Long-Term Outcomes and Biomarker Correlates of a Multi-Institutional Phase II Study of Hypofractionated Proton Beam Therapy for Unresectable Primary Liver Tumors

PURPOSE: To evaluate long-term outcomes and determine whether longitudinal plasma profiling provides biological insight into disease progression after proton hypofractionated ablative radiation therapy (HART) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: In this single-arm, multi-institutional phase II trial, 92 patients with localized unresectable HCC or ICC with Child-Pugh class A/B liver function received HART (up to 67.5 GyE in 15 fractions). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Plasma samples were collected at baseline, days 1, 8, 15, and 1-month after treatment for exploratory correlative analyses. RESULTS: Among evaluable patients (44 HCC, 39 ICC), median OS was 29.2 months (HCC) and 20.8 months (ICC), with 5-year OS rates of 25.9% and 12.3%, respectively. Median PFS was 13.8 months (HCC) and 8.4 months (ICC). In-field local failure occurred in 2 HCC (4.5%) and 7 ICC (17.9%) patients, whereas out-of-field intrahepatic/distant progression remained the predominant pattern of failure. No grade >3 treatment-related toxicities were observed. Exploratory plasma profiling identified distinct biological signatures associated with progression: HCC was characterized by markers of hypoxia, inflammation, vascular remodeling, stromal activation, and hepatic regeneration, whereas associations in ICC predominantly involved signatures of hypoxia and vascular remodeling. CONCLUSIONS: HART provides durable long-term in-field local control with minimal toxicity, but disease progression remains predominantly out-of-field intrahepatic/distant. Exploratory correlative analyses suggest that biological signatures reflecting vascular remodeling, hypoxia, inflammation, stromal activation, and hepatic reserve are associated with progression despite successful local therapy, informing future translational studies and combination strategies.