Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. METHODS: We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. FINDINGS: We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6-35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1-38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9-19·5) in the sorafenib group and 8·4 months (2·9-19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780-1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. INTERPRETATION: Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.

Two-year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecavir: results from a multicentre study.

BACKGROUND & AIMS: We aimed to compare the viral suppression, safety and rate of drug resistance between besifovir (a new acyclic nucleotide analogue) and entecavir. METHODS: Treatment-naïve chronic hepatitis B patients receiving besifovir 90 mg (n=31), 150 mg (n=28) and entecavir 0.5 mg (n=30) were monitored for liver biochemistry, viral serology, HBV DNA levels, development of drug resistance mutations, and adverse events throughout 96 weeks of treatment. RESULTS: The mean decline of HBV DNA levels from baseline to week 96 were 5.29, 5.15, and 5.67 logs IU/ml for patients receiving besifovir 90 mg, 150 mg and entecavir 0.5 mg, respectively (p>0.05). Undetectable HBV DNA (<20 IU/ml) were achieved in 80.7%, 78.6%, and 80%; ALT normalization in 90.3%, 78.6%, and 93.3%; and loss of HBeAg in 20%, 21.4%, and 22.2% of patients respectively (all p>0.05). One patient receiving besifovir 90 mg had a virological breakthrough due to drug non-compliance. No patient developed drug resistance mutations. Ten patients had serious adverse events, which were not related to the study medications. The most common side effect related to besifovir was carnitine depletion. Carnitine supplements were prescribed to 83.9% and 100% of patients, who had low carnitine level for any one time during follow-up, receiving besifovir 90 mg and 150 mg respectively. No patient had increased creatinine>0.5 mg/dl from baseline. CONCLUSIONS: Besifovir had the same antiviral property as compared to entecavir over 96 weeks of treatment for chronic hepatitis B patients. Besifovir was well tolerated and also had a good clinical safety profile.

Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice.

Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen α1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor α showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.

Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study.

BACKGROUND AND AIM: Sorafenib is recommended as a standard treatment for advanced hepatocellular carcinoma (HCC). The efficacy and safety of sorafenib as a first-line therapy in Korean patients with advanced HCC were investigated. METHODS: From 2007 to 2012, 86 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) treated with sorafenib as a first-line therapy were enrolled from five tertiary hospitals. Predictors of overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: The median age was 59.5 years, and 71 (82.6%) were males; 57 (66.3%) patients were in Child-Pugh class A. The median OS and PFS were 5.0 (range 4.0-5.9) and 3.2 (range 2.6-3.7) months, respectively. Regarding OS, Child-Pugh class A (6.0 vs 2.8 months), tumor diameter < 5 cm (6.0 vs 4.3 months), baseline α-fetoprotein < 200 ng/mL (5.8 vs 4.1 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (5.9 vs 4.0 months) were independent favorable predictors (all P < 0.05). Similarly, regarding PFS, Child-Pugh class A (4.3 vs 2.1 months), tumor diameter < 5 cm (3.9 vs 2.8 months), baseline α-fetoprotein < 200 ng/mL (5.6 vs 2.8 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (4.5 vs 2.6 months) were independent favorable predictors (all P < 0.05). All toxicities during sorafenib treatment were manageable. CONCLUSIONS: Because the efficacy of sorafenib seems marginal in Korean patients with treatment-naïve HCC, how to select candidates with favorable outcomes should be further investigated.

Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B.

BACKGROUND: Besifovir (LB80380) is an acyclic nucleotide phosphonate effective in hepatitis B virus (HBV) DNA suppression for both treatment-naive and lamivudine-resistant chronic hepatitis B (CHB) patients in preliminary studies. DESIGN: We aimed to compare the safety and antiviral activity of two doses of besifovir (90 mg and 150 mg daily) with entecavir 0.5 mg daily in CHB patients. 114 patients were randomised to receive besifovir 90 mg daily (n=36), besifovir 150 mg daily (n=39) or entecavir 0.5 mg daily (n=39). HBV DNA and liver biochemistry, including serum L-carnitine levels, were monitored. RESULTS: At week 48, in the intention-to-treat population, the proportion of patients achieving undetectable HBV DNA (<20 IU/mL) were 63.6%, 62.9% and 58.3%, respectively (p>0.05). The serum mean log10 HBV DNA changes from baseline for the HBeAg-positive patients were -5.84, -5.91 and -6.18, respectively; and for the HBeAg-negative patients were -4.65, -4.55 and -4.67, respectively (p>0.05). There were no differences in the proportions of patients achieving normalisation of alanine aminotransferase (91.7%, 76.9%, 89.7%, respectively) and HBeAg seroconversion (11.11%, 15%, 9.52%, respectively) among all three groups. None of the patients had resistant mutations or increase in serum creatinine of >0.5 mg/dL from baseline. 64 (94.1%) patients on besifovir had lowering of serum L-carnitine (not tested in entecavir patients). L-carnitine levels returned to normal with carnitine supplement. CONCLUSIONS: At 48 weeks, 90 mg and 150 mg daily of besifovir were non-inferior to entecavir 0.5 mg daily in treatment-naive CHB patients. The only significant side effect of besifovir was L-carnitine depletion, requiring carnitine supplementation.

Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats.

UNLABELLED: We sought to determine the hepatic fibrosis-reversal effects upon simultaneous administration of lithospermate B (LAB), an anti-oxidant, and nivocasan, a caspase inhibitor, to rats compared with each compound alone. Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (TAA). Rats were treated with TAA and then given LAB and (or) nivocasan. Fibrotic areas were evaluated quantitatively by computerized morphometry. Apoptosis was assessed using a TUNEL assay, and immunohistochemical staining for malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE) was performed to assess oxidative stress levels. Real-time quantitative PCR was used to quantify expression of fibrosis-related genes. The degree of hepatic fibrosis was significantly reduced in rats treated with LAB and nivocasan compared to either treatment alone (P < 0.001). Treatment with each compound significantly decreased expression of fibrosis-related genes, such as type I collagen α1 (col1α1), α-SMA and TGF-ß1 (P < 0.05). Co-treatment with LAB and nivocasan further reduced col1α1 expression compared to treatment with either compound. A TUNEL assay revealed that hepatocyte apoptosis was significantly decreased in the group treated with nivocasan compared to other groups (P < 0.01). Immunohistochemistry showed a decrease in MDA and 4HNE, reflecting amelioration of oxidative stress, when LAB or LAB+nivocasan was administered compared to nivocasan alone (P < 0.01). Nivocasan was found to inhibit caspase-1, -3, -7, -9 and gliotoxin-induced death of rat-derived hepatic stellate cells was inhibited by nivocasan administration without overexpression of α-SMA. CONCLUSIONS: Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat.

Antifibrotic effects of magnesium lithospermate B on hepatic stellate cells and thioacetamide-induced cirrhotic rats.

Magnesium lithospermate B (MLB) is one of the major active components of Salvia miltiorrhizae. The anti-oxidative effects of Salvia miltiorrhizae have been previously reported. The aim of this study was to investigate the effect of purified MLB on hepatic fibrosis in rats and on the fibrogenic responses in hepatic stellate cells (HSCs). Hepatic fibrosis was induced in rats by intraperitoneal thioacetamide (TAA) injections over a period of 8 or 12 weeks. MLB was orally administered daily by gavage tube. Serum AST and ALT levels in TAA+ MLB group were significantly lower than those in TAA only group at week 8. Hepatic fibrosis was significantly attenuated in TAA+MLB group than in TAA only group at week 8 or 12. Activation of HSCs was also decreased in TAA+MLB group as compared to TAA only group. Hepatic mRNA expression of α-smooth muscle actin (α-SMA), TGF-ß1, and collagen α1(I) was significantly decreased in TAA+MLB group as compared to TAA only group. Incubation with HSCs and MLB (>or=100 µM) for up to 48 h showed no cytotoxicity. MLB suppressed PDGF-induced HSC proliferation. MLB inhibited NF-ΚB transcriptional activation and monocyte chemotactic protein 1 (MCP-1) production in HSCs. MLB strongly suppressed H(2)O(2)-induced reactive oxygen species (ROS) generation in HSCs, and MLB inhibited type I collagen secretion in HSCs. We concluded that MLB has potent antifibrotic effect in TAA-treated cirrhotic rats, and inhibits fibrogenic responses in HSCs. These data suggest that MLB has potential as a novel therapy for hepatic fibrosis.

PIVKA-II is a useful tumor marker for recurrent hepatocellular carcinoma after surgical resection.

OBJECTIVES: The aim of this study is to assess the usefulness of prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) in monitoring of recurrent hepatocellular carcinoma (HCC) after curative resection. METHODS: From April 2001 to March 2004, a total of 245 patients with histologically proven HCC and 267 non-HCC patients were recruited. Serial follow-up measurements of both alpha-fetoprotein (AFP) and PIVKA-II were performed in 27 patients who had recurrent HCC after resection. RESULTS: In the initial HCC diagnosis, the sensitivity of AFP and PIVKA-II was 48.6% (119/245) and 75.1% (184/245), respectively, at the cutoff of 20 ng/ml for AFP and 40 mAU/ml for PIVKA-II (p < 0.01). The specificity was 81.3% (217/267) and 94.8% (253/267), respectively. When AFP and PIVKA-II were combined, the sensitivity and specificity was 83.3% (204/245) and 77.2% (206/267), respectively. In 27 patients developing recurrent HCC after curative surgical resection, the sensitivity of AFP and PIVKA-II was 40.7% (11/27) and 74.1% (20/27), respectively. Several fluctuating patterns of AFP and PIVKA-II were observed from initial diagnosis to recurrence. CONCLUSION: Our data suggest that PIVKA-II is a useful tumor marker for HCC, complementary to AFP. Serial measurements of both markers after resection might be helpful for early diagnosis of tumor recurrence.