Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan, where chronic viral hepatitis is common. Patients with HCC typically have impaired liver function because of virus- or alcohol- induced cirrhosis and viral hepatitis, and only approximately 20% of them are appropriate candidates for surgery. The 5-year overall survival for patients treated by surgery is approximately 30%-70%. For those not treated with surgery, liver function affected by an underlying liver disease has a strong influence on clinical outcomes, and complicates treatment strategies further than for other tumors. Maximal preservation of normal liver volume and function is an important consideration in the choice of treatment.

Proton beam has been applied to HCC treatment in Japan for longer than a decade, and several retrospective results showed excellent 3-5 years local control rate ranging from 85-95% and nearly no major complications. The investigators also retrospectively reviewed 75 index tumors sized 3.1-7.0cm in 70 patients receiving multiple-electrode radiofrequency ablation with switching controller (ME-SWC RFA) treatments in the period between 1 January 2009 and 31 December 2011 (Oral report in Taiwan Digestive Disease Week, October, 2012). Estimated 1-, 2-, and 3-year cumulative overall survival rates and local control rates were 94%, 85%, 81% and 89%, 83%, 67%, respectively.

Since ME-SWC RFA is the present one of standard modalities for non-surgery, moderate to larger (3-7 cm) HCC, and based on retrospective studies the local control rate of proton therapy was better than radiofrequency ablation, this prospective trial is aimed to compare the effects of these two modalities in 3-7 cm HCC patients who are not candidates for surgery or refuse surgery. This prospective study has high possibility to confirm the role of proton beam in HCC.

Along with the clinical trial, the investigators will also use next generation sequencing (NGS) to exam gene expression profile of tumor samples and find out candidate genes related to local control, intrahepatic control (treatment out-field control in liver), regional lymph node relapse, distant metastasis, and treatment response in HCC.

Inclusion Criteria:

• Pathologically confirmed hepatocellular carcinoma or lesion with typical triphasic CT or MRI imaging features for HCC
• Single tumor and tumor size > 3cm, ≦7cm in diameter
• Patients are unsuitable for resection or unwilling to accept surgery.
• Age ≥20 years old
• Eastern Cooperative Oncology Group performance status score of 0 or 1
• Child-Pugh score ≦ 8
• Willing to sign informed consent regarding participation in this study

Exclusion Criteria:

• Patients have received any treatment for HCC before this study
• Pregnancy/breast feeding women
• Tumor adjacent to bowel <1cm
• Extrahepatic metastasis
• Extrahepatic invasion
• Portal or hepatic vein tumor invasion/thrombosis
• Uncontrolled ascites
• Glomerular filtration rate (GFR) < 30 ml/min*
• Platelet count < 50,000/L*
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 5 years
• Ongoing medically significant active infection.
• MRI incompatible devices
• * Baseline laboratories results must be within the protocol range prior to sign informed consent. Repeat lab tests are permitted to evaluate eligibility during the Screening Period.