Clinical Management of Hepatocellular Carcinoma: Current Options

1. Clinical Management of Hepatocellular Carcinoma: Current Options Abdel-Naser Elzouki, MBChB, DTM&H, MSc, MD, PhD, FRCP (UK) Professor & Sr. Consultant, Department of Medicine, Hamad Medical corporation, Doha, Qatar Email: nelzouki_1999@yahoo.com

2. Hepatocellular Carcinoma (HCC): Content Burden of HCC Diagnosis of HCC Staging of HCC Treatment of HCC: - Very early / early HCC - Intermediate HCC - Advanced HCC A Look to the future

3. HCC: Common and Increasing 694,000 deaths from liver cancer yearly worldwide[1] Age-adjusted US incidence has increased 2-fold from 1985-1998[2] - Expected to continue to increase until 2015-2020[3] American Cancer Society statistics for liver cancer in 2010[4] - Estimated new cases: 24,120 - Estimated deaths: 18,910 - 5th leading cause of cancer deaths in males HCC, hepatocellular carcinoma. � Jorge A. Marrero, MD, MS: Worldwide, HCC is a common cancer, with 694,000 deaths from liver cancer yearly worldwide. The American Cancer Society estimated that there were approximately 24,000�cases in the United�States in 2010. Hepatocellular carcinoma is the fifth leading cause of cancer death in males in the United States.HCC, hepatocellular carcinoma. � Jorge A. Marrero, MD, MS: Worldwide, HCC is a common cancer, with 694,000 deaths from liver cancer yearly worldwide. The American Cancer Society estimated that there were approximately 24,000�cases in the United�States in 2010. Hepatocellular carcinoma is the fifth leading cause of cancer death in males in the United States.

4. Evolving Guidelines for Clinical Management of Hepatocellular Carcinoma

5. Radiological Diagnosis of Hepatocellular Carcinoma in Patients With Cirrhosis: EASL/AASLD Guidelines

7. Ultrasound Diagnosis of Early-stage HCC in Patients with Cirrhosis. Meta-analysis

9. Staging Systems and Treatment Strategies in Hepatocellular Carcinoma

10. Variables Used in HCC Staging Systems BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of Liver Italian Program; CTP, Child-Turcotte-Pugh; CUPI, Chinese University Prognostic Index; GETCH, Groupe d'Etude de Traitement du Carcinome Hepatocellular; HCC, hepatocellular carcinoma; JIS, Japanese Integrated Staging System; TNM, tumor node metastasis. � Josep M. Llovet, MD: Several staging systems have been proposed for HCC. All systems include an assessment of tumor stage and most also include liver function. An exception is the tumor necrosis metastasis (TNM) system, which measures fibrosis rather than liver function. Only a few staging systems capture variables related to health status such as Eastern Cooperative Oncology Group (ECOG) performance or Karnofsky score. In fact, only the Barcelona Clinic Liver Cancer (BCLC) system includes ECOG performance score; the French Groupe d'Etude de Traitement du Carcinome Hepatocellular system includes Karnofsky score, and the Chinese University Prognostic Index (CUPI) system includes the presence of symptoms. � In the West, the staging systems that are most widely applied are the BCLC system and, less so, the TNM system. The Japanese Integrated Staging System score and the CUPI system are widely used in Asia. � For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Collections/2005%20JO%20Hepatitis%20Volume%202/Articles/Marrero-Hep-2005-04/Capsule.aspx �BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of Liver Italian Program; CTP, Child-Turcotte-Pugh; CUPI, Chinese University Prognostic Index; GETCH, Groupe d'Etude de Traitement du Carcinome Hepatocellular; HCC, hepatocellular carcinoma; JIS, Japanese Integrated Staging System; TNM, tumor node metastasis. � Josep M. Llovet, MD: Several staging systems have been proposed for HCC. All systems include an assessment of tumor stage and most also include liver function. An exception is the tumor necrosis metastasis (TNM) system, which measures fibrosis rather than liver function. Only a few staging systems capture variables related to health status such as Eastern Cooperative Oncology Group (ECOG) performance or Karnofsky score. In fact, only the Barcelona Clinic Liver Cancer (BCLC) system includes ECOG performance score; the French Groupe d'Etude de Traitement du Carcinome Hepatocellular system includes Karnofsky score, and the Chinese University Prognostic Index (CUPI) system includes the presence of symptoms. � In the West, the staging systems that are most widely applied are the BCLC system and, less so, the TNM system. The Japanese Integrated Staging System score and the CUPI system are widely used in Asia. � For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Collections/2005%20JO%20Hepatitis%20Volume%202/Articles/Marrero-Hep-2005-04/Capsule.aspx �

