Deteriorated portal flow may cause liver failure in patients with hepatocellular carcinoma being treated with sorafenib

Abstract

We encountered two patients with hepatocellular carcinoma (HCC) who showed rapid progression of liver failure during sorafenib treatment. One had portal vein tumor thrombus (PVTT) and the other developed portal vein thrombosis (PVT) during the treatment, and both of them experienced the elevation of serum lactate dehydrogenase (LDH) concentration during the administration of sorafenib. Their clinical courses indicate that the liver failure might have been caused by sorafenib-induced liver hypoxia, being amplified in the circumstances with reduced portal flow. To our best knowledge, all the reported patients who achieved complete remission (CR) during sorafenib monotherapy had a condition that could decrease portal blood flow. We hypothesized that pathogenesis of disease may be similar in HCC patients who achieve CR and those who experience liver failure while on sorafenib. Sorafenib treatment of patients with HCC and deteriorated portal flow may be a double-edged sword.

Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90

“…One possible reason why sorafenib was superior in prolonging overall survival might be its safety in patients with liver cirrhosis. However, recent data suggest that sorafenib also transiently reduced hepatic reserve 21 , suggesting that other potential mechanisms may exist to explain the superiority of sorafenib compared with other molecularly targeted agents. Sorafenib is considered to target mainly vascular endothelial cells to inhibit angiogenesis 22 , but our data suggest that sorafenib effectively inhibited CD90 + liver CSCs to suppress de novo metastasis.…”

Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines

“…A recent meta‐analysis, which included more than 3000 patients, reported an approximately twofold increased risk for hepatotoxicity in patients treated with TKIs compared to control patients (Teo, Ho, & Chan, ). Liver failure and fatalities are rare, but have been reported for crizotinib (Sato et al, ; van Geel et al, ), pazopanib (Klempner et al, ), ponatinib (Price, Saleem, Lee, & Steinberg, ), regorafenib (Akamine et al, ; Raissouni et al, ; Sacre et al, ) and sorafenib (Brandi et al, ; Fairfax et al, ; Murad, Rabinowitz, & Lee, ; Rao et al, ; Yamasaki et al, ). The mechanisms of hepatotoxicity of TKIs are poorly understood, but are probably not related to kinase inhibition in hepatocytes (Shah et al, ).…”

A combination of portal vein stent insertion and endovascular iodine-125 seed-strip implantation, followed by transcatheter arterial chemoembolization with sorafenib for treatment of hepatocellular carcinoma-associated portal vein tumor thrombus

“…It was postulated that this might be due to multiple reasons, including liver function damaged by chemotherapy and embolization that could cause damage to normal liver tissue, further aggravating the loss of the remaining liver function. Additionally, sorafenib itself has a potential to reduce portal blood flow, increasing the risk of liver failure [ 18 , 25 , 26 ]. However, in group A, PVS insertion and endovascular 125 I seed-strip implantation were performed before TACE-S. PVS provided immediate restoration of the blood flow of obstructed portal vein, improving the hepatic blood supply.…”