Low Hepatic Toxicity in Primary and Metastatic Liver Cancers after Stereotactic Ablative Radiotherapy Using 3 Fractions.

This study evaluated the incidence of hepatic toxicity after stereotactic ablative radiotherapy (SABR) using 3 fractions to the liver, and identified the predictors for hepatic toxicity. We retrospectively reviewed 78 patients with primary and metastatic liver cancers, who underwent SABR using 3 fractions between 2003 and 2011. To examine the incidence of hepatic toxicity, we defined newly developed hepatic toxicity≥grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 within 3 months after the end of SABR as a significant adverse event. To identify the predictors for hepatic toxicity, we analyzed several clinical and dosimetric parameters (rV5Gy-rV35Gy: normal liver volume receiving liver cancers produces low hepatic toxicity, especially in patients with a baseline CP score of 5. However, further studies are needed to minimize hepatic toxicity in patients with baseline CP scores≥6. Graphical Abstract Keywords: Child-Pugh Score, Liver Neoplasms, Hepatic Toxicity, Predictor, Stereotactic Body Radiotherapy INTRODUCTION Hepatic injury after external beam radiotherapy (EBRT) to the liver was first described in the early 1960s; its clinical symptoms comprised rapid weight gain, an increase in abdominal girth, hepatomegaly, occasionally ascites or jaundice, and an elevation of liver enzymes, particularly serum alkaline phosphatase (1). The underlying pathology was identified as veno-occlusive disease, and this has become a classic model of radiation-induced liver disease (RILD) (2). Notwithstanding these clinical and pathological studies on RILD, EBRT has played a limited role in the treatment of liver cancers due to technical barriers over the past 30 yr. With the introduction of 3-dimensional conformal radiotherapy (3D-CRT) in the 1990s, however, multiple beams that are not in the axial plane can spare adequate volumes of the normal liver, and the use of dose-volume histograms (DVHs) can quantify the dose delivered to the normal liver (3). These technological advances have expanded EBRT indications for liver cancers. RILD was subdivided into classic RILD and non-classic RILD, and hepatic toxicity after 3D-CRT has been fairly well established with these endpoints (4). On the other hand, RILD rarely occurs after stereotactic ablative radiotherapy (SABR), which is a newly emerging treatment method to deliver a high dose to the target, utilizing either a single dose or a small number of fractions with a high degree of precision within the body (5,6,7). Therefore, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) or the progression of Child-Pugh (CP) class have been used in evaluating hepatic toxicity after SABR. To date, a few studies have reported several predictors that affect hepatic toxicity after SABR using various fractionation schemes (8,9,10,11,12,13,14). Considering that the main obstacle for safe application of SABR remains the unavailability of data that allow the unambiguous determination of the parameters for fractionation schemes and dose prescriptions, however, additional studies should be needed to establish hepatic toxicity (15). Therefore, this study included SABR in only 3 fractionations to avoid the ambiguity that arises while converting total doses from different fractions to the biologically equivalent dose. We evaluated the incidence of hepatic toxicity in primary and metastatic liver cancers after SABR using 3 fractions, and identified the predictors for hepatic toxicity.