Explore the vast range of titles available.

The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544–0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. Pfizer Inc.

Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6·5 months (95% CI 5·56–7·56) in patients treated with sorafenib, compared with 4·2 months (3·75–5·46) in those who received placebo (hazard ratio [HR] 0·68 [95% CI 0·50–0·93]; p=0·014). Median TTP was 2·8 months (2·63–3·58) in the sorafenib group compared with 1·4 months (1·35–1·55) in the placebo group (HR 0·57 [0·42–0·79]; p=0·0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10·7%]), diarrhoea (nine patients [6·0%]), and fatigue (five patients [3·4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11·4%]) and diarrhoea (11 patients [7·4%]); these adverse events rarely led to discontinuation. Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma. Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc.

No effective therapy is available for advanced hepatocellular carcinoma. In this randomized trial involving 602 patients with advanced hepatocellular carcinoma, sorafenib, a multikinase inhibitor of Raf, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, improved median survival by 3 months, as compared with placebo (10.7 vs. 7.9 months, P<0.001). Adverse events, including diarrhea and weight loss, were more frequent in patients receiving sorafenib. No effective therapy is available for advanced hepatocellular carcinoma. In this trial involving patients with advanced hepatocellular carcinoma, sorafenib improved median survival by 3 months, as compared with placebo. Hepatocellular carcinoma is a major health problem, accounting for more than 626,000 new cases per year worldwide. 1 The incidence of hepatocellular carcinoma is increasing in the United States and Europe, and it is the third highest cause of cancer-related death globally, behind only lung and stomach cancers. 1 In the West, the disease is diagnosed in 30 to 40% of all patients at early stages and is amenable to potentially curative treatments, such as surgical therapies (resection and liver transplantation) and locoregional procedures (radiofrequency ablation). 2 Five-year survival rates of up to 60 to 70% can be achieved in well-selected patients. 2 However, . . .

The prognosis in metastatic renal-cell cancer, especially of the dominant clear-cell type, is dismal. This trial compared sorafenib, an orally active inhibitor of the proliferation of cancer cells and tumor angiogenesis, with placebo in patients with metastatic clear-cell renal cancer. The results with sorafenib were modest but encouraging enough to test the drug as an initial adjuvant treatment. This trial compared sorafenib, an orally active inhibitor of the proliferation of cancer cells and tumor angiogenesis, with placebo in patients with metastatic clear-cell renal cancer. The results with sorafenib were modest but encouraging enough to test the drug as an initial adjuvant treatment. The 5-year survival rate for patients with metastatic renal-cell carcinoma is less than 10%. 1 High-dose interleukin-2 therapy rarely induces a durable complete response, and interferon alfa provides only a modest survival advantage. Until recently, there have been no other treatments for patients with renal-cell carcinoma who are ineligible for, or unable to tolerate, these cytokines. 2 – 6 Sorafenib, an orally active multikinase inhibitor with effects on tumor-cell proliferation and tumor angiogenesis, was initially identified as a Raf kinase inhibitor. 7 It also inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; platelet-derived growth factor receptor β (PDGFRβ); FMS-like tyrosine kinase . . .

Two phase 3 clinical trials (SAINT I and SAINT II) evaluated the free-radical–trapping agent NXY-059 for the treatment of acute ischemic stroke. The SAINT I trial, reported last year, suggested that NXY-059 might be effective. The authors now report the results of the SAINT II trial, which clearly shows that NXY-059 is not effective for ischemic stroke. The discrepancy in the findings of the two trials is best explained by chance false positive findings in the SAINT I trial. The authors report the results of the SAINT II trial, which clearly shows that the free-radical–trapping agent NXY-059 is not effective for ischemic stroke. Currently, thrombolysis with alteplase (tissue plasminogen activator [rt-PA]) is the only widely approved treatment for acute stroke, and it is underused. There is an urgent need for new therapies that are safer and can be offered to a higher percentage of patients. Cerebral tissue can be protected in animal models by a variety of agents that attenuate neuronal injury after ischemia, 1 but none of these putative neuroprotectants have been confirmed as an effective therapy in clinical trials. NXY-059, a free-radical–trapping agent, has been extensively tested in animal models of focal ischemic stroke and has been shown to improve functional recovery . . .

Objective The objective of this study was to assess the efficacy and safety of Remimazolam in the context of combined spinal-epidural anesthesia for sedation during orthopedic surgery. Methods This randomized controlled trial enrolled patients scheduled for orthopedic surgery under combined spinal-epidural anesthesia ( N  = 80), who were randomly allocated to receive either dexmedetomidine (Group-D) or remimazolam (Group-R). The target sedation range aimed for a Ramsay score of 2–5 or a BIS value of 60–80 to evaluate the effectiveness and safety of remimazolam during sedation. Results The time taken to achieve the desired level of sedation was significantly shorter in the remimazolam group compared to the dexmedetomidine group (3.69 ± 0.75 vs. 9.59 ± 1.03; P  < 0.0001). Patients in the remimazolam group exhibited quicker recovery, fewer intraoperative adverse events, more consistent vital signs, and greater satisfaction at various time points throughout the surgery. Conclusion This preliminary study demonstrates that remimazolam tosilate serves as a safe and effective sedative for orthopedic surgery performed under combined spinal-epidural anesthesia, in comparison with dexmedetomidine.

