الفهرس 
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Abstract
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. The oncological community is faced with a steady increase in the incidence of hepatocellular carcinoma being a major cause of morbidity and mortality. HCC is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths globally. In 2008, an estimated 748,000 new cases of liver cancer occurred and approximately 696,000 people died of this cancer worldwide (Ferlay et al., 2010).
In Egypt, Hepatocellular carcinoma (HCC) contributes 2.5% of all of total number of cancer cases reported annually with median age 53 years and male predominance of 5:1 (EL-Bolkainy et al., 2006). Recent investigations in Egypt have shown the increasing importance of HCV infection in the etiology of liver cancer, estimated to account for 40–50% of cases, and the declining influence of HBV and HBV/HCV infection (25% and 15%, respectively) (El-Zayadi et al., 2005).
Advances in diagnostic imaging, medical device development, interventional radiology, surgical techniques and liver transplantation have also resulted in considerable improvements in management of HCC (Ju Dong Yang and Lewis R. Roberts., 2010).
According to the BCLC (Barcelona Clinic Liver Cancer) staging system, curative treatment (resection, liver transplantation, or percutaneous local ablative treatment) is primarily appropriate for asymptomatic patients with very early and early (both stage A) HCCs. Transarterial chemoembolization (TACE) is primarily indicated for patients with asymptomatic, multinodular HCC (intermediate, or stage B). Alternative treatment options for patients with unresectable disease include sorafenib, combined locoregional therapy, stereotactic body radiation therapy (SBRT), best supportive care, or chemotherapy (systemic or intra-arterial) with or without RT in the context of a clinical trial (Forner et al., 2010).
Since HCC is a highly genomic heterogeneous solid tumor, multiple oncogenic signaling pathways can be activated simultaneously. As of yet, no single dominant signaling pathway has been found to be specifically altered during the pathogenesis of HCC. It is therefore reasonable to develop therapeutic treatment for HCC by targeting multiple signaling pathways simultaneously using a single agent. Disrupted signaling pathways that are associated with HCC carcinogenesis are promoting angiogenesis, enhancing growth, and inhibiting apoptosis, all of which can lead to uncontrolled growth of tumor cells. Many pathways are discussed due to their critical role in the course of HCC pathogenesis (Bruix et al., 2010).
The recent identification of several key molecular pathways implicated in the pathogenesis of HCC has led to the development of new targeted therapies for this devastating disease. Targeting the various effectors of these pathways with pharmacologic inhibitors may inhibit HCC cell growth and angiogenesis. Several promising novel anticancer agents are currently under investigation for the treatment of HCC. Ongoing clinical trials are offering hope to improve the progression-free survival of patients with advanced HCC (Cervello et al., 2012).
The specific action of the new molecular-targeted agents minimizes the toxicity typical of systemic chemotherapy, although attention needs to be paid to the onset and management of side effects related to treatment with these new agents (Cervello et al., 2012).
The success of sorafenib in the treatment of patients with advanced HCC has established sorafenib as a new standard of care for patients with advanced HCC and encourages a number of novel agents being tested in clinical trials. Results of pharmacokinetics, safety, and efficacy obtained from those finished and ongoing trials will definitely provide valuable information for the future improvement of the targeted therapies in HCC (Zhengyu et al., 2013).
Combination therapy with either conventional cytotoxic drugs or another inhibitor which targets a specific molecule in a different signal transduction pathway is also a key approach for improving the effectiveness and usefulness of new molecular-targeted agents (Cervello et al., 2012).
This avenue of investigation has not been pursued rigorously as it could be, often due to the conflicting interests of the pharmaceutical companies, since different companies will often have competing interests for the different inhibitors and chemotherapeutic drugs. Nevertheless, the field of molecular-targeted therapy in cancer therapy has already come a long way. It is not hard to see an even brighter future on the horizon. However, many additional clinical trials, as well as the development of novel, innovative approaches to cure or suppress the further development of HCC need to be performed and developed to improve therapy in HCC patients (Cervello et al., 2012).
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