Abstract
This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).
Highlights
IntroductionThe incidence of hepatocellular carcinoma (HCC) and the associated mortality are increasing in North America and several European regions and declining in Japan and parts of China [1]
The results revealed that colony formation of HA22T were decreased in the presence of the indicated concentrations
[19] that that blocks blocks the the activity activity of protein kinases involved in angiogenesis (vascular endothelial growth factor receptor protein kinases involved in angiogenesis (vascular endothelial growth factor receptor (VEGFR)-1
Summary
The incidence of hepatocellular carcinoma (HCC) and the associated mortality are increasing in North America and several European regions and declining in Japan and parts of China [1]. The oral multikinase inhibitor sorafenib (Nexavar, Bayer Pharma AG, Berlin, Germany) is the first-line systemic treatment and has shown clinical benefits in overall survival [2,3]. Most HCC patients experience disease progression during sorafenib treatment, and the overall survival is approximately eight months [4,5,6]. Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany), a diaryl urea
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