Pretreatment plasma HGF as potential biomarker for susceptibility to radiation-induced liver dysfunction after radiotherapy

Theodore S Hong,Clemens Grassberger,Christine E Eyler,Thomas F Delaney,Dan G Duda,Beow Y Yeap,Simona Dima,Andrew X Zhu,Irinel Popescu,Jennifer Y Wo,Christopher H Crane,Jeffrey W Clark,Lipika Goyal,Eugene J Koay,Wenqing Jiang

doi:10.1038/s41698-018-0065-y

Abstract

Radiotherapy shows excellent local control in liver cancers but carries the risk of radiation-induced liver dysfunction and liver failure. We conducted a study of plasma hepatocyte growth factor (HGF) in a clinical trial of proton radiotherapy in patients with unresectable liver cancers (NCT00976898), and in an observational study for liver cancer patients undergoing surgical treatments. Liver dysfunction within 3 months after radiotherapy—a Childs−Turcotte−Pugh (CTP) score increase of 1 point or more—occurred in 9/34 (26%) of patients. Patients with no increase in CTP score had lower pretreatment plasma HGF level (p = 0.015). Both the increase in CTP score (p = 0.034) and the pretreatment plasma HGF (p = 0.017) were associated with OS. Plasma HGF was significantly associated with presence of cirrhosis (p = 0.0027) and with Model for End-stage Liver Disease (MELD) score (p < 0.0001), but not with OS in surgical liver cancer patients. Pretreatment plasma HGF is a candidate biomarker for patient selection for radiotherapy.

Highlights

Many liver cancers patients are not candidates for curative surgeries because they are not medically fit, have unresectable tumors, or liver transplantation is not feasible
We evaluated the impact of plasma hepatocyte growth factor (HGF) levels on overall survival (OS) and hepatic function after hypofractionated radiotherapy with protons for unresectable liver cancers[3] and after surgery in resectable liver cancers
When stratified at the median value, patients with high plasma HGF had a 2-year OS of 14% compared to 69% in patients with low plasma HGF (Fig. 2c), while they showed no difference in progression-free survival (p = 0.348)

Summary

INTRODUCTION

Many liver cancers patients are not candidates for curative surgeries because they are not medically fit, have unresectable tumors, or liver transplantation is not feasible. Prior strategies to mitigate hepatic dysfunction have focused on adjusting dosimetric parameters and exclusion of patients with advanced cirrhosis.[2,5] Other approaches have used imaging biomarkers[6] and early changes in circulating serum hepatocyte growth factor (HGF)[7]. No pretreatment circulating biomarkers are available to predict the susceptibility for worsening of the hepatic function, which would allow selection of cirrhotic liver cancer patients and dose for high-dose radiotherapy. HGF/ Met pathway activation is known to have protective effects on hepatocytes.[10] HGF/MET pathway activation has been associated with the progression of cancer.[11] We evaluated the impact of plasma HGF levels on overall survival (OS) and hepatic function after hypofractionated radiotherapy with protons for unresectable liver cancers[3] and after surgery in resectable liver cancers (see Tables S1-S4)

RESULTS

DISCUSSION

METHODS