Current Strategy for Staging and Treatment: The BCLC Update and Future Prospects

ABSTRACT

Staging and treatment indication are relevant topics in the management of patients with hepatocellular carcinoma (HCC) and for optimal results, they have to take into account liver function, tumor stage, and physical status. For any staging system to be meaningful it has to link staging with treatment indication; this should be based on robust scientific data. Currently, the sole proposal that serves both aims is the Barcelona Clinic Liver Cancer (BCLC) approach. It takes into account the relevant parameters of all important dimensions and divides patients into very early/early, intermediate, advanced, and end-stage. Early-stage HCC patients should be considered for potentially curative options such as resection, ablation, and transplantation. Patients at intermediate stage benefit from chemoembolization, whereas patients at an advanced stage, or who cannot benefit from options of higher priority, have sorafenib as the standard treatment. Finally, patients at end-stage should merely receive palliative care.

KEYWORDS

Hepatocellular carcinoma - staging - prognosis - treatment - survival

REFERENCES

• 1 Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases . Management of hepatocellular carcinoma.  Hepatology. 2005;  42(5) 1208-1236
• 2 Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors.  Gastroenterology. 2004;  127(5, Suppl 1) S35-S50
• 3 Llovet J M, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.  Semin Liver Dis. 1999;  19(3) 329-338
• 4 Primack A, Vogel C L, Kyalwazi S K, Ziegler J L, Simon R, Anthony P P. A staging system for hepatocellular carcinoma: prognostic factors in Ugandan patients.  Cancer. 1975;  35(5) 1357-1364
• 5 Nagasue N, Yukaya H, Hamada T, Hirose S, Kanashima R, Inokuchi K. The natural history of hepatocellular carcinoma. A study of 100 untreated cases.  Cancer. 1984;  54(7) 1461-1465
• 6 Chlebowski R T, Tong M, Weissman J et al.. Hepatocellular carcinoma. Diagnostic and prognostic features in North American patients.  Cancer. 1984;  53(12) 2701-2706
• 7 Attali P, Prod'Homme S, Pelletier G et al.. Prognostic factors in patients with hepatocellular carcinoma. Attempts for the selection of patients with prolonged survival.  Cancer. 1987;  59(12) 2108-2111
• 8 Falkson G, Cnaan A, Schutt A J, Ryan L M, Falkson H C. Prognostic factors for survival in hepatocellular carcinoma.  Cancer Res. 1988;  48(24 Pt 1) 7314-7318
• 9 Calvet X, Bruix J, Brú C et al.. Natural history of hepatocellular carcinoma in Spain. Five year's experience in 249 cases.  J Hepatol. 1990;  10(3) 311-317
• 10 Sørensen J B, Klee M, Palshof T, Hansen H H. Performance status assessment in cancer patients. An inter-observer variability study.  Br J Cancer. 1993;  67(4) 773-775
• 11 O'Leary J G, Lepe R, Davis G L. Indications for liver transplantation.  Gastroenterology. 2008;  134(6) 1764-1776
• 12 Okuda K, Ohtsuki T, Obata H et al.. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients.  Cancer. 1985;  56(4) 918-928
• 13 Calvet X, Bruix J, Ginés P et al.. Prognostic factors of hepatocellular carcinoma in the west: a multivariate analysis in 206 patients.  Hepatology. 1990;  12(4 Pt 1) 753-760
• 14 Stuart K E, Anand A J, Jenkins R L. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival.  Cancer. 1996;  77(11) 2217-2222
• 15 A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators.  Hepatology. 1998;  28(3) 751-755
• 16 Chevret S, Trinchet J C, Mathieu D, Rached A A, Beaugrand M, Chastang C. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire.  J Hepatol. 1999;  31(1) 133-141
• 17 Villa E, Moles A, Ferretti I et al.. Natural history of inoperable hepatocellular carcinoma: estrogen receptors' status in the tumor is the strongest prognostic factor for survival.  Hepatology. 2000;  32(2) 233-238
• 18 Leung T W, Tang A M, Zee B et al.. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients.  Cancer. 2002;  94(6) 1760-1769
• 19 Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score).  J Gastroenterol. 2003;  38(3) 207-215
• 20 Omagari K, Honda S, Kadokawa Y et al.. Preliminary analysis of a newly proposed prognostic scoring system (SLiDe score) for hepatocellular carcinoma.  J Gastroenterol Hepatol. 2004;  19(7) 805-811
• 21 Tateishi R, Yoshida H, Shiina S et al.. Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients.  Gut. 2005;  54(3) 419-425
• 22 Bonnetain F, Paoletti X, Collette S et al.. Quality of life as a prognostic factor of overall survival in patients with advanced hepatocellular carcinoma: results from two French clinical trials.  Qual Life Res. 2008;  17(6) 831-843
• 23 Schag C C, Heinrich R L, Ganz P A. Karnofsky performance status revisited: reliability, validity, and guidelines.  J Clin Oncol. 1984;  2(3) 187-193
• 24 Castells A, Bruix J, Brú C et al.. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients.  Gastroenterology. 1995;  109(3) 917-922
• 25 Bruix J, Llovet J M, Castells A et al.. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution.  Hepatology. 1998;  27(6) 1578-1583
• 26 Llovet J M, Bustamante J, Castells A et al.. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials.  Hepatology. 1999;  29(1) 62-67
• 27 Beaugrand M, Sala M, Degos F et al.. Treatment of advanced hepatocellular carcinoma by seocalcitol (a vit D analogue): an International randomized double-blind placebo-controlled study in 747 patients.  J Hepatol. 2005;  42 17A
• 28 Llovet J M, Ricci S, Mazzaferro V SHARP Investigators Study Group et al. Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008;  359(4) 378-390
• 29 Cheng A L, Kang Y K, Chen Z et al.. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.  Lancet Oncol. 2009;  10(1) 25-34
• 30 Marrero J A, Fontana R J, Barrat A et al.. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.  Hepatology. 2005;  41(4) 707-716
• 31 Cillo U, Bassanello M, Vitale A et al.. The critical issue of hepatocellular carcinoma prognostic classification: which is the best tool available?.  J Hepatol. 2004;  40(1) 124-131
• 32 Llovet J M, Di Bisceglie A M, Bruix J Panel of Experts in HCC-Design Clinical Trials et al. Design and endpoints of clinical trials in hepatocellular carcinoma.  J Natl Cancer Inst. 2008;  100(10) 698-711
• 33 Forner A, Ayuso C, Isabel Real M et al.. [Diagnosis and treatment of hepatocellular carcinoma].  Med Clin (Barc). 2009;  132(7) 272-287
• 34 Jelic S. ESMO Guidelines Working Group . Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.  Ann Oncol. 2009;  20(Suppl 4) 41-45
• 35 Ikai I, Arii S, Kojiro M et al.. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey.  Cancer. 2004;  101(4) 796-802
• 36 Imamura H, Matsuyama Y, Tanaka E et al.. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.  J Hepatol. 2003;  38(2) 200-207
• 37 Todo S, Furukawa H. Japanese Study Group on Organ Transplantation . Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan.  Ann Surg. 2004;  240(3) 451-459, discussion 459–461
• 38 Takayasu K, Arii S, Ikai I Liver Cancer Study Group of Japan et al. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients.  Gastroenterology. 2006;  131(2) 461-469
• 39 Livraghi T, Giorgio A, Marin G et al.. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.  Radiology. 1995;  197(1) 101-108
• 40 Zhu A X, Sahani D V, Duda D G et al.. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.  J Clin Oncol. 2009;  27(18) 3027-3035
• 41 N'Kontchou G, Mahamoudi A, Aout M et al.. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis.  Hepatology. 2009;  50(5) 1475-1483
• 42 Kitai S, Kudo M, Minami Y et al.. Validation of a new prognostic staging system for hepatocellular carcinoma: a comparison of the biomarker-combined Japan Integrated Staging Score, the conventional Japan Integrated Staging Score and the BALAD Score.  Oncology. 2008;  75(Suppl 1) 83-90
• 43 Cammà C, Di Marco V, Cabibbo G et al.. Survival of patients with hepatocellular carcinoma in cirrhosis: a comparison of BCLC, CLIP and GRETCH staging systems.  Aliment Pharmacol Ther. 2008;  28(1) 62-75
• 44 Cabibbo G, Enea M, Attanasio M et al.. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma.  Hepatology. , In press
• 45 Llovet J, Peña C, Shan M, Lathia C, Bruix J. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma: results from the randomized phase III SHARP trial.  J Hepatol. 2009;  50(Suppl 1) S385
