Phase 1 trial of apatinib combined with intensity-modulated radiotherapy in unresectable hepatocellular carcinoma
Abstract Background To investigate the maximum tolerated dose (MTD) of apatinib delivered during and after intensity-modulated radiotherapy (IMRT) for unresectable hepatocellular carcinoma (HCC). Methods Patients with unresectable HCC who were not eligible for radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or residual/recurrent after the prior local treatment were enrolled. Patients were scheduled to be treated with IMRT at 50–60 Gy/25–30 fractions. Apatinib was administered concurrently with IMRT and continued after IMRT. In this study, we used a 3 + 3 dose-escalation design. Three dose levels of apatinib (250, 500, and 750mg) were designed. Grade 3 or more severe adverse events (AEs) were defined as dose-limiting toxicities (DLTs). The treatment response was calculated using the Modified Response Evaluation Criteria in Solid Tumour. Results Nine patients with Barcelona Clinic Liver Cancer stage C were included in this study. One patient withdrew from the apatinib 250mg group and another patient was added. No DLT occurred in the apatinib 250mg group. Five patients were included in the apatinib 500mg group, and 2 cases of DLT (grade 3 leukopenia) were found among them. Dose escalation was terminated and the MTD was determined to be 250mg. Common AEs of grade 1–2 included fatigue, hypertension, dizziness, bone marrow suppression, and hyperbilirubinemia. The median follow-up time for all patients was 16.0 months. Three patients achieved complete response and another three achieved partial response. The objective response rate was 6/9 (66.7%), and the disease control rate was 9/9 (100%). Three patients relapsed out of the radiation field. The median progression-free survival was 17.0 months, and the median overall survival was 16.7 months. Conclusions When combined with IMRT, apatinib 250mg daily was recommended for a phase 2 study of unresectable HCC. The antitumor activity of the combination treatment was encouraging. The safety and efficacy of apatinib combined with IMRT for unresectable HCC should be further investigated in future studies.