Heterogeneity of Patients with Intermediate (BCLC B) Hepatocellular Carcinