Pre-treatment sTNFR1 and HGF levels predict toxicity and overall survival after 90Y radioembolization: potential novel application of biomarkers for personalized management of hepatotoxicity.

Liver function may be negatively affected by radiation for treatment of hepatic malignancy. Pretreatment blood cytokine levels are biomarkers for prediction of toxicity and survival after external beam radiation therapy. We hypothesized that cytokines may also predict outcomes after radioembolization, enabling a biomarker-driven personalized approach to treatment. Methods: Pre-therapy blood samples from patients enrolled on a prospective protocol evaluating 90Y radioembolization for management of intrahepatic malignancy were analyzed for two cytokines selected based on prior studies in stereotactic body radiotherapy (SBRT), soluble tumor necrosis factor receptor 1 (sTNFR1) and hepatocyte growth factor (HGF), via enzyme-linked immunosorbent assay (ELISA), and key dosimetric parameters were derived from post-treatment 90Y PET/CT imaging. Toxicity was defined as a change in albumin-bilirubin score (ALBI) from baseline to follow up [3-6-month post-treatment (ΔALBI)]. Associations of cytokine levels, dose metrics, and baseline liver function with toxicity and overall survival were assessed. Results: Data from 43 patients treated with 90Y radioembolization for primary [48.8% (21/43)] or secondary [51.2% (22/43)] malignancy were assessed. Examined dose metrics and baseline liver function were not associated with liver toxicity; however, levels of sTNFR1 (P = 0.045) and HGF (P = 0.005) were associated with liver toxicity in univariate models. Cytokines were the only predictors of toxicity in multivariable models including dose metrics and prior liver directed therapy. sTNFR1 (HR 12.3; CI 3.5-42.5, p<0.001) and HGF (HR 7.5; CI 2.4-23.1, p<0.001) predicted overall survival, and findings were similar when models were controlled for absorbed dose and presence of metastatic disease. Conclusion: Pretreatment cytokine levels predict liver toxicity and overall survival. These pathways can be targeted with available drugs, an advantage over previously studied dose metrics and liver function tests. Interventions directed at the TNF alpha axis should be considered in future studies for prevention of liver toxicity, and HGF should be explored further to determine whether its elevation drives toxicity or indicates ongoing liver regeneration after prior injury.