Initial Clinical Outcomes of Real-Time-Image Gated Spot-Scanning Proton Beam Therapy for Hepatocellular Carcinomas

In 2014, we developed a real-time-image gated proton beam therapy (RGPT) system using internal fiducials and with two sets of fluoroscopic X-ray attachments in the gantry to minimize the interplay effect and utilized it for hepatocellular carcinomas (HCC). Local control rates and acute adverse effects regarding Radiation Induced Liver Disease (RILD) were retrospectively evaluated in this study. There were 43 patients with 56 tumors who were enrolled in 3 different prospective studies from December 2014 to March 2018. The median age was 70 years (range: 44–88). The maximum tumor diameter was from 5 to 145 mm with a median of 28 mm. Before the RGPT, 36 patients were evaluated as Child -Pugh class A, 7 patients as class B. Nine patients had 2 tumors and 2 patients had 3 tumors. A margin of 5 mm including internal and setup margins was applied lateral to the beam direction. Distal and proximal margins, which were calculated as 3.5% of the range plus 1 mm, were added to account for range uncertainties. Several dose fractionation schedules were used in the 3 different protocols. The calculated biologically effective dose (10) using the linear-quadratic model was from 78 Gy (relative biological effectiveness: RBE) to 109.6 Gy (RBE) with a median of 104.9 Gy (RBE). The tumor responses were evaluated based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The overall survival (OS), progression-free survival (PFS) and local control (LC) rates were calculated from the starting date of the RGPT using the Kaplan-Meier method. The RILD was defined as Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or higher elevations of the level of liver transaminase or a worsening of the CP score by 2 or more without evidence of disease progression. The median follow-up period was 20 months (range: 6–45). The rate of RILD occurring within 3 months after RGPT was 5.3 %. The 1-year and 2-year LC rates, OS rates, and PFS rates, were 98.1 % and 94.3 %, 90.1 % and 73.9 %, and 60.3 % and 38.2 % respectively. For the 8 tumors larger than 100 cc, the LC rates was 100 % and 100 % respectively at 1-year and 2-years and the RILD rate at 3 months was 0 %. The RGPT for patients with HCC was effective with low incidence of RILD at 3 months. A prospective randomized study or well-designed non-randomized study is required to establish a clinical benefit of RGPT.