• 46 Pugh R N, Murray-Lyon I M, Dawson J L, Pietroni M C, Williams R. Transection of the oesophagus for bleeding oesophageal varices.  Br J Surg. 1973;  60(8) 646-649
• 47 Kamath P S, Wiesner R H, Malinchoc M et al.. A model to predict survival in patients with end-stage liver disease.  Hepatology. 2001;  33(2) 464-470
• 48 Huo T I, Lin H C, Hsia C Y et al.. The model for end-stage liver disease based cancer staging systems are better prognostic models for hepatocellular carcinoma: a prospective sequential survey.  Am J Gastroenterol. 2007;  102(9) 1920-1930
• 49 Greene F L, Page D L, Fleming I D et al.. AJCC. Cancer staging handbook. TNM Liver classification. In: American Joint Committee (AJCC) on Cancer Staging Manual. 6th ed New York; Springer-Verlag 2002: 131-144
• 50 Toso C, Asthana S, Bigam D L, Shapiro A M, Kneteman N M. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database.  Hepatology. 2009;  49(3) 832-838
• 51 Bruix J, Castells A, Bosch J et al.. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure.  Gastroenterology. 1996;  111(4) 1018-1022
• 52 Ishizawa T, Hasegawa K, Aoki T et al.. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma.  Gastroenterology. 2008;  134(7) 1908-1916
• 53 Sala M, Fuster J, Llovet J M Barcelona Clinic Liver Cancer (BCLC) Group et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation.  Liver Transpl. 2004;  10(10) 1294-1300
• 54 Wayne J D, Lauwers G Y, Ikai I et al.. Preoperative predictors of survival after resection of small hepatocellular carcinomas.  Ann Surg. 2002;  235(5) 722-730, discussion 730–731
• 55 Vauthey J N, Lauwers G Y, Esnaola N F et al.. Simplified staging for hepatocellular carcinoma.  J Clin Oncol. 2002;  20(6) 1527-1536
• 56 Pawlik T M, Delman K A, Vauthey J N et al.. Tumor size predicts vascular invasion and histologic grade: Implications for selection of surgical treatment for hepatocellular carcinoma.  Liver Transpl. 2005;  11(9) 1086-1092
• 57 Poon R T, Fan S T. Evaluation of the new AJCC/UICC staging system for hepatocellular carcinoma after hepatic resection in Chinese patients.  Surg Oncol Clin N Am. 2003;  12(1) 35-50, viii
• 58 Llovet J M, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.  Hepatology. 1999;  30(6) 1434-1440
• 59 Yao F Y, Bass N M, Ascher N L, Roberts J P. Liver transplantation for hepatocellular carcinoma: lessons from the first year under the Model of End-Stage Liver Disease (MELD) organ allocation policy.  Liver Transpl. 2004;  10(5) 621-630
• 60 Volk M L, Choi H, Warren G J, Sonnenday C J, Marrero J A, Heisler M. Geographic variation in organ availability is responsible for disparities in liver transplantation between Hispanics and Caucasians.  Am J Transplant. 2009;  9(9) 2113-2118
• 61 Freeman R B, Edwards E B, Harper A M. Waiting list removal rates among patients with chronic and malignant liver diseases.  Am J Transplant. 2006;  6(6) 1416-1421
• 62 Mazzaferro V, Llovet J M, Miceli R Metroticket Investigator Study Group et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.  Lancet Oncol. 2009;  10(1) 35-43
• 63 Llovet J M, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma.  Semin Liver Dis. 2005;  25(2) 181-200
• 64 Yao F Y, Bass N M, Nikolai B et al.. A follow-up analysis of the pattern and predictors of dropout from the waiting list for liver transplantation in patients with hepatocellular carcinoma: implications for the current organ allocation policy.  Liver Transpl. 2003;  9(7) 684-692
• 65 Sala M, Llovet J M, Vilana R Barcelona Clínic Liver Cancer Group et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.  Hepatology. 2004;  40(6) 1352-1360
• 66 Cammà C, Di Marco V, Orlando A Unità Interdipartimentale Neoplasie Epatiche (U.I.N.E) Group et al. Treatment of hepatocellular carcinoma in compensated cirrhosis with radio-frequency thermal ablation (RFTA): a prospective study.  J Hepatol. 2005;  42(4) 535-540
• 67 Hanahan D, Weinberg R A. The hallmarks of cancer.  Cell. 2000;  100(1) 57-70
• 68 Lee J S, Chu I S, Heo J et al.. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling.  Hepatology. 2004;  40(3) 667-676
• 69 Boyault S, Rickman D S, de Reyniès A et al.. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.  Hepatology. 2007;  45(1) 42-52
• 70 Chiang D Y, Villanueva A, Hoshida Y et al.. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.  Cancer Res. 2008;  68(16) 6779-6788
• 71 Hoshida Y, Nijman S M, Kobayashi M et al.. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.  Cancer Res. 2009;  69(18) 7385-7392
• 72 Hoshida Y, Villanueva A, Kobayashi M et al.. Gene expression in fixed tissues and outcome in hepatocellular carcinoma.  N Engl J Med. 2008;  359(19) 1995-2004
• 73 Takayama T, Makuuchi M, Hirohashi S et al.. Early hepatocellular carcinoma as an entity with a high rate of surgical cure.  Hepatology. 1998;  28(5) 1241-1246
• 74 Kojiro M, Roskams T. Early hepatocellular carcinoma and dysplastic nodules.  Semin Liver Dis. 2005;  25(2) 133-142
• 75 Forner A, Vilana R, Ayuso C et al.. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.  Hepatology. 2008;  47(1) 97-104
• 76 Llovet J M, Chen Y, Wurmbach E et al.. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis.  Gastroenterology. 2006;  131(6) 1758-1767
• 77 Mazzaferro V, Regalia E, Doci R et al.. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.  N Engl J Med. 1996;  334(11) 693-699
• 78 Lencioni R A, Allgaier H P, Cioni D et al.. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection.  Radiology. 2003;  228(1) 235-240
• 79 Lencioni R, Cioni D, Crocetti L et al.. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation.  Radiology. 2005;  234(3) 961-967
• 80 Llovet J M, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.  Hepatology. 2003;  37(2) 429-442
• 81 Llovet J M, Real M I, Montaña X Barcelona Liver Cancer Group et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.  Lancet. 2002;  359(9319) 1734-1739
• 82 Lo C M, Ngan H, Tso W K et al.. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.  Hepatology. 2002;  35(5) 1164-1171
• 83 Bruix J, Salo J, Bru C et al.. Spontaneous regression of hepatocellular carcinoma.  Eur J Gastroenterol Hepatol. 1992;  4(4) 329-333
• 84 Livraghi T, Meloni F, Di Stasi M et al.. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice?.  Hepatology. 2008;  47(1) 82-89
• 85 Huang G T, Lee P H, Tsang Y M et al.. Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study.  Ann Surg. 2005;  242(1) 36-42
• 86 Chen M S, Li J Q, Zheng Y et al.. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma.  Ann Surg. 2006;  243(3) 321-328
• 87 Vivarelli M, Guglielmi A, Ruzzenente A et al.. Surgical resection versus percutaneous radiofrequency ablation in the treatment of hepatocellular carcinoma on cirrhotic liver.  Ann Surg. 2004;  240(1) 102-107
• 88 Shiina S, Teratani T, Obi S et al.. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma.  Gastroenterology. 2005;  129(1) 122-130
• 89 Lin S M, Lin C J, Lin C C, Hsu C W, Chen Y C. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.  Gut. 2005;  54(8) 1151-1156
• 90 Bismuth H, Majno P E, Adam R. Liver transplantation for hepatocellular carcinoma.  Semin Liver Dis. 1999;  19(3) 311-322
• 91 Jonas S, Bechstein W O, Steinmüller T et al.. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.  Hepatology. 2001;  33(5) 1080-1086
• 92 Navasa M, Bruix J. Multifaceted perspective of the waiting list for liver transplantation: the value of pharmacokinetic models.  Hepatology. 2010;  51(1) 12-15
• 93 Yao F Y, Ferrell L, Bass N M et al.. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.  Hepatology. 2001;  33(6) 1394-1403
• 94 Yao F Y, Xiao L, Bass N M, Kerlan R, Ascher N L, Roberts J P. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.  Am J Transplant. 2007;  7(11) 2587-2596
• 95 Herrero J I, Sangro B, Pardo F et al.. Liver transplantation in patients with hepatocellular carcinoma across Milan criteria.  Liver Transpl. 2008;  14(3) 272-278
• 96 Toso C, Trotter J, Wei A et al.. Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma.  Liver Transpl. 2008;  14(8) 1107-1115
• 97 Duffy J P, Vardanian A, Benjamin E et al.. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA.  Ann Surg. 2007;  246(3) 502-509, discussion 509–511
• 98 Majno P E, Adam R, Bismuth H et al.. Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis.  Ann Surg. 1997;  226(6) 688-701, discussion 701–703
• 99 Otto G, Herber S, Heise M et al.. Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma.  Liver Transpl. 2006;  12(8) 1260-1267
