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

Department of Gastroenterology, Internal Medicine, Kitasato University East Hospital, 2-1-1 Asamizodai, Minami-ku, Sagamihara, Kanagawa, 252-0380, Japan, .
Journal of Gastroenterology (Impact Factor: 4.52). 03/2012; 47(9):1030-5. DOI: 10.1007/s00535-012-0563-6
Source: PubMed


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.

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Available from: Hisashi Hidaka, Sep 21, 2015
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    • "Involvement of the main PVTT is associated with poor prognosis, possibly because of increased risk of tumor spread, elevated portal venous pressure causing variceal hemorrhage, and decreased portal flow resulting in ascites, jaundice, hepatic encephalopathy, and liver failure [7,9,23,26]. Sorafenib can compromise hepatic function by decreasing portal blood flow, as we previously demonstrated that sorafenib induced significant vasoconstriction of the portal venous area and significantly reduced portal venous flow, according to Doppler ultrasonography in patients with unresectable HCC [27]. Other investigators have used magnetic resonance imaging to show similar results [28]. "
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    ABSTRACT: Background This study investigated the survival benefits of sorafenib vs. radiotherapy (RT) in patients with unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT) in the main trunk or the first branch. Methods Ninety-seven patients were retrospectively reviewed. Forty patients were enrolled by the Kanagawa Liver Study Group and received sorafenib, and 57 consecutive patients received RT in our hospital. Overall survival was compared between the two groups with PVTT by propensity score (PS) analysis. Factors associated with survival were evaluated by multivariate analysis. Results The median treatment period with sorafenib was 45 days, while the median total radiation dose was 50 Gy. The Child-Pugh class and the level of invasion into hepatic large vessels were significantly more advanced in the RT group than in the sorafenib group. Median survival did not differ significantly between the sorafenib group (4.3 months) and the RT group (5.9 months; P = 0.115). After PS matching (n = 28 per group), better survival was noted in the RT group than in the sorafenib group (median survival, 10.9 vs. 4.8 months; P = 0.025). A Cox model showed that des-γ-carboxy prothrombin <1000 mAU/mL at enrollment and RT were significant independent predictors of survival in the PS model (P = 0.024, HR, 0.508; 95% CI, 0.282 to 0.915; and P = 0.007, HR, 0.434; 95% CI, 0.235 to 0.779; respectively). Conclusions RT is a better first-line therapy than sorafenib in patients who have advanced unresectable HCC with PVTT.
    Full-text · Article · May 2014 · BMC Gastroenterology
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    ABSTRACT: Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time. Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: −0.1799–0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point. Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.
    Full-text · Article · Oct 2012 · Alimentary Pharmacology & Therapeutics
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    ABSTRACT: AimsEarly evaluation of the response to sorafenib for patients with HCC remains unclear. This prospective study investigated the early evaluation of the efficacy of sorafenib in patients with advanced HCC using duplex Doppler ultrasonography (DDU).Methods Thirty-seven Child-Pugh class-A advanced HCC patients treated with sorafenib 400 mg bid were enrolled. Changes in portal venous area (PVA) and portal venous flow velocity (PVV) revealed by DDU before and after 2 weeks of sorafenib treatment were evaluated. The relation between the congestion index (PVA/PVV), which reflects the pathophysiological hemodynamics of the portal venous system and the tumor response, according to the modified Response Evaluation Criteria In Solid Tumors (mRECIST), was also assessed.ResultsThe median progression-free survival and overall survival of all the patients were 2.8 months (95% CI: 2.6–3.2) and 12.8 months (95% CI: 8.7–17.0), respectively. Overall, 3 patients (8%) had a partial response (PR), 15 patients (41%) had a stable disease (SD), and 17 patients (46%) had a progressive disease, according to the mRECIST, and 2 patients (6%) could not be evaluated because of worsened conditions. The decrease in the congestion index was significantly larger in the disease control group (PR/SD) after the sorafenib treatment (P = 0.035); furthermore, the congestion index was the only significant independent predictor of disease control (P = 0.033; hazard ratio: 8.456; 95% CI: 1.182–60.484).ConclusionA decrease in the congestion index revealed by DDU provides an early evaluation of response in patients taking sorafenib for advanced HCC.
    Full-text · Article · Oct 2014 · Hepatology Research
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