Modeling of Normal Tissue Complications Using Imaging and Biomarkers After Radiation Therapy for Hepatocellular Carcinoma

Abstract

To develop normal tissue complications (NTCP) models for hepatocellular cancer (HCC) patients who undergo liver radiation therapy (RT) and to evaluate the potential role of functional imaging and measurement of blood-based circulating biological markers before and during RT to improve the performance of these models. The data from 192 HCC patients who had undergone RT from 2005 to 2014 were evaluated. Of the 192 patients, 146 had received stereotactic body RT (SBRT) and 46 had received conventional RT to a median physical tumor dose of 49.8Gy and 50.4Gy, respectively. The physical doses were converted into 2-Gy equivalents for analysis. Two approaches were investigated for modeling NTCP: (1) a generalized Lyman-Kutcher-Burman model; and (2) a generalization of the parallel architecture model. Three clinical endpoints were considered: the change in albumin-bilirubin (ALBI), change in Child-Pugh (C-P) score, and grade ≥3 liver enzymatic changes. Local dynamic contrast-enhanced magnetic resonance imaging portal venous perfusion information was used as an imaging biomarker for local liver function. Four candidate inflammatory cytokines were considered as biological markers. The imaging findings and cytokine levels were incorporated into NTCP modeling, and their role was evaluated using goodness-of-fit metrics. Using dosimetric information only, the Lyman-Kutcher-Burman model for the ALBI/C-P change had a steeper response curve compared with grade ≥3 enzymatic changes. Incorporating portal venous perfusion imaging information into the parallel architecture model to represent functional reserve resulted in relatively steeper dose-response curves compared with dose-only models. A larger loss of perfusion function was needed for enzymatic changes compared with ALBI/C-P changes. Increased transforming growth factor-β1 and eotaxin expression increased the trend of expected risk in both NTCP modeling approaches but did not reach statistical significance. The incorporation of imaging findings and biological markers into NTCP modeling of liver toxicity improved the estimates of expected NTCP risk compared with using dose-only models. In addition, such generalized NTCP models should contribute to a better understanding of the normal tissue response in HCC SBRT patients and facilitate personalized treatment.