Literature review Epidemiology Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer worldwide with an annual incidence of over 711,000 new cases, and the third most common cause of cancer death with an annual mortality of 679,000 patients. Most commonly HCC develops in cirrhosis, irrespective of the etiology. In the western world, chronic alcohol abuse and nonalcoholic stratohepatitis are about the as important etiologic factors for cirrhosis as chronic hepatitis c. In chronic hepatitis C it is estimated that about 20% of patients will eventually develop cirrhosis after 20-30 years of infection. Once cirrhosis is established, the annual risk of developing HCC is estimated to be between 3 and 4 %, largely irrespective of the etiology of cirrhosis. Diagnosis of HCC HCC is mostly asymptomatic in early stage disease. Without proper surveillance programs of cirrhotic patients, diagnosis is only established in advanced stage disease. The efficacy of surveillance by Ultrasound (and to a lesser extent by alpha-fetoprotein measurement) has been established in prospective trials in the west as well in the east. surveillance by experienced sonographers makes curative treatment possible treatment possible in up to 75% of patients,while there is no curative treatment without proper surveillance. Surveillance is recommended for the following groups of patients: Hepatitis B carriers Asian males > 40 years, Asian females >50 years, All cirrhotic hepatitis B carriers, Family history of HCC, Africans over age 20. For non-cirrhotic hepatitis B carriers not listed above the risk of HCC varies depending on the severity of the underlying liver disease, the Long-Term Comprehensive National Plan for Science, Technology and Innovation inflammatory activity. Patients with high HBV DNA concentrations and those with ongoing hepatic inflammatory activity remain at risk for HCC. Non-hepatitis B cirrhosis Hepatitis C, Alcoholic cirrhosis, Genetic hemochromatosis, Primary biliary cirrhosis. Although the following groups have an increased risk of HCC no recommendations for or against surveillance can be made because a lack of data precludes an assessment of whether surveillance would be beneficial - Alpha1-antitrypsin deficiency ,Non-alcoholic steatohepatitis, Autoimmune hepatitis. Once a lesion is detected by ultrasound, the diagnosis can be established radiologically in lesions with typical appearance above 1 cm in diameter. Biopsy is mandated only in cases with atypical presentation on imaging. Staging of HCC Staging of HCC can be done using several systems. currently, the most widely used staging system is the Barcelona Clinic Liver Cancer (BCLC) staging system , which takes the underlying liver disease, tumor characteristics, as well as the general performance status into account . This staging system is popular as it is directly linked to treatment, making treatment decisions easy. Advanced stage HCC: the current role of medical therapies In western countries, about 30 % of patients are identified with an HCC in BCLC stage 0 or A, either through surveillance or by chance. For those patients curative options can be applied, which currently involve only surgical or interventional treatments. However , curatively treated patients , except for those who underwent transplantation, will have a tumor recurrence in 70 to 80 % of cases within 5 years of therapy and will eventually progress to BCLC B or BCLC C stage disease. Another 20 % of patients are diagnosed at very advanced stages BCLC D, being either symptomatic from the decompensated cirrhosis (Child-Pugh C) or having an advanced tumor. Those patients have a very short survival, which cannot be influenced by any therapeutic intervention and are only eligible to receive best supportive care. Currently, the domain of medical therapies for HCC is in the setting of advanced stage BCLC C. Conventional chemotherapy of any kind has never shown any meaningful therapeutic benefit, particularly in overall survival in randomized controlled trials in adult patients and cannot be recommended for the treatment of HCC today. Conventional cisplatin-based chemotherapy, Technology and Innovation without doxorubicine only has a place in the treatment of childhood hepatoblastoma, which is a distinctly