Staging Strategy and Treatment for Patients With HCC PST 0, Child-Pugh A PST 0-2, Child-Pugh A-B PST > 2, Child-Pugh C Very early stage Early stage Intermediate stage Advanced stage Terminal stage Single < 2 cm Single or 3 nodules Multinodular, PST 0 Portal invasion, ≤ 3 cm, PST 0 N1, M1, PST 1-2 Single 3 nodules ≤ 3 cm Portal pressure/bilirubin   Increased Associated diseases Normal No Yes Resection Liver transplant RFA/PEI TACE Sorafenib Curative treatments Palliative treatments Symptomatic Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects.Semin Liver Dis. 2010;30(1):61-74 1

BCLC Staging and Treatment Strategy HCC PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D) Single < 2 cm Carcinoma in situ Single or 3 nodules Portal invasion, < 3 cm, PS 0 N1, M1, PS 1-2 Multinodular, PS 0 Single 3 nodules ≤ 3 cm Portal pressure/bilirubin With appropriate use of resection, transplantation, and local ablation, 5-year survival rates > 50% can be expected, rising to 70% with resection and liver transplantation. How does one choose between radiofrequency ablation and resection, given that there are data from a randomized trial showing no difference in overall survival between the 2 strategies?  If the tumor is < 2 cm in diameter, radiofrequency ablation can achieve a complete response rate of up to 98%, which is comparable with resection.   For tumors > 2 cm in diameter, in my experience, local ablation does not achieve a complete response rate of 100%, and as the tumor size increases, the response rate decreases, such that for a tumor of 4-5 cm in diameter, radiofrequency ablation achieves complete response in approximately 50% to 60% of cases. This does not compete well with resection. Therefore, resection remains a first-line treatment option for tumors > 2 cm in diameter.   Increased Associated diseases Normal No Yes Resection Liver transplantation RFA/PEI TACE Sorafenib Symptomatic (20%); survival < 3 mos Curative treatments (30%); 5-yr survival: 40%-70% RCTs (50%); 3-yr survival: 10%-40% Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10):698-711, by permission of Oxford University Press. 2

BCLC Staging System HCC Stage 0 Stage A-C Stage D PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D) Single < 2 cm Carcinoma in situ Single or 3 nodules Portal invasion, < 3 cm, PS 0 N1, M1, PS 1-2 Multinodular, PS 0 BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PST, performance status. Josep M. Llovet, MD:   The Barcelona system differentiates 5 stages of HCC disease. Stage 0 cases are chronic patients with small lesions, < 2 cm in size, with single tumors, and no evidence of vascular invasion or extrahepatic spread. These should be asymptomatic, Child-Pugh A class patients. Early-stage patients have a single tumor or 3 nodules < 3 cm according to the Milan criteria, and an ECOG performance score of 0, whereas intermediate-, advanced-, and terminal-stage patients have multinodular or disseminated disease. Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10):698-711, by permission of Oxford University Press. 3

Liver Transplantation for HCC: Milan Criteria (Stage 1 and 2) Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm + Absence of macroscopic vascular invasion, absence of extrahepatic spread HCC, hepatocellular carcinoma.   Josep M. Llovet, MD: For patients with liver dysfunction, such as portal hypertension or abnormal bilirubin or those with Child-Pugh class B disease, the first-line treatment option is liver transplantation. When used appropriately, transplantation has been associated with 5-year survival rates of 70% and a 5-year recurrence rates of < 15%. However, there is a shortage of donors in almost every country worldwide. Were this not the case, liver transplantation could be considered in patients with single tumors not > 5 cm or with up to 3 tumors < 3 cm that are not resectable. 5-yr survival with transplantation: ~ 70% 5-yr recurrent rates: < 15% Mazzaferro V, et al. N Engl J Med. 1996;334:693-699. Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.

Candidates for RFA/PEI Includes individuals who are not candidates for surgery Radiofrequency ablation generally preferred over percutaneous ethanol injection Necrotic effect more predictable across tumor sizes Meta-analyses suggest survival benefit with radiofrequency ablation vs percutaneous ethanol injection PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.   Josep M. Llovet, MD: A third option is percutaneous local ablation. This procedure is suitable for patients who are not candidates for surgery or liver transplantation. Radiofrequency ablation is considered the first-line treatment option for these patients based on data from 4 randomized, controlled trials that found this approach to be significantly more effective than percutaneous ethanol injection regarding local control of disease. In addition, meta-analyses suggest there may be an overall survival benefit in favor of radiofrequency ablation. Bruix J, et al. AASLD HCC guidelines. July 2010.

