Clinical Outcomes of Carbon-Ion Radiotherapy for Large-Sized (≥4cm) Hepatocellular Carcinoma

Abstract

Radical treatment options for bulky unresectable locally advanced hepatocellular carcinoma (HCC) are limited. The purpose of this study is to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for bulky (≥4cm) locally advanced HCC. We performed a retrospective cohort study of patients with bulky (≥4cm) locally advanced HCC treated by C-ion RT between April 2000 and March 2020 in our institution. The eligibility criteria for this study were: (1) the treatment protocols of 45.0-48.0 Gy/2 fractions or 52.8-60.0 Gy/4 fractions, which proven the safety and efficacy in the past clinical trials; (2) Tumors within 3 intrahepatic lesions and with a maximum tumor diameter of 4 cm or greater; (3) N0M0 status; (4) an Eastern Cooperative Oncology Group performance status of 0 to 2; (5) controllable ascites; (6) Child-Pugh grade was A or B. Overall survival (OS), progression-free survival (PFS), and local control rate (LC) were calculated by the Kaplan-Meier method, and Cox regression analysis was used for multivariate analysis. Adverse events were evaluated by CTCAE ver. 5.0. JMP® 12 (SAS Institute Inc., Cary, NC, USA) was used for all analyses. We defined p < 0.05 as statistically significant. A total of 187 patients met the criteria and were evaluated. The median patient age was 73 years (range, 37-90), and 139 of 187 patients were male. Child-Pugh grade was A in 163 patients and B in 24. Modified albumin-bilirubin (mALBI) grade was 1 in 96 patients, 2a in 50, and 2b in 41. The number of HCV-related HCC cases was in 80, HBV in 32 and non-B and non-C in 75. In 51 patients, identification of vascular invasion to the first-order branch of the portal vein and/or major hepatic vein was confirmed. The median maximum tumor diameter was 5.1 cm (4.0-13.5 cm). In 76 patients, C-ion RT were treated for recurrence. With a median follow-up period of 25.9 months (range, 1.1-215.1), 2-year overall survival, progression-free survival and local control rates were 68.3% (95% confidence interval [CI], 64.7-72.0%), 39.0% (95% CI, 35.2 - 42.8%) and 86.7% (95% CI, 84.7 - 89.7%), respectively. Late adverse events were observed in 3 patients (1.6%) with Grade 3 liver dysfunction and in 3 patients (1.6%) with Grade 3 skin disorders, but there were no cases of Grade 4 or higher. Multivariate analysis of prognostic factors for overall survival revealed that mALBI grade in 2b(HR:3.13, 1.97-4.78, p<0.0001), tumor status in recurrent treatment (HR:1.50, 1.02-2.21, p = 0.039), the number of tumors in 2 or more (HR:2.16, 1.01-2.17, p = 0.045), and maximum tumor diameter in larger than 6 cm (HR:2.34, 1.50-3.61, p = 0.0001) were the predominant prognostic factors, while age, presence of vascular invasion, AFP and DCP were not. The safety and efficacy of C-ion RT for bulky (≥4cm) locally advanced HCC was demonstrated. These results suggested that C-ion RT may be a new treatment option for locally advanced bulky HCC with no curative treatment options.