different disease entity. In hepatoblastoma cisplatin-based chemotherapy does improve survival and can even provide a cure in over 80% of patients when combined with resection. Medical treatment of HCC changed dramatically in 2007 , when the first data from the successful use of targeted agents in advanced stage HCC, in particular tyrosine kinase inhibitors, were presented. Up-regulated signaling through the mitogen-activated protein kinase (MAPK) intracellular signal transduction pathway plays a crucial role in the development of hepatocellular carcinoma , as does tumor angiogenesis .The MAPK pathway comprises Raf ,MAPK kinase (MEK ) and extracellular signal-regulated Kinase (ERK), and is a mediator of tumor proliferation, differentiation and survival. The identification of pivotal pathways, such as the MAPK cascade, led to the development of targeted treatments, such as Sorafenib. Sorafenib is an orally active multikinase inhibitor that inhibits cell surface tyrosine kinases, as well as downstream intracellular Raf kinases in the MAPK cascade. Sorafenib is widely available for the use in the treatment of advanced renal cell carcinoma and has been reviewed in this indication previously. Recently, Sorafenib was also approved in the US and the EU for use in the treatment of hepatocellular carcinoma, the first systemic drug to be approved in this indication. Indeed, current US treatment guidelines recommend Sorafenib as the first-lone treatment option in patients with unresectable HCC who are Child-Pugh class A. Receptor tyrosine Kinases inhibited by Sorafenib include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, Platelet-derived growth factor receptor (PDGFR)-B, cKIT, FMS-like tyrosine kinase 3 (FLT-3) and RET. Intracellular Raf serine/threonine kinase isoforms inhibited by Sorafenib include Raf-1(or C-Raf), wild -type B-Raf and Mutant B-Raf. These kinases are involved in tumor cell proliferation and tumor angiogenesis. In vitro, dose-dependent inhibition of cell proliferation was seen with Sorafenib in the human hepatocellular carcinoma cell lines PLC/PRF/5 and HepG2. Moreover, dose dependent induction of apoptosis was seen after Sorafenib exposure, as assessed by TUNEL (terminal deoxynucleotide transferase d-uridine triphosphate nick end labeling) staining. Inhibition by Sorafenib of the Raf/MEK/ERK signaling pathway in PCL/PRF/5 and HepG2 cells was shown by, among other things, the inhibition of MEK and ERK phosphorylation. Sorafenib demonstrated Protocol number: 1.0 dated 01Aug2013 Short title: HCC - Sorafenib study Confidential Page 14 The Long-Term Comprehensive National Plan for Science, Technology and Innovation dose-dependent antitumor activity in murine xenograft model of PCL/PRF/5 human hepatocellular carcinoma. Significant tumor growth inhibition of 49% and 78% was seen in mice receiving oral Sorafenib 10 or 30 mg/kg/day for 16 or 21 days ( both P 16 weeks and 48 (35.0%) had progressive disease (the remaining 32 patients [23.4%] were not available for independent review). With Sorafenib, the median time to progression was 4.2 months (investigator assessment) or 5.5 months (independent assessment), and the median overall survival duration was 9.2 months. Phase III trial The clinical efficacy of oral Sorafenib was examined in patients with advanced HCC in a randomized, double-blind, placebo-controlled, multi center, phase III trial (the SHARP study) (22). Inclusion criteria were histologically proven, advanced hepatocellular carcinoma, with at least one measurable untreated lesion, an ECOG performance status of 0-2, Child-Pugh class A and no prior systemic treatment . 