Determining and Incorporating the Optimal Predictive Biomarkers in Hepatocellular Carcinoma Patients Treated with Radiotherapy

Abstract

Radiotherapy (RT) is one of the treatment options for treating hepatocellular carcinoma (HCC) patients. However, treatment responses to RT are heterogeneous and no robust predictive biomarker has been found. Previously, our institution reported the possibility of soluble programmed cell death ligand-1 (sPD-L1), plasma cell-free DNA (cfDNA), inter-alpha inhibitor H4 (ITIH4), interleukin (IL)-6, and IL-10 as predictive biomarkers after RT. However, using a single biomarker to predict treatment outcomes has limitations since the heterogeneity of the tumor and the host-immune system both affect tumor response and oncologic outcomes. Thus, we investigated the optimal biomarkers and incorporated them to predict treatment outcomes in HCC patients treated with RT. Hundred-four HCC patients treated with RT between July 2016 and October 2018 were prospectively enrolled. Conventional RT was performed in all patients, with a median RT dose of 100 Gy (range, 60–100 Gy) for GTV and a median RT dose of 60 Gy (range, 45–60 Gy) for PTV. Peripheral blood was collected at baseline and after RT. A total of six biomarkers, sPD-L1, IL-10, IL-6, cfDNA, ITIH4 and IFN-γ, were analyzed. Median follow up period was 14.7 months (range, 2.3–28.9 months). Median age was 61 (range, 33–80), 44 patients (44.4%) had single tumor and the median tumor size was 6.5 cm (range, 1.3–21.0 cm). Nine patients had node-positive disease and 52 patients had portal vein tumor thrombosis or invasion. One-year overall survival rates and progression-free rates were 85.1% and 38.6%, respectively. The most common first pattern of failure was regional only failure, followed by distant only failure. Recursive partitioning analysis revealed four prognostic groups for regional failure based on sPD-L1, IL-10, and number of hepatic lesions: group 1, sPD-L1 < 8.17 pg/mL; group 2, sPD-L1 ≥ 8.17 pg/mL, single tumor; group 3, sPD-L1 ≥ 8.17 pg/mL, multiple tumors, IL-10 < 3.64 pg/mL; group 4, sPD-L1 ≥ 8.17 pg/mL, multiple tumors, IL-10 ≥ 3.64 pg/mL. Regional failure rate was highest in group 4 and lowest in group 1 (p < 0.001). Also, three prognostic groups for progression using post-RT biomarker values were defined based on cfDNA and sPD-L1: group 1, cfDNA < 4.47 μg/mL, sPD-L1 < 19.38 pg/mL; group 2, cfDNA < 4.47 μg/mL, sPD-L1 ≥ 19.38 pg/mL; group 3, cfDNA ≥ 4.47 μg/mL. Progression rate was highest in group 3 and lowest in group 1 (p < 0.001). This is the first study to incorporate multiple blood-based biomarkers to predict treatment outcomes in HCC patients who received RT. Baseline sPD-L1 and IL-10 level for regional recurrence and post-RT cfDNA and sPD-L1 level for progression showed potential as predictive biomarkers. However, the potential to predict survival or overall progression remains limited and further validation in a larger cohort is needed.