11. Comparison of HCC Staging Systems BCLC system uses key independent predictors of survival: Performance score, portal vein thrombosis, tumor diameter Compared with other staging systems in cohort study BCLC had best stratification of survival across all stages BCLC was only system to have independent predictive value on survival BCLC is the only staging system that stratifies patients into treatment groups BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma. � Josep M. Llovet, MD: Dr. Marrero led a comparative study of HCC staging systems in a cohort of American patients that identified the BCLC system as the best predictor of survival. In addition, the BCLC system is the only system that stratifies patients into treatment groups as well as provides prognostic stratification. � For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Collections/2005%20JO%20Hepatitis%20Volume%202/Articles/Marrero-Hep-2005-04/Capsule.aspx � BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma. � Josep M. Llovet, MD: Dr. Marrero led a comparative study of HCC staging systems in a cohort of American patients that identified the BCLC system as the best predictor of survival. In addition, the BCLC system is the only system that stratifies patients into treatment groups as well as provides prognostic stratification. � For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Collections/2005%20JO%20Hepatitis%20Volume%202/Articles/Marrero-Hep-2005-04/Capsule.aspx �

13. Therapies used in the management of HCC Surgery: - Resection - Liver transplantation Locoregional therapy: - Percutaneous ethanol injection - Radiofrequancy thermal ablation - Trans-Arterial Chemo-Emobilisation (TACE) - Trans-Arterial Radio-Emobilisation (TACE) Systemic therapy: - Targeted molecular therapy - Symptomatic treatment

14. Treatment of Very Early / Early Stage HCC

16. Early Stage Hepatocellular Carcinoma: Survival after Resection Is Influenced by Portal Hypertension and Bilirubin Best candidates for resection : Solitary HCC = 5 cm Child-Pugh A: Low portal hypertension Normal bilirubin

17. Liver Transplantation for HCC:Milan Criteria (Stage 1 and 2) HCC, hepatocellular carcinoma.HCC, hepatocellular carcinoma.

19. Patients with Cirrhosis and a HCC within Milan CriteriaLiver Resection or Transplantation

20. Treatment of Early HCC: the Initial Tumor Volume Predicts Survival After Percutaneous Ablation

21. Ablation of HCC Percutaneous ethanol injection (PEI) Cryotherapy Radiofrequency ablation (RFA)

22. Superiority of Resection vs Alcohol Injection in the Treatment of 2-5 cm HCC: A Nationwide Survey in Japan

25. Treatment of Intermediate Stage HCC

27. Treatment of HCC: Chemoembolization Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery Tumor receives most of its blood supply from the hepatic artery Injection into the hepatic artery spares most of the normal liver Embolization of the hepatic artery induces ischemic necrosis of tumor

