Phase II Study of Image-Guided Proton Therapy for Solitary Primary Hepatocellular Carcinoma with Indication for Standard Treatment

Abstract

The aim of this study was to evaluate the efficacy and safety of image-guided proton therapy (IGPT) for solitary primary hepatocellular carcinoma (HCC) that was amenable to standard treatment (resection or ablation). Eligibility criteria were as follows: (1) histologically-confirmed or image-diagnosed solitary primary HCC staged as T1N0M0 (UICC TNM 7th ed.); (2) no history of previous HCC; (3) patient refusal of surgery or radiofrequency ablation; (4) no previous radiation therapy around the lesion; (5) age > 20 and ≤ 80 years; (6) ECOG-PS ≤ 1; (7) Child-Pugh classification A5, 6 or B7; (8) dose constraints of the organs at risk achievable; (9) tumor diameter ≤ 12 cm; and (10) written informed consent. Primary endpoint was the 2-year overall survival (OS). Secondary endpoint was the local control rate (LCR), incidence of Grade 3 or higher adverse events, and change of quality of life (QOL). Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. QOL score were evaluated with the EORTC QLQ-C30 version 3.0 and QLQ-HCC18. We hypothesized that the 2-year OS would be increased from a baseline of 68% to 84% and calculated that 45 patients would need to be enrolled to have a 90% chance of demonstrating improvement using a 2-sided test with a significance level of .05 and 5% of drop-out patients. Survival was analyzed by using the Kaplan-Meier method. Prior to treatment planning, a fiducial marker was placed near the tumor. Proton therapy was performed using respiratory-gated and image-guided techniques. From June 2013 to February 2016, 45 patients were enrolled. The major underlying liver diseases were hepatitis B infection (n=16), hepatitis C infection (n=13), alcoholic hepatitis (n=3), and nonalcoholic fatty liver disease (NAFLD) (n=13). Thirty-three patients had a Child-Pugh score of A5, 8 had a score of A6, and 4 had a score of B7. Twelve patients had Barcelona Clinic Liver Cancer stage 0 disease, 30 had stage A disease, and 3 had stage C disease. Thirty-seven patients with a peripherally located tumor were given 66 GyE in 10 fractions and 8 patients with a centrally located tumor received 72.6 GyE in 22 fractions. Maximum tumor diameter ranged from 10 to 100 mm (median, 25). The median follow-up period of surviving patients was 37.0 months (range: 24.0-50.5). The 2-year OS and LCR were 87% (95% confidence interval: 77-97%) and 95% (86-100%), respectively. There were significant differences in 2-year OS between the NAFLD group and others (P = 0.033). Only 1 grade 3 radiation-induced liver disease was observed. There were no significant differences in the QOL score before treatment and after 1 year except for body image (QLQ-HCC-18). IGPT is safe and effective for treating solitary primary HCC. As a new treatment modality, IGPT may become one of standard treatments for solitary primary HCC.