A Prospective Phase II Study of Safety and Efficacy of Sorafenib Followed by (90)Y Glass Microspheres for Patients with Advanced or Metastatic Hepatocellular Carcinoma

PURPOSE: The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres ((90)Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors. METHODS: We enrolled 38 Child–Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by (90)Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival. RESULTS: A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III–IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8–14.4) and 13.2 months (95% CI 7.9–18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3–90) weeks, and average dose was 622 (466–800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-(90)Y treatment. CONCLUSION: This is the first prospective study to evaluate sorafenib followed by (90)Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01900002.