29. Treatment of Advanced Stage HCC

31. Levels of Evidence in the Assessment of Benefits in the Treatment of �Advanced� HCC

32. Randomized Controlled Trials of Sorafenib in Advanced Hepatocellular Carcinoma

33. Treatment of Terminal Stage HCC

35. Tailoring Treatment According to the Clinical Stage of HCC

36. A Look To The Future

37. Molecular Therapies Under Evaluation for HCC in Phase III (2011) ASCO, American Society for Clinical Oncology; HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization. � Josep M. Llovet, MD: Trials emerging in this area are exciting. In 2011, at least 12 phase�III trials of molecular therapies are ongoing. In first-line therapy, several studies are evaluating the combination of sorafenib with another agent, for example, erlotinib. This tyrosine kinase inhibitor blocks epidermal growth factor receptor 1. In HCC, epidermal growth factor signaling is activated and is a factor in the pathogenesis of the disease. Sorafenib does not target epidermal growth factor signaling, and so the combination of these 2 agents may provide dual activity. � Another phase III trial is comparing sorafenib vs brivanib in the first-line setting. Brivanib is another novel tyrosine kinase inhibitor, which blocks several pathways, including vascular endothelial growth factor (VEGF) and FGF receptor. A trial comparing sorafenib with sunitinib was halted in 2010 for futility and toxicity, and sunitinib is no longer under investigation in the setting of advanced HCC. Sunitinib is a potent multikinase inhibitor that blocks several signaling cascades, some of which are also blocked by sorafenib. � Gefitinib, another multikinase inhibitor is also under evaluation as first-line therapy, and there are additional trials involving other types of therapies. One is evaluating sorafenib with or without internal radiation with yttrium�90. Another study is investigating first-line use of sorafenib plus or minus doxorubicin. This combination showed some efficacy in a phase�II study, although there is concern about potential cardiac toxicity. � For patients with progression on sorafenib, there are 3 trials of second-line therapy under way. One compares brivanib with placebo, and another involves everolimus, an mammalian target of rapamycin inhibitor that has shown some efficacy in HCC. Finally, there is the phase�III, placebo-controlled study of ramucirumab, a monoclonal antibody against VEGF receptor 2. � These phase�III trials provide a range of options to the patient. In addition, there are a number of phase�II studies ongoing, involving c-Met inhibitors, for instance, monoclonal antibodies against glypican�3 or hedgehog protein 90. ASCO, American Society for Clinical Oncology; HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization. � Josep M. Llovet, MD: Trials emerging in this area are exciting. In 2011, at least 12 phase�III trials of molecular therapies are ongoing. In first-line therapy, several studies are evaluating the combination of sorafenib with another agent, for example, erlotinib. This tyrosine kinase inhibitor blocks epidermal growth factor receptor 1. In HCC, epidermal growth factor signaling is activated and is a factor in the pathogenesis of the disease. Sorafenib does not target epidermal growth factor signaling, and so the combination of these 2 agents may provide dual activity. � Another phase III trial is comparing sorafenib vs brivanib in the first-line setting. Brivanib is another novel tyrosine kinase inhibitor, which blocks several pathways, including vascular endothelial growth factor (VEGF) and FGF receptor. A trial comparing sorafenib with sunitinib was halted in 2010 for futility and toxicity, and sunitinib is no longer under investigation in the setting of advanced HCC. Sunitinib is a potent multikinase inhibitor that blocks several signaling cascades, some of which are also blocked by sorafenib. � Gefitinib, another multikinase inhibitor is also under evaluation as first-line therapy, and there are additional trials involving other types of therapies. One is evaluating sorafenib with or without internal radiation with yttrium�90. Another study is investigating first-line use of sorafenib plus or minus doxorubicin. This combination showed some efficacy in a phase�II study, although there is concern about potential cardiac toxicity. � For patients with progression on sorafenib, there are 3 trials of second-line therapy under way. One compares brivanib with placebo, and another involves everolimus, an mammalian target of rapamycin inhibitor that has shown some efficacy in HCC. Finally, there is the phase�III, placebo-controlled study of ramucirumab, a monoclonal antibody against VEGF receptor 2. � These phase�III trials provide a range of options to the patient. In addition, there are a number of phase�II studies ongoing, involving c-Met inhibitors, for instance, monoclonal antibodies against glypican�3 or hedgehog protein 90.

38. Conclusion Burden of HCC is increasing Requirements for diagnosis depends on patient characteristics and tumor characteristics BCLC staging system recommended by US and European guidelines BCLC system provides framework for selection of treatment Many studies ongoing for treatment of HCC Jorge A. Marrero, MD, MS: This concludes the presentation. We have discussed the diagnosis of HCC with either biopsy or imaging, depending on the tumor characteristics on imaging. We have discussed staging systems and treatment options for patients with early-, intermediate- and advanced-stage HCC. Jorge A. Marrero, MD, MS: This concludes the presentation. We have discussed the diagnosis of HCC with either biopsy or imaging, depending on the tumor characteristics on imaging. We have discussed staging systems and treatment options for patients with early-, intermediate- and advanced-stage HCC.