• 100 Yao F Y, Kerlan Jr R K, Hirose R et al.. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis.  Hepatology. 2008;  48(3) 819-827
• 101 Liaw Y F, Sung J J, Chow W C Cirrhosis Asian Lamivudine Multicentre Study Group et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease.  N Engl J Med. 2004;  351(15) 1521-1531
• 102 Mazzaferro V, Romito R, Schiavo M HCC Italian Task Force et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis.  Hepatology. 2006;  44(6) 1543-1554
• 103 Roayaie S, Blume I N, Thung S N et al.. A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma.  Gastroenterology. 2009;  137(3) 850-855
• 104 Cho Y K, Kim J K, Kim M Y, Rhim H, Han J K. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies.  Hepatology. 2009;  49(2) 453-459
• 105 Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials.  Am J Gastroenterol. 2009;  104(2) 514-524
• 106 Zhang L, Zhu H, Jin C et al.. High-intensity focused ultrasound (HIFU): effective and safe therapy for hepatocellular carcinoma adjacent to major hepatic veins.  Eur Radiol. 2009;  19(2) 437-445
• 107 Kamada K, Kitamoto M, Aikata H et al.. Combination of transcatheter arterial chemoembolization using cisplatin-lipiodol suspension and percutaneous ethanol injection for treatment of advanced small hepatocellular carcinoma.  Am J Surg. 2002;  184(3) 284-290
• 108 Lencioni R, Crocetti L, Petruzzi P et al.. Doxorubicin-eluting bead-enhanced radiofrequency ablation of hepatocellular carcinoma: a pilot clinical study.  J Hepatol. 2008;  49(2) 217-222
• 109 Shiraishi R, Yamasaki T, Saeki I et al.. Pilot study of combination therapy with transcatheter arterial infusion chemotherapy using iodized oil and percutaneous radiofrequency ablation during occlusion of hepatic blood flow for hepatocellular carcinoma.  Am J Clin Oncol. 2008;  31(4) 311-316
• 110 Bruix J, Sala M, Llovet J M. Chemoembolization for hepatocellular carcinoma.  Gastroenterology. 2004;  127(5, Suppl 1) S179-S188
• 111 Varela M, Real M I, Burrel M et al.. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics.  J Hepatol. 2007;  46(3) 474-481
• 112 Malagari K, Chatzimichael K, Alexopoulou E et al.. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients.  Cardiovasc Intervent Radiol. 2008;  31(2) 269-280
• 113 Poon R T, Tso W K, Pang R W et al.. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead.  Clin Gastroenterol Hepatol. 2007;  5(9) 1100-1108
• 114 Sangro B, Bilbao J I, Boan J et al.. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma.  Int J Radiat Oncol Biol Phys. 2006;  66(3) 792-800
• 115 Kulik L M, Carr B I, Mulcahy M F et al.. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis.  Hepatology. 2008;  47(1) 71-81
• 116 Salem R, Lewandowski R J, Mulcahy M F et al.. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.  Gastroenterology. 2009;  , September 18 (Epub ahead of print)
• 117 Lopez P M, Villanueva A, Llovet J M. Systematic review: evidence-based management of hepatocellular carcinoma—an updated analysis of randomized controlled trials.  Aliment Pharmacol Ther. 2006;  23(11) 1535-1547
• 118 Yeo W, Mok T S, Zee B et al.. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma.  J Natl Cancer Inst. 2005;  97(20) 1532-1538
• 119 Llovet J M, Bruix J. Molecular targeted therapies in hepatocellular carcinoma.  Hepatology. 2008;  48(4) 1312-1327
• 120 Schoenleber S J, Kurtz D M, Talwalkar J A, Roberts L R, Gores G J. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis.  Br J Cancer. 2009;  100(9) 1385-1392
• 121 Liu L, Cao Y, Chen C et al.. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.  Cancer Res. 2006;  66(24) 11851-11858
• 122 Wilhelm S, Carter C, Lynch M et al.. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer.  Nat Rev Drug Discov. 2006;  5(10) 835-844
• 123 Abou-Alfa G, Amadori D, Santoro A et al.. Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis?.  J Clin Oncol. 2008;  26(Suppl) A4518
• 124 Bruix J, Llovet J M. Major achievements in hepatocellular carcinoma.  Lancet. 2009;  373(9664) 614-616
• 125 Therasse P, Arbuck S G, Eisenhauer E A et al.. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.  J Natl Cancer Inst. 2000;  92(3) 205-216