Portal hemodynamic effects of sorafenib in patients with advanced hepatocellular carcinoma: a prospective cohort study.
ABSTRACT Sorafenib is currently in clinical use as an oral multikinase inhibitor that blocks tumor growth and cell proliferation in advanced hepatocellular carcinoma (HCC). It has been demonstrated in a translating study that sorafenib had a beneficial effect on portocollateral circulation in cirrhotic animals with portal hypertension. This study was prospectively performed to evaluate the portal hemodynamic effect of sorafenib in patients with advanced HCC using duplex Doppler ultrasonography (DDU).
Twenty-five Child-Pugh class-A patients with advanced HCC had received sorafenib at a dose of 400 mg twice daily. Primary outcomes were changes in portal venous area (PVA; cm(2)) as seen by using DDU before and after a 2-week administration of sorafenib. Secondary outcomes included the changes of laboratory data and other flow data revealed on DDU.
PVA was significantly decreased after a 2-week administration (0.78 ± 0.23 vs. 0.64 ± 0.25, P = 0.023), while the portal venous flow velocity (PVV; cm/s) was not significantly changed (0.22 ± 0.06 vs. 0.24 ± 0.07, P = 0.17). Therefore, the congestion index (PVA/PVV), which reflects the pathophysiological hemodynamics of portal venous system, was significantly decreased (3.9 ± 1.7 vs. 3.0 ± 1.4, P = 0.042).
We demonstrated the portal hemodynamic effect of sorafenib in patients with advanced HCC. Considering that this was a short-term study, because sorafenib could be a potential beneficial therapeutic agent for portal hypertension, it will be necessary to verify its clinical benefits for portal hypertension in future studies.
- SourceAvailable from: ajronline.org[show abstract] [hide abstract]
ABSTRACT: The "congestion index" is used to mean the ratio between the cross-sectional area (cm2) and the blood flow velocity (cm/sec) of the portal vein, as determined by a duplex Doppler system. The indices as determined in normal subjects and patients with liver disease were as follows: normal subjects (n = 85), 0.070 +/- 0.029 cm X sec; acute hepatitis (n = 11), 0.071 +/- 0.014 cm X sec; chronic active hepatitis (n = 42) 0.119 +/- 0.084 cm X sec; cirrhosis (n = 72), 0.171 +/- 0.075 cm X sec; and idiopathic portal hypertension (n = 11), 0.180 +/- 0.107 cm X sec. There was a statistically significant difference between the congestion indices from the normal subject group and indices obtained from patients with chronic hepatitis, cirrhosis, and idiopathic portal hypertension. A weak positive correlation was obtained between the congestion index and the portal venous pressure, measured simultaneously through a percutaneously placed catheter (n = 64, r = 0.45, p less than 0.01). It is suggested that the congestion index reflects the pathophysiological hemodynamics of the portal venous system in portal hypertension.American Journal of Roentgenology 05/1986; 146(4):735-9. · 2.90 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. CONCLUSION: Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.Hepatology 12/2008; 49(4):1245-56. · 12.00 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.)New England Journal of Medicine 07/2008; 359(4):378-90. · 51.66 Impact Factor