Phase 1/2 Trial Of Stereotactic Body Radiation Therapy For Hepatocellular Carcinoma In Cirrhotic Patients

Studies of stereotactic body radiotherapy (SBRT) have shown high control rates for malignant liver tumors; however, its efficacy in cirrhotic liver has not been explored. A phase I/II trial of SBRT for hepatocellular carcinoma (HCC) in cirrhotic patients was conducted between 2012 and 2014. Eligible patients had liver cirrhosis (diagnosis of cirrhosis was obtained by histopathology, clinical presentation with imaging studies or transient elastography), Child-Turcotte-Pugh’s Class (CTP) A or B, ≤ 3 lesions, and cumulative tumor diameter of ≤ 6 cm, with at least 700 mL of uninvolved liver. Abdominal compression and 4-dimensional computed tomography was used during simulation, and helical intensity-modulated radiotherapy-based SBRT plan was carried out. Starting at 36 Gy in four fractions, dose was escalated with 2 Gy/fraction for phase I. All patients were treated every-other-day with on-board mega-voltage CT for image-guidance. Common Terminology Criteria for Adverse Events v3.0 ≥ grade 3 gastrointestinal toxicity and radiation induced liver disease defined dose-limiting toxicity (DLT). Thirty-two patients with 36 lesions were enrolled, with 4, 3, 8, and 17 patients in dose levels 1, 2, 3, and 4, respectively. Cirrhosis was related to HBV infection in 23 patients, HCV in 5 patients, and alcohol in 4 patients. CTP score was 5 in 28 patients and 6 in 4 patients. The median cumulative tumor diameter was 2.1 cm (range 1.0-4.5 cm). Dose was initially escalated to 52 Gy (13 Gy/fraction), and the protocol was amended for a further escalation to 60 Gy (15 Gy/fraction), which was the dose level used for phase II. DLT was not reached. One local, 4 outfield intrahepatic, 3 distant, 2 concurrent local and outfield, and 1 concurrent local, outfield, and distant failures occurred. The worst toxicity was grade 3 hematologic in 9 patients and grade 2 hepatic in 5 patients, with no gastrointestinal toxicity > grade 1. With median follow-up of 27 months (range 12-55 months), 2-year local control, outfield intrahepatic control, and overall survival rates were 80.9%, 46.7%, and 81.3%, respectively. Two-year local control rates for dose levels 1, 2, 3, and 4 were 25.0%, 66.7%, 87.5%, and 94.1%, respectively. Dose levels 3/4 (versus 1/2) and multi-segment recurrences prior to SBRT (versus none) were independent prognostic factors for local (p = 0.028) and out-field intrahepatic control (p = 0.001), respectively. Helical IMRT-based SBRT for HCC in cirrhotic patients has shown safe and effective. Patients with multi-segment recurrences prior to SBRT need to be watched closely for outfield failures.