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Are there opportunities for chemotherapy in the treatment of hepatocellular cancer?
Asghar, U, Meyer, T
Journal of hepatology. 2012;(3):686-95
Abstract
Hepatocellular cancer is a significant global health problem yet the prognosis for the majority of patients has not changed significantly over the past few decades. For patients with advanced disease, sorafenib is currently the standard of care providing a survival advantage of 2-3 months in selected patients. Cytotoxic chemotherapy has been used for over 30 years but definite evidence that it prolongs survival has been lacking. Resistance remains a significant barrier for both targeted and cytotoxic agents and an understanding of the underlying mechanisms is critical if outcomes are to be improved. Here, we summarise the past and current data that constitute the evidence base for chemotherapy in HCC, review the causes of chemoresistance and suggest strategies to overcome these barriers.
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2.
Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development.
Ranieri, G, Gadaleta-Caldarola, G, Goffredo, V, Patruno, R, Mangia, A, Rizzo, A, Sciorsci, RL, Gadaleta, CD
Current medicinal chemistry. 2012;(7):938-44
Abstract
Angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAF kinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients.
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3.
Advanced HCC: emerging molecular therapies.
Finn, RS
Minerva gastroenterologica e dietologica. 2012;(1):25-34
Abstract
Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease and represents the third-leading cause of death world-wide. While the majority of cases occur in Asia, the incidence has been rising in the West for some time. This is driven not only by the Hepatitis C epidemic but also the rising incidence of non-alcoholic steatohepatitis and resulting liver disease. Despite its frequency, treatments for HCC have generally been limited. Curative treatments are limited to surgical resection or liver transplant for a subset of patients and locally ablative techniques such as radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE) have been shown to extend survival for patients with unresectable and intermediate stage liver cancer. For patients with advanced HCC, sorafenib, a small molecule multitargeted kinase inhibitor is the only agent that has been shown to improve survival. At this time there is an abundance of research activity in HCC with an emphasis on developing new agents that target specific molecular alterations in HCC. In this review, we will focus on those agents currently in Phase III studies for front-line, second-line and other indications.
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4.
Management of hepatocellular carcinoma: beyond sorafenib.
Chan, SL, Mok, T, Ma, BB
Current oncology reports. 2012;(3):257-66
Abstract
The positive results of sorafenib have unveiled a new direction of research in the management of hepatocellular carcinoma (HCC). Since then intensive efforts have been focused on development of novel management strategy to further improve the outcome for patients with HCC. Emerging data have suggested that tumor progression of HCC is driven by a number of deregulated signaling pathways and/or epigenetic mechanism. Thus much effort is dedicated to identification of novel agents targeting these dysregulated pathways. Combinations of targeted therapeutics and transarterial chemoembolization (TACE), or different systemic therapeutics also hold the promise to improve treatment outcome beyond sorafenib. This review aims to summarize the current status of clinical development of treatment in HCC. Perspectives on future direction of research will also be discussed.
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5.
Strategies for assessing and managing the adverse events of sorafenib and other targeted therapies in the treatment of renal cell and hepatocellular carcinoma: recommendations from a European nursing task group.
Edmonds, K, Hull, D, Spencer-Shaw, A, Koldenhof, J, Chrysou, M, Boers-Doets, C, Molassiotis, A
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2012;(2):172-84
Abstract
PURPOSE As a group of European nurses familiar with treating patients with renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) using targeted/chemo- therapies, we aimed to review strategies for managing adverse events (AEs) associated with one targeted therapy, sorafenib. METHOD Focusing on the AEs we considered the most difficult to manage (hand-foot skin reaction [HFSR], diarrhoea, fatigue and mucositis/stomatitis), we reviewed the literature to identify strategies relevant to sorafenib. Given the paucity of published work, this included strategies concerning targeted agents in general. This information was supplemented by considering the wider literature relating to management of these AEs in other tumour types and similar toxicities experienced during conventional anti-cancer therapy. Together with our own experience, this information was used to compile an AE management guide to assist nurses caring for patients receiving sorafenib. RESULTS Our collated experience suggests the most commonly reported AEs with sorafenib and other targeted agents are HFSR, diarrhoea, fatigue, rash and mucositis/stomatitis; these generally have an acute (appearing at ∼0-1 months) or delayed onset (appearing at ∼3 months). Most management strategies in the literature were experience-based rather than arising from controlled studies. However, strategies based on controlled studies are available for HFSR and mucositis/stomatitis. CONCLUSIONS Evidence, especially from controlled studies, is sparse concerning management of AEs associated with sorafenib and other targeted agents in RCC/HCC. However, recommendations can be made based on the literature and clinical experience that encompasses targeted and conventional therapies, particularly in the case of non-specific toxicities e.g. diarrhoea and fatigue.
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6.
[Sorafenib in combination with chemotherapy in the induction therapy for FLT3-ITD positive acute monocytic leukemia: a case report and literature review].
Wei, SN, Wei, H, Mi, YC, Liu, BC, Liu, KQ, Zhou, CL, Li, QH, Wang, JX
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2011;(1):8-11
Abstract
OBJECTIVE To explore the safety and efficacy of sorafenib in combination with chemotherapy for the treatment of FLT3 positive acute myeloid leukemia (AML), to highlight the impact of FLT3 mutations and targeting therapy on response of AML. METHODS The clinical and laboratory features and the treatment response, especially the safety profile of sorafenib in an acute monocytic leukemia patient with FLT-ITD were reported. RESULTS The patient achieved clinical and molecular CR after sorafenib was added to the second course of combination chemotherapy. The side effects of sorafenib were mild and tolerable. CONCLUSION The patient responded well to the combination of sorafenib and standard chemotherapy of AML without significant adverse effects.