BCLC Staging and Treatment Strategy HCC PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D) Single < 2 cm Carcinoma in situ Single or 3 nodules Portal invasion, < 3 cm, PS 0 N1, M1, PS 1-2 Multinodular, PS 0 Single 3 nodules ≤ 3 cm Unresectable HCC Portal pressure/bilirubin BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PEI, percutaneous ethanol injection; PS, performance score; RCT, randomized controlled trial; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.   Josep M. Llovet, MD: For patients with intermediate-stage B disease who have multinodular tumors without symptoms, no portal invasion, extrahepatic spread, or lymph node involvement, the recommended treatment is transarterial chemoembolization. Surgery is not indicated in patients who have satellite lesions or portal hypertension. Other treatment options include internal radiation with yttrium 90, which is currently in phase III study. Early data are encouraging, but there is insufficient evidence on which to base a recommendation at this point. Increased Associated diseases Normal No Yes Resection Liver transplantation RFA/PEI TACE Sorafenib Symptomatic (20%); survival < 3 mos Curative treatments (30%); 5-yr survival: 40%-70% RCTs (50%); 3-yr survival: 10%-40% Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10):698-711, by permission of Oxford University Press. 6

Arterial Embolization for HCC Meta-analysis of 6 RCTs (2-Yr Survival) Random Effects Model, OR (95% CI) Author, Journal Yr Patients, n Lin, Gastroenterology 1988 63 GETCH, NEJM 1995 96 Bruix, Hepatology 1998 80 Pelletier, J Hepatol 1998 73 Lo, Hepatology 2002 79 Llovet, Lancet 2002 112 Overall 503 0.01 0.1 0.5 1 2 10 100 GETCH, Groupe d'Etude de Traitement du Carcinome Hepatocellular; HCC, hepatocellular carcinoma; OR, odds ratio; RCT, randomized controlled trial.   Josep M. Llovet, MD: Several randomized, controlled trials have been conducted in this patient population. The results of a meta-analysis published in 2003 found that chemoembolization was significantly more effective than best supportive care or suboptimal therapies, with a median survival of 20 months. Based on these data, both the European Association for the Study of the Liver and AASLD guidelines recommend chemoembolization as the first-line treatment option for this patient group. Z = -2.3 P = .017 Median survival: ~ 20 mos Favors Treatment Favors Control Llovet JM, et al. Hepatology. 2003;37:429-442.

Contraindications to TACE Extrahepatic tumor spread Lack of portal blood flow Portal vein thrombosis, portosystemic anastomoses or hepatofugal flow Advanced liver disease (Child-Pugh Class B or C) Clinical symptoms of end-stage cancer TACE, transarterial chemoembolization.   Josep M. Llovet, MD: Chemoembolization is not appropriate for all patients with intermediate-stage disease. For instance, extrahepatic spread, lack of portal blood flow, advanced disease, or clinical symptoms of end-stage cancer are contraindications for chemoembolization. Bruix J, et al. AASLD HCC guidelines. July 2010.

BCLC Staging and Treatment Strategy HCC PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D) Single < 2 cm Carcinoma in situ Single or 3 nodules Portal invasion, < 3 cm, PS 0 N1, M1, PS 1-2 Multinodular, PS 0 Single 3 nodules ≤ 3 cm Portal pressure/bilirubin BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PEI, percutaneous ethanol injection; PS, performance score; RCT, randomized controlled trial; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.   Josep M. Llovet, MD: Patients with advanced HCC meeting the criteria for BCLC stage C disease are candidates for systemic therapy with sorafenib. Increased Associated diseases Normal No Yes Resection Liver transplantation RFA/PEI TACE Sorafenib Symptomatic (20%); survival < 3 mos Curative treatments (30%); 5-yr survival: 40%-70% RCTs (50%); 3-yr survival: 10%-40% Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10):698-711, by permission of Oxford University Press. 9