Efficacy of Proton Beam Therapy for Hepatocellular Carcinoma With Portal Vein or Inferior Vena Cava Tumor Thrombosis

Abstract

Vascular invasion, such as portal vein tumor thrombosis (PVTT) and inferior vena cava tumor thrombosis (IVCTT), is a common condition in advanced hepatocellular carcinoma (HCC). HCC patients with PVTT or IVCTT have an extremely poor prognosis. In order to clarify the clinical outcome of proton beam therapy (PBT) for HCC with PVTT or IVCTT, this prospective study was performed. This was a clinical study for HCC with PVTT or IVCTT using PBT based on protocols determined at Nagoya Proton Therapy Center. The primary and secondary endpoints were overall survival (OS) and complication rates, respectively. The number of patients required for this study was estimated to be 31 using the chi-square test (type 1 error=0.05, power=0.8, P0=0.3, P1=0.6). Response after PBT was evaluated using modified RECIST. OS rates were calculated using the Kaplan-Meier method and were compared using the log-rank test. Toxicities were graded according to the common terminology criteria for adverse events (v4.03). Between September 2013 and January 2017, 34 patients (27 males and 7 females) were enrolled, assuming dropout of a few patients. The median follow-up period was 8.4 months (interquartile range (IQR), 4.7-19.1). Median patient age was 68 years (IQR, 61-73). Twenty patients had Child-Pugh A liver function, 12 had Child-Pugh B, and 2 had Child-Pugh C. Etiology of HCC was hepatitis B (7), hepatitis C (18), alcoholism (5), autoimmune hepatitis (1), and nonalcoholic steatohepatitis (1). Median alpha-fetoprotein and PIVKA-II levels were 171.2 ng/mL (IQR, 28.9-5241.3) and 2620 mAU/ml (IQR, 135-12800), respectively. Median gross tumor volume was 220.0 ml (IQR, 87.6-620.6). The median biologically effective dose 10 (BED10) was 81.3 GyE (IQR, 75-96.6). Twenty-one (62%) lesions achieved a complete (15%) or partial response (47%). Stable and progressive diseases were observed in 12 (35%) and 1 (3%), respectively. Tumor thrombosis was present in the portal vein trunk (15), portal vein branch (18), or inferior vena cava (8). The 1-year OS rate was 55%. Eighteen patients in whom all tumors could be included in the irradiation field had good prognoses (P<0.05). The prognoses of 16 patients whose tumor thrombosis shrank after irradiation were good (P<0.05). One patient had grade 3 acute dermatitis. Grade 3 liver enzyme elevation was observed in 2 patients at 3 months after radiotherapy. However, no severe radiation-induced liver disease was observed. No late gastrointestinal symptoms with grade 3 or higher toxicity, such as ulceration, bleeding, perforation, and ileus were recorded. PBT for advanced HCC with PVTT or IVCTT is a safe and effective treatment without severe complications. When all the tumors can be included in the irradiation field, PBT may be effective even for large HCC.