Outcome of Proton Beam Therapy for Primary Hepatocellular Carcinoma with “Unfavorable” Macroscopic Classification

Abstract

Transcatheter arterial chemoembolization (TACE) is the standard treatment for early to intermediate-stage hepatocellular carcinoma (HCC) unfit for hepatectomy or radiofrequency/microwave ablation (RFA/MWA). Putting aside its hepatic toxicity, local control of TACE is far from satisfactory, especially with non- "simple nodular type" appearances, to an extent where systemic therapy is suggested to be more beneficial. We here analyzed the outcome of proton beam therapy (PBT) for primary HCC by macroscopic classification. Primary HCC treated with PBT between 2010 and 2018 were extracted from an all-in treatment database. The macroscopic classification was defined by CT or MRI prior to PBT. Local recurrence was defined as tumor re-enlargement or the appearance of arterial phase hyperenhancement. Adverse events were evaluated by CTCAE v5.0. Overall survival, local control, intrahepatic recurrence-free survival, and extrahepatic recurrence-free survival were determined by the Kaplan-Meier method, and the association with treatment factors was analyzed by log-rank and cox regression model. A total of 202 primary HCC cases were extracted, all not a candidate for hepatectomy nor RFA/MWA. Out of them, 75 cases were simple nodular type, 79 were simple nodular type with extranodular growth, 38 were confluent multinodular type, and 10 were infiltrative type. 26 cases were HBV positive, and 84 cases were HCV positive. 35 cases had macroscopic vascular invasion (MVI). With a median follow-up period of 3.72 years (IQR: 1.79-5.85years), the 3-year overall survival rate was 68.1% (95% CI 61.0 - 74.3%), the 3-year local control rate was 89.6% (95% CI 83.4-93.5), the 3-year intrahepatic recurrence-free survival rate was 53.7% (95% CI 45.9-60.8%), and the 3-year extrahepatic recurrence-free survival rate was 87.4% (95% CI: 81.5-91.6%). Simple nodular type had better overall survival (73.2% vs 65.2% p = 0.012) and extrahepatic recurrence free survival (96.9% vs 81.9% p<0.01), but there was no statistically significant difference in local control (92.7% vs 87.6% p = 0.06) and intrahepatic recurrence-free survival (62.0% vs 48.5% p = 0.114). Multivariate analysis of risk factors against OS, including age, sex, AFP, MVI, and macroscopic classification, revealed age and macroscopic classification as independent risk factors. Adverse events of grade 3 included 2 cases of gastrointestinal bleeding, 7 cases of liver function disorder, 1 cases of biliary hemorrhage, and 1 case of pleural effusion. Other than one case of early death (2 weeks after treatment) with an unknown causal relationship, there were no adverse events of grade 4 or severe. PBT for non- "simple nodular type" primary HCC appears to be safe and effective, whilst suppression of out-of-field recurrence is needed for further survival prolongment.