Sorafenib for the treatment of unresectable hepatocellular carcinoma

Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-β). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients

Inspiratie boven de Moerdijk? : Een analyse van de territoriale, bestuurlijke, functionele en financiële organisatie van de Nederlandse provincies

Deze bijdrage brengt in kaart welk profiel de Nederlandse provincies hebben en op basis van welke bestuurscultuur hun takenpakket tot stand is gekomen. We belichten vier verschillende dimensies: de territoriale dimensie focust op de plaats van de Nederlandse provincies in het binnenlands bestuur, de bestuurlijke dimensie brengt de rol van interbestuurlijke overlegorganen in kaart, de functionele dimensie schetst de effectieve taken en bevoegdheden van de Nederlandse provincies en de financiële dimensie werpt een blik op de inkomsten en uitgaven en de financiële verhoudingen tussen de besturen

Purpose, use, and preparation of clinical practice guidelines for the management of biliary tract and ampullary carcinomas

Apart from periampullary carcinoma, the prognosis of biliary tract carcinomas, including hilar cholangiocarcinoma, extrahepatic biliary tract carcinoma, and gallbladder carcinoma, remains poor. Sophisticated diagnostic skills and treatment methods and their application are naturally required to achieve better treatment results for biliary tract carcinomas. However, it is not too much to say that, due to the paucity of high-level evidence for the management of these carcinomas, medical care by healthcare providers in clinics and at medical institutes throughout the world is currently delivered without common consensus and common standards. The clinical practice guidelines for the management of biliary carcinoma outlined here were produced with the aim that they could be used by physicians involved in the care of biliary tract carcinomas, as indicators that could help them provide their patients with the most appropriate care possible at this time. Also, the guidelines were prepared to provide measures that could assure patients with biliary tract carcinomas of safe medical care. The present guidelines are characterized by their clarification of clinical questions assumed to be often shared by healthcare professionals. For clarity, we divided the contents of the guidelines into eight areas. In each area, clinical questions are presented, together with recommendations of clinical actions in response to the question. As mentioned already, there is a paucity of high-level evidence in this area; therefore, the recommendations are classified into grades, of which there are five: A, strongly recommend performing the clinical action; B, recommend performing the clinical action; C1, the clinical action may be useful, although there is a lack of high-level scientific evidence; C2, clinical action not definitively recommended ecause of insufficient scientific evidence; D, recommend not performing the clinical action. The grading of the recommendations is based on the determination of the level of evidence in references on which the recommendation is based

Guidance for peptide vaccines for the treatment of cancer

Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system - a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area. Guidance for Peptide Cancer Vaccines

Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.

OBJECTIVE:This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN:Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS:Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION:TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER:NCT01217034

Guideline on the use of new anticancer drugs for the treatment of Hepatocellular Carcinoma 2010 update

The "Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma" was prepared by the Study Group on New Liver Cancer Therapies established by the "Research Project on Emergency Measures to Overcome Hepatitis" under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents "clinical questions" on issues pertaining to medical care, makes "recommendations" on diagnosis and treatment in response to each of these clinical questions, and provides a rationale for these recommendations in the form of "scientific statements". © 2012 The Japan Society of Hepatology