902 patients were screened and 602 were randomized to receive oral Sorafenib 400 mg twice daily (n=299) or placebo (n=303). The median duration of treatment was 23 weeks in Sorafenib recipients and 19 weeks in placebo recipients. Prior to randomization, patients were stratified according to macroscopic vascular invasion and/or extrahepatic spread, ECOG performance status and Geographical region. In terms of baseline characteristics, mean patient age was 65.5 years; 87% of patients were male; 87.5% of patients were from Europe; 96.5% of patients were Child-Pugh class A; 54%, 38.5% and 7.5% of patients had an ECOG performance status of 0, 1, 2 at baseline; 17.5% and 82.5% of patients had Barcelona Clinic Liver Cancer Group stage B and C cancer; and 70% of patients had vascular invasion and/or extrahepatic spread . The primary endpoints were overall survival and time to symptomatic progression (defined as the time from randomization to a 4-point decline from baseline in patient response to the Functional Assessment Of Cancer Treatment Hepatobiliary Symptom index [FHSI-8] confirmed at next visit , deterioration to ECOG performance status 4, or death). The time to progression (assessed by independent central review) was a pre-specified secondary endpoint. Tumor response rates were assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Analyses were conducted in the intent-to-treat (ITT) population (22). Sorafenib significantly improved survival in patients with advanced hepatocellular carcinoma in the SHARP trial (22). The median duration of survival was 10.7 months with Sorafenib and 7.9 months with placebo, yielding a hazard ratio (HR) of 0.69 (95% CI 0.55, 0.88; P = 0.00058). Following the second planned interim analysis, the SHARP study was terminated early on the basis of this survival result. At the time of study termination, there was no significant difference between Sorafenib and placebo recipients in the time to symptomatic progression (assessed using FHSI-8 criteria). The median time to progression (assessed by independent central review) was significantly longer in patients receiving Sorafenib than those receiving placebo (5.5 vs. 2.8 months), with an HR of 0.58(95% CI 0.44, 0.74; P Overall study design Screening and Pre-Treatment Period Investigator/ Co-Investigator/Study Coordinator • Medical history • Biopsy and review of pathology • Physical examination and vital signs • Review of previous or concurrent medications and procedures • Child-Pugh assessment • ECOG assessment • Lesion(s) measurement • Determination of study eligibility • Written, signed and date informed consent Laboratory investigations • Hematology: CBC, Differential • Serology: HBV, HCV, and HIV • The levels of the Bimarkers: c-KIT, Soluble VEGFR-2,-3. • Coagulation: platelets, PT, PTT, INR • Liver function tests • Serum pregnancy test (as appropriate) Radiological investigations • CT scan (or MRI) of the chest • CT scan (or MRI) of the abdomen • PET Scan Patient • Review of patient information leaflet Treatment period Baseline Visit - Day 1 Investigator/ Co-Investigator/Study Coordinator • Review of concomitant medications and therapies • Review of ECOG • Prescription of Sorafenib Patient • Start of the Sorafenib 6-8 weeks cycle Sorafenib Cycle Week 0-6/8 Laboratory investigations to be done on a weekly basis • Hematology: CBC, Differential • Serology: HBV, HCV, and HIV • Coagulation: platelets, PT, PTT, INR results of laboratory investigations on a weekly basis • See patients every other week Patient • Takes the appropriate dose of Sorafenib • Goes for blood test every week • Consult with the investigator/co-investigator every other week Visit after first Sorafenib cycle (Week 5 + 1 week) Investigator/ Co-Investigator/Study Coordinator • Physical examination • Review of concomitant medications and therapies • Child-Pugh re-assessment • ECOG re-assessment • Lesion(s) measurement • Recording of Adverse events Laboratory investigations • Hematology: CBC, Differential • Coagulation: platelets, PT, PTT, INR • Liver function tests Radiological investigations • CT scan (or MRI) of the abdomen Follow-up Visits (Every 3 months)* Investigator/ Co-Investigator/Study Coordinator • Physical examination • Review of concomitant medications and therapies • Child-Pugh re-assessment • ECOG re-assessment • Lesion(s) measurement • Recording of Adverse events Laboratory investigations • Hematology: CBC, Differential • Coagulation: platelets, PT, PTT, INR • The Bio-markers: c-KIT, VEGFR -2,-3 at week 12. • Liver function tests Radiological investigations • CT scan (or MRI) of the abdomen *The patient is going to be followed up in the basis of either stable disease or partial response or progression this based on radiological profession (which is assessed by RECIST). For those with progression other Biopsy will be taken and the tissue to be evaluated further.