A trial of carbon ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) was first conducted in April 1995 at the National Institute of Radiological Sciences (NIRS) in Japan. A total of 193 patients with HCC were enrolled in this clinical trial. In the first and second phase I/II clinical trials, dose escalation studies were carried out in incremental steps of 10%, resulting in the confirmation of both the safety and efficacy of short-course regimens of 12, 8, and 4 fractions. Based on the results, a phase II clinical study with fixed fractionation, that is, 52.8 GyE/4 fractions, was performed. A total of 47 patients were treated during this phase II study, which resulted in low toxicity and attained a high local control rate (96%) for 5 years after treatment. The last clinical study was conducted from April 2003 to August 2005, with a more hypofractionated regimen of 2 fractions/2 days, in which 36 patients were safely treated within a dose escalation range from 32.0 GyE to 38.8 GyE. The 2-fraction therapy protocol is continuing under the license of Highly Advanced Medical Technology. There have been no therapy-related deaths and no severe adverse events. We conclude that, because of the low toxicity and high local control rate, C-ion RT is a promising new, radical, and minimally invasive therapeutic option for HCC