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7.
Sorafenib-associated hand-foot syndrome in Japanese patients.
Iijima, M, Fukino, K, Adachi, M, Tsukamoto, T, Murai, M, Naito, S, Minami, H, Furuse, J, Akaza, H
The Journal of dermatology. 2011;(3):261-6
Abstract
Sorafenib (Nexavar) is an oral multi-kinase inhibitor that targets tumor growth and angiogenesis, having encouraging efficacy and tolerability in patients with metastatic renal cell carcinoma (RCC) and other tumors. However, hand-foot syndrome (HFS), a frequently reported adverse event under sorafenib treatment, sometimes causes interruption of the treatment or dose reduction. This study was conducted to review sorafenib-associated HSF in Japanese patients, to facilitate improvement of the management of HFS in clinical practice. We reviewed the combined results on HFS in three sorafenib studies in Japanese patients: (A) a phase II study of metastatic renal cell carcinoma; (B) a phase I study of solid tumor; and (C), phase I study of hepatocellular carcinoma. Severity of HFS was graded as 1-3 based on the modified grading scale of National Cancer Institute - Common Toxicity Criteria version 2.0 and Common Terminology Criteria for Adverse Events version 3.0. A total of 189 patients were included for analyses. The incidence of all-grade HFS was 51% (55% in A, 39% in B and 44% in C), and the incidence of grade 3 HFS was 7% (9% in A, 0% in B and 7% in C). Incidence of HFS seemed dose-dependent. These events were observed within 3-9 weeks after initiation of sorafenib treatment. The majority of HFS was manageable with symptomatic treatment and HFS caused permanent discontinuation of sorafenib in only one patient (in study A). The incidence of sorafenib-associated HFS is high compared to other adverse events. However, the present analyses showed that HFS under sorafenib treatment is well manageable in Japanese patients.
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8.
Sorafenib-induced erythema multiforme: three cases.
Namba, M, Tsunemi, Y, Kawashima, M
European journal of dermatology : EJD. 2011;(6):1015-6
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9.
[Myocardial metastasis from renal cell carcinoma treated with sorafenib].
Tokuyama, Y, Iwamura, M, Fujita, T, Sugita, A, Maeyama, R, Bessho, H, Ishikawa, W, Tabata, K, Yoshida, K, Baba, S
Hinyokika kiyo. Acta urologica Japonica. 2011;(10):555-8
Abstract
We present a case of myocardial metastasis from renal cell carcinoma (RCC) during the treatment with sorafenib. A 63-year-old male, who had undergone right radical nephrectomy, received interferon-alpha (IFN), interleukin (IL-2) and 5-flurouracil (5-FU) for the treatment of lung and pleural metastases. However, since this metastasis showed progressive disease, we administered sorafenib. Nine months after the introduction of sorafenib, he complained of dyspnea. Chest computed tomography and cardiac ultrasonography revealed a low density mass at the cardiac muscle of the left cardiac ventricle, suggesting myocardial metastasis of RCC. Molecular targeted therapy achieved a longer survival in advanced RCC patients in comparison with the immunotherapy using cytokines. Therefore, in metastasis evaluation, some organs which have been regarded as rare sites should be carefully evaluated.
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10.
Meta-analysis of dermatological toxicities associated with sorafenib.
Zhang, L, Zhou, Q, Ma, L, Wu, Z, Wang, Y
Clinical and experimental dermatology. 2011;(4):344-50
Abstract
A meta-analysis was performed to determine the type, incidence and risks of dermatological toxicities associated with the multikinase inhibitor sorafenib. A literature search was performed using the electronic databases PubMed and EMBASE, and conference abstracts published by the American Society of Clinical Oncology. Eligible studies included prospective phase II or III clinical trials, and expanded-access programmes (i.e. outside a clinical trial) of patients with solid tumours assigned sorafenib at a starting dose of 400 mg twice daily. The overall incidences and risk ratios of dermatological toxicities associated with sorafenib were analysed. For patients assigned sorafenib, the overall incidence of all-grade rash/desquamation was 35.4% (95% CI 0.29-0.43), hand-foot skin reaction (HFSR) 39.0% (95% CI 0.32-0.47), alopecia 25.5% (95% CI 0.18-0.35), pruritus 14.0% (95% CI 0.10-0.20) and dry skin 14.1% (95% CI 0.10-0.20). High-grade rash/desquamation events occurred in 5.0% (95% CI 0.04-0.07), HFSR in 9.0% (95% CI 0.082-0.098), alopecia in 4/1793, pruritus in 2/1265 and dry skin in 0/1689 of patients assigned sorafenib. Meta-analysis of risk ratio showed that sorafenib was associated with a significantly increased risk of rash/desquamation [risk ratio (RR) 2.73; 95% CI 1.66-4.49)], HFSR (RR 7.50; 95% CI 3.90-14.40) and alopecia (RR 7.55; 95% CI 5.26-10.84) in patients with solid tumours, but risk of pruritus (RR 1.80; 95% CI 0.77-4.22) or dry skin (RR 2.18; 95% CI 0.88-5.40) was not increased. In conclusion, the most frequent dermatological toxicities associated with sorafenib were HFSR, rash/desquamation, alopecia, pruritus and dry skin. There was a significantly increased risk of HFSR, rash/desquamation and alopecia with sorafenib compared with placebo. Skin toxicities were mainly mild or moderate in severity. Appropriate prevention and management are recommended.