib. Though the TACE and the agent showed survival benefit in several randomized phase III trials, the benefit was modest.

Recently, radiotherapy (RT), especially conformal and higher dose with the advancement of RT techniques, showed favorable response rate with acceptable local control rate. Based on those promising results, RT was actively applied in HCC who are not indicated with surgery and/or radiofrequency ablation.

Many researchers reported that there is a relationship between RT dose and tumor response rate. RT dose, however, is frequently limited because the complications (like radiation induced liver disease (RILD), radiation induced gastro-duodenal toxicity, etc.) are also closely related with higher exposed RT dose.

Proton beam has characteristic depth-dose distribution contrast to photon, the "Bragg peak". The advantage of this dose distribution could be more highlighted in HCC management, because of the weakness and maintenance importance of liver function itself in HCC patients. In fact, the superior results of proton beam therapy in HCC were constantly reported in several groups as prospectively as well as retrospectively.

In this background, the investigators planned the present study to evaluate the efficacy and safety of proton beam therapy in HCC patients who are not indicated with surgery and/or radiofrequency ablation (RFA).

Inclusion Criteria:

• Hepatocellular carcinoma (HCC) patients (Pathologically proven or HCC diagnosed based on American Association for the Study of Liver Diseases (AASLD) guideline)
• Not indicated with surgical resection and/or RFA
• Discussion in tumor board including gastroenterologist, radiologist, radiation oncologist
• Eastern Cooperative Oncology Group performance status 0 to 2 within 1 week before participate
• Adequate bone marrow function (absolute neutrophil count ≥ 1.0 x 109/l, platelet ≥ 30 x 109/l, hemoglobin ≥ 8 g/dl)
• Adequate liver/renal function within 1 week before participate
• Total bilirubin <3.0 mg/dL, Prothrombin time/International normalized ratio <1.7, Albumin≥2.8g/dL, Aspartate aminotransferase/alanine aminotransferase<6 times of upper normal limit Serum creatinine < 1.5 x upper normal limit, glomerular filtration rate > 50 ml/min
• Informed consent
• If viable tumor is single, 1 cm to 10 cm
• Less than 3 nodules
• Child-Pugh class A, B, or early C (score ≤ 10)
• Women of childbearing potential and male participants must agree to practice adequate contraception while on study and for at least 6 months following the last dose of RT

Exclusion Criteria:

• Uncontrolled hepatic encephalopathy
• Previous history of upper abdominal radiotherapy
• Status of pregnancy or breast feeding
• Less than 12 weeks of expected survival
• Uncontrolled ascites
• Combined with disease known as radiosensitive disorder (connective tissue disorder, Ataxia-telangiectasia)
• Hard to maintain stable respiration less than 5 minutes related with respiratory disease
• Combined with uncontrolled severe acute disease other than liver