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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.

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.

Hepatocellular carcinoma (HCC) is one of the few cancers in which a continued increase in incidence has been observed over several years. As such, there has been a focus on safe and accurate diagnosis and the development of treatment algorithms that take into consideration the unique complexities of this patient population. In the past decade, there have been improvements in nonsurgical treatment platforms and better standardization with respect to the diagnosis and patient eligibility for liver transplant. How to navigate patients through the challenges of treatment is difficult and depends on several factors: 1) patient-related variables such as comorbid conditions that influence treatment eligibility; 2) liver-related variables such as Child-Pugh score; and 3) tumor-related variables such as size, number, pattern of spread within the liver, and vascular involvement. The objectives of this review are to put into perspective the current treatment options for patients with HCC, the unique advantages and disadvantages of each treatment approach, and the evidence that supports the introduction of sorafenib into the multidisciplinary management of HCC. [PUBLICATION ABSTRACT]

To the Editor: Llovet et al. (July 24 issue) 1 report that their study of sorafenib therapy in patients with hepatocellular carcinoma showed a higher overall incidence of treatment-related adverse events with sorafenib than with placebo (80% vs. 52%), although the difference was not noted to be significant. The availability of new therapies, with expected small variations in objective end points, has heightened awareness of the importance of the impact of treatment on patients' overall lives. 2 Besides the traditional end points (e.g., median overall survival and time to radiologic progression), quality of life has been acknowledged as an important issue in . . .

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, . . .

This article summarizes the consensus of an early morning workshop on the multidisciplinary management of nonresectable hepatocellular carcinoma (HCC) held on July 4, 2010, under the auspices of the 1st Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE) Scientific Advisory Committee. Important points are as follows: (1) nonresectable HCC consists of locally advanced HCC and HCC with extrahepatic spread. The grouping system for locally advanced HCC comprises the following categories: nodular, massive with intrahepatic metastases, diffuse, and disease with vascular invasion. (2) In actual clinical practice, the orchestration of multimodality treatment options is keenly needed for successful treatment of individual patients with nonresectable HCC. Physicians in charge tend to prefer maximal cytoreductive measures as long as the condition of the individual patient allows. (3) There are a few studies on the combined use of radiation therapy and transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy in the form of phase I and II trials. (4) At this stage, scientific evidence on multidisciplinary management of nonresectable HCC is lacking. Further studies on multidisciplinary management should focus on the subcategory of locally advanced HCC. (5) Further discussion is needed in the upcoming APPLE meeting to clarify the guidelines as well as to determine a practical multidisciplinary approach for nonresectable HCC patients.

Key Points Increased understanding of the molecular basis of cancer since the 1980s has shifted the focus of drug discovery and development away from non-specific chemotherapeutics and towards rationally designed drugs that target cancer-specific pathways. The Raf serine/threonine kinase isoforms (A-Raf, B-Raf and Raf1(or C-Raf)) are the first kinases in the MAPK cascade and are pivotal regulators of cellular proliferation and survival. In 1989, it was shown that disrupting the raf1 gene using the specific antisense oligonucleotide (ASON) ISIS 5132 inhibits the growth of human lung, breast and ovarian tumour xenografts in athymic mice, providing the first proof-of-concept that the raf1 gene is a valid anticancer target. By 1994, Bayer and Onyx had engaged in a collaboration to discover novel therapies targeting the RAS–RAF–MEK–ERK pathway. HTS screening for Raf1 kinase inhibitory activity was initiated in 1995, and identified a promising lead compound that was subsequently optimized by medicinal chemistry efforts to give sorafenib. Sorafenib directly blocks the autophosphorylation of several receptor tyrosine kinases (RTKs) —VEGFR1, 2 and3, PDGFRβ, c-Kit and RET — as well as inhibiting downstream Raf kinase isoforms in cell lines. The targeting of several RTKs involved in angiogenesis (VEGFR1, 2, 3 and PDGFRβ) and tumorigenesis (Flt-3, c-Kit and RET) might be responsible for its broad-spectrum activity in several models of human cancer. As the molecular targets of sorafenib are involved in the aetiology of many common malignancies, it was first evaluated in a mixed population of patients with several forms of advanced solid tumours. On the basis of the promising preliminary activity in renal cell carcinoma (RCC) patients across the Phase I trials, Bayer and Onyx decided to evaluate sorafenib monotherapy as a treatment for RCC by enriching the recruitment of RCC in an accruing Phase II trial, with a randomized discontinuation trial design. The very high rate of RCC patients who were progression-free after 12 weeks of dosing in this Phase II trial led to the initiation of the Phase III study to assess the safety and activity of sorafenib. These two randomized controlled trials confirmed sorafenib's activity against RCC by showing that it significantly prolonged progression-free survival (PFS) compared with placebo in patients with advanced disease The Phase II/III results established oral sorafenib (400 mg bid) as a safe and effective new treatment for metastatic RCC and formed the basis for its FDA marketing approval in December 2005 for the treatment of advanced RCC. Future issues for the development of sorafenib include the identification and validation of appropriate biomarkers for improved patient selection, prognostication and/or as response endpoints. In December 2005, sorafenib became the first new treatment to be approved for advanced renal cancer in more than a decade. Wilhelm and colleagues provide the history of this drug, which inhibits several kinases involved in tumour signalling and angiogenesis. Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) — from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 — was completed in just 11 years, with approval being received ∼5 years after the initiation of the first Phase I trial.

Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.

Summary Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every 6 months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour might be curable by resection, liver transplantation, or ablation, and 5-year survival higher than 50% can be achieved. Patients with small solitary tumours and very well preserved liver function are the best candidates for surgical resection. Liver transplantation is most beneficial for individuals who are not good candidates for resection, especially those within Milano criteria (solitary tumour ≤5 cm and up to three nodules ≤3 cm). Donor shortage greatly limits its applicability. Percutaneous ablation is the most frequently used treatment but its effectiveness is limited by tumour size and localisation. In asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread not amenable to curative treatments, chemoembolisation can provide survival benefit. Findings of randomised trials of sorafenib have shown survival benefits for individuals with advanced hepatocellular carcinoma, suggesting that molecular-targeted therapies could be effective in this chemoresistant cancer. Research is active in the area of pathogenesis and treatment of hepatocellular carcinoma.

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 . . .