Portal hemodynamic effects of lenvatinib in patients with advanced hepatocellular carcinoma: A prospective cohort study

Abstract

Aim Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor, which suppress tumor angiogenesis and tumor progression. It was non‐inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma (HCC). Sorafenib had a beneficial effect on portocollateral circulation with portal hypertension in translating and clinical studies. However, the hemodynamic effects of lenvatinib appear to be different from those of sorafenib because the efficacy of lenvatinib for vascular endothelial growth factor receptors and fibroblast growth factor receptors is different from that of sorafenib. This study was prospectively performed to evaluate the portal hemodynamic effect of lenvatinib in patients with advanced HCC using duplex Doppler ultrasonography. Methods In total, 28 Child‐Pugh class A or B patients with advanced HCC received lenvatinib depending on body weight daily for 2 weeks. Primary outcomes were changes in the hemodynamics of the portal venous system using duplex Doppler ultrasonography before and after the 2‐week administration of lenvatinib. Results The portal venous flow velocity (cm/s) significantly reduced (27 ± 12.1 vs. 22.6 ± 8.0, P = 0.019), while portal venous area (cm2) did not change after the 2‐week administration (0.80 ± 0.36 vs. 0.82 ± 0.27, P = 0.665). Therefore, the congestion index (portal venous area/portal venous flow velocity), which reflects the pathophysiological hemodynamics of the portal venous system significantly worsened (0.037 ± 0.025 vs. 0.043 ± 0.024, P = 0.045). Conclusions Considering that this was a short‐term study, because lenvatinib could be an agent that aggravates portal hypertension, it will be necessary to verify its clinical effects for portal hypertension in future studies.

The Role of the Albumin-Bilirubin Score for Predicting the Outcomes in Japanese Patients with Advanced Hepatocellular Carcinoma Treated with Ramucirumab: A Real-World Study

“…Treatment with a VEGF inhibitor significantly increased the risk of bleeding as an AE according to the meta-analysis [31]. In addition, lenvatinib, which acts as a multikinase inhibitor, including the VEGF/VEGFR pathway, was previously reported to aggravate portal hypertension [32, 33]. Accordingly, ramucirumab may have induced esophageal varices rupture, so screening for varices might be needed before starting ramucirumab treatment.…”

Lenvatinib for Hepatocellular Carcinoma: A Literature Review

“…One hypothesis is that VEGF inhibitors, including lenvatinib, increase intrahepatic vascular resistance and reduce intrahepatic blood flow via a reduction in nitric oxide production [51]. In fact, the portal venous flow velocity that was assessed by Doppler ultrasonography during lenvatinib treatment was significantly reduced in comparison to baseline [52,53]. Accordingly, the administration of lenvatinib aggravated the portal hypertension and increased the blood flow in portosystemic shunt, which resulted in the occurrence of hepatic encephalopathy.…”

Influence of NOS3 rs2070744 genotypes on hepatocellular carcinoma patients treated with lenvatinib

“…The NOS3 rs2070744 TC/CC genotypes may reduce the promoter activity of the NOS3 gene compared to the TT genotype, resulting in reduced NO production [25][26][27] . As is the case with the portal hemodynamic study 14,15 , the effects of NO with the NOS3 rs2070744 when treated with lenvatinib may differ from the results of a previous study 12 . Therefore, we presumed that the NOS3 rs2070744 and FGFR4 rs351855 genotypes could be useful predictors of the clinical response to lenvatinib treatment.…”

“…This infers that the portal hemodynamic effects of lenvatinib are different from those of sorafenib. Lenvatinib significantly aggravates the Congestion index (− 23.1% vs. + 16.2%), which reflects portal hemodynamics, and may exacerbate portal hypertension in patients with advanced HCC 14,15 .…”