Outcomes with Proton and Photon Radiotherapy for Unresectable Hepatocellular Carcinoma

Abstract

Emerging data suggest improved outcomes for hepatocellular carcinoma (HCC) with proton radiotherapy (RT), but the data nonetheless remain limited. Based on prior observations, we hypothesized that protons may better mitigate lymphocyte depletion and preserve liver function as compared to photon RT. We retrospectively examined liver function, lymphocyte counts, and survival outcomes for proton or photon RT for patients with HCC. We reviewed the records of 143 patients (111 male, 32 female) treated with RT for unresectable HCC from 2006-2016 at our institution. Serial absolute lymphocyte counts were graded according to CTCAE 4.0. Child-Pugh score (CPS) was calculated at RT start and at peak value within 9 months of RT completion. Univariate and multivariate logistic regressions were used to identify factors associated with change in CPS. Comparisons of distant metastasis-free survival (DMFS) and overall survival (OS) were assessed using the log-rank test and predictors of OS were evaluated using Cox proportional-hazards models. Median age at treatment was 66 years (range, 19-90 years). Portal vein thrombus (PVT) was present in 55%. Treatment modality used was 72% photon and 28% proton; baseline characteristics between these groups were similar. The mean pre-treatment CPS for both groups was 5.8. Median biologically equivalent dose (BED) was 84Gy (range, 44-180Gy) and 97GyE (range, 39-140GyE) for patients treated with photons and protons, respectively. The mean change in CPS was +1.8 (95% confidence interval [CI], 1.3-2.2) for photon patients vs. +0.8 (95% CI, 0.3-1.2) for proton patients (p=0.0058). Grade 3+ (G3+) lymphopenia in patients treated with photons vs. protons was 76% vs. 55% (p=0.015). On univariate analysis, stage 3+, G3+ lymphopenia, pre-treatment CP Class B, and presence of PVT were associated with increased likelihood of worsening CPS. Multivariate analysis revealed that age (odds ratio [OR], 1.069, p=0.03), pre-treatment liver function (CP Class B vs. A, OR, 6.72, p=0.03) and treatment modality (proton vs. photon, OR, 0.26, p=0.03) were associated with liver decompensation. For clinical outcomes, median follow-up was 10 months (range, 1-70 months). For photon-treated patients, median DMFS was 9 months (95% CI, 6-13 months) and median OS was 13 months (95% CI, 10-24 months). For proton-treated patients, median DMFS was 22 months (95% CI, 13-28 months) and median OS was 30 months (95% CI, 15-60 months). Multivariate analysis revealed an increased risk of mortality associated independently with increase in CPS (hazard ratio [HR] 1.79, p<0.001), G3+ lymphopenia (HR 5.44, p=0.04), higher volume of PTV (HR 1.0007, p=0.04), and PVT (HR 4.35, p=0.03). Post-RT liver decompensation and G3+ lymphopenia are independently associated with reduced survival, and proton therapy may mitigate these toxicities compared to photons, especially in patients with advanced cirrhosis. Further investigation is warranted to clarify the role of protons for HCC.