Background The incidence of thyroid cancer and the number of patients who die from this disease are increasing globally. Differentiated thyroid cancer (DTC) is the histologic subtype present in most patients and is primarily responsible for the increased overall incidence of thyroid cancer. Sorafenib is a multikinase inhibitor that targets several molecular signals believed to be involved in the pathogenesis of thyroid cancer, including those implicated in DTC. In phase II studies of patients with DTC, sorafenib treatment has yielded a median progression-free survival (PFS) of 58 to 84 weeks and disease control rates of 59% to 100%. The DECISION trial was designed to assess the ability of sorafenib to improve PFS in patients with locally advanced or metastatic, radioactive iodine (RAI)-refractory DTC. Methods/design DECISION is a multicenter, double-blind, randomized, placebo-controlled phase III study in patients with locally advanced/metastatic RAI - refractory DTC. Study treatment will continue until radiographically documented disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent. Efficacy will be evaluated every 56 days (2 cycles), whereas safety will be evaluated every 28 days (1 cycle) for the first 8 months and every 56 days thereafter. Following disease progression, patients may continue or start sorafenib, depending on whether they were randomized to receive sorafenib or placebo, at investigator discretion. Patients originally randomized to receive sorafenib will be followed up every 3 months for overall survival (OS); patients originally randomized to receive placebo will be followed up every month for 8 months after cross-over to sorafenib. The duration of the trial is expected to be 30 months from the time the first patient is randomized until the planned number of PFS events is attained. The primary endpoint is PFS; secondary endpoints include OS, time to disease progression, disease control rate, response rate, duration of response, safety, and pharmacokinetic analysis. Discussion The DECISION study has been designed to test whether sorafenib improves PFS in patients with locally advanced or metastatic RAI-refractory DTC. Trial Registration ClinicalTrials.gov Identifier: NCT00984282 ; EudraCT: 2009-012007-25.

Background: Preclinical investigations support combining sorafenib with IL-2 in the treatment of metastatic renal cell carcinoma (mRCC). Methods: In this open-label, phase II study, 128 patients with mRCC were randomised to receive oral sorafenib, 400 mg twice daily, plus subcutaneous IL-2, 4.5 million international units (MIU) five times per week for 6 in every 8 weeks, or sorafenib alone. After enrolment of the first 40 patients, IL-2 dose was reduced to improve the tolerability. Results: After a median follow-up of 27 months, median progression-free survival (PFS) was 33 weeks with sorafenib plus IL-2, and 30 weeks with sorafenib alone ( P =0.109). For patients receiving the initial higher dose of IL-2, median PFS was 43 weeks vs 31 weeks for those receiving the lower dose. The most common adverse events were asthenia, hand–foot syndrome, hypertension, and diarrhoea. Grade 3–4 adverse events were reported for 38 and 25% of patients receiving combination and single-agent treatment, respectively. Conclusion: The combination of sorafenib and IL-2 did not demonstrate improved efficacy vs sorafenib alone. Improvements in PFS appeared greater in patients receiving higher-dose IL-2.

Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients.

Purpose To characterize the cardiovascular profile of sorafenib, a multitargeted kinase inhibitor, in patients with advanced cancer. Methods Fifty-three patients with advanced cancer received oral sorafenib 400 mg bid in continuous 28-day cycles in this open-label study. Left ventricular ejection fraction (LVEF) was evaluated using multigated acquisition scanning at baseline and after 2 and 4 cycles of sorafenib. QT/QTc interval on the electrocardiograph (ECG) was measured in triplicate with a Holter 12-lead ECG at baseline and after 1 cycle of sorafenib. Heart rate (HR) and blood pressure (BP) were obtained in duplicate at baseline and after 1 and 4 cycles of sorafenib. Plasma pharmacokinetic data were obtained for sorafenib and its 3 main metabolites after 1 and 4 cycles of sorafenib. Results LVEF (SD) mean change from baseline was −0.8 (±8.6) LVEF(%) after 2 cycles ( n  = 31) and −1.2 (±7.8) LVEF(%) after 4 cycles of sorafenib ( n  = 24). The QT/QTc mean changes from baseline observed at maximum sorafenib concentrations ( t max ) after 1 cycle ( n  = 31) were small (QTcB: 4.2 ms; QTcF: 9.0 ms). Mean changes observed after 1 cycle in BP ( n  = 31) and HR ( n  = 30) at maximum sorafenib concentrations ( t max ) were moderate (up to 11.7 mm Hg and −6.6 bpm, respectively). No correlation was found between the AUC and C max of sorafenib and its main metabolites and any cardiovascular parameters. Conclusions The effects of sorafenib on changes in QT/QTc interval on the ECG, LVEF, BP, and HR were modest and unlikely to be of clinical significance in the setting of advanced cancer treatment.