High-Serum Hgf and Low-Serum Cd40l Are Associated with Liver Toxicity after Stereotactic Body Radiation Therapy

We hypothesized that serum cytokine levels can predict radiation induced liver toxicity prior to clinical manifestations in patients receiving liver SBRT. As part of an IRB approved phase 2 trial of adaptive liver SBRT, patients were initially treated with 3 fractions of liver SBRT and reassessed 1 month later. An additional 2 fractions of SBRT were administered per protocol guidelines based on changes in indocyanine green clearance. Blood samples were collected at baseline and 1 month after the initial 3-fraction course of SBRT. Child-Turcotte-Pugh (CTP) scores were prospectively acquired for each patient at baseline and 1, 3, and 6 months after completing treatment. A 2 point increase in CTP score was considered a clinically significant change. Serum cytokine levels were analyzed using a bead-based multiplex assay. Fourteen cytokines were selected based on their potential role in liver disease. Forty-five of the 90 patients on the study were selected for the initial screen, including all of the patients who had a change in CTP score. Logistic regression models were used to determine the probability of a 2 point change in CTP score as a function of serum cytokine concentration. Receiver operating characteristic (ROC) curves were generated and the area under the curve (AUC) was calculated with confidence intervals. Baseline CTP scores were 5 or 6 in 34 patients, 7 or 8 in 10 patients, and 9 in 1 patient; 39 patients had hepatocellular carcinoma, 2 had cholangiocarcinoma, and 4 had liver metastases. Eleven patients experienced a CTP score increase of 2 points or more within 6 months of starting liver SBRT. Interestingly, the treatment planning normal tissue complication probability for all of these patients was <1%. We found that high-serum levels of hepatocyte growth factor (HGF) 1 month after 3 of the 5 planned fractions of liver SBRT, was associated with an increased risk of subsequently developing liver toxicity with an ROC AUC value of 0.83 (CI 0.70 to 0.97, P = .003). Additionally, low-serum CD40 ligand obtained 1 month after 3 fractions of SBRT was associated with an increased risk of developing liver toxicity with an ROC AUC value of 0.85 (CI 0.69 to 1.00, P = .007). Serum levels of HGF and CD40L may be early biomarkers of radiation induced liver toxicity from SBRT. High-serum HGF has previously been shown to be elevated in patients with acute and chronic liver disease. The low levels of serum CD40L seen in our study may be related to liver sequestration of activated T cells targeting the epithelium. These findings need to be validated in a larger patient cohort but could aid in personalized adaptive radiation therapy.