Proton Beam Therapy for Large Localized Hepatocellular Carcinomas in Western Patients

Optimal management of large, unresectable hepatocellular carcinoma (HCC) remains uncertain. Proton beam therapy (PBT) offers dosimetric advantages for sparing the normal liver. Clinical outcomes for these patients in Western populations are limited. This study evaluated clinical outcomes, toxicity, and patterns of failure among Western patients with large localized HCC treated with PBT.

A retrospective single-institution cohort of patients with HCC tumors ≥5 cm, ineligible for surgery or other liver-directed therapies, and treated with PBT was analyzed. Patients with uncontrolled extrahepatic metastases, concurrent systemic therapy, or mixed histology were excluded. All patients received 45.0 to 67.5 Gy(RBE) in 15 fractions. Competing risk and Kaplan-Meier methods were used to assess local failure (LF), overall survival (OS), progression-free survival, and radiation-induced liver disease (RILD). Univariate Cox regression evaluated predictors of OS, LF, and nonclassic RILD.

Fifty-one patients met the criteria and had the following high-risk features: Barcelona Clinic Liver Cancer stage C (45%), Child-Pugh (CP)-B/C cirrhosis (26%), vascular invasion (39%), and a median tumor size of 9.2 cm. Median follow-up for survivors was 51 months. The 1-, 2-, and 3-year cumulative incidences of LF were 4%, 13%, and 13%, respectively. Most failures were out-of-field intrahepatic (50%) or distant (21%); only 4% developed isolated LF. One-, 2-, and 3-year OS rates were 65%, 46%, and 30%, respectively. Tumor size independently predicted OS (HR, 1.18; P < .01). Nonclassic RILD occurred in 15% and was 6% in CP-A and 43% in CP-B+ patients.

Dose-escalated PBT achieves excellent local control with acceptable toxicity for large HCC in Western patients, including tumors >10 cm. Patients with preserved liver function derive the greatest benefit, whereas those with CP-B cirrhosis have higher hepatotoxicity risks. Out-of-field intrahepatic and distant progression remain dominant failure patterns, highlighting opportunities to integrate systemic therapy with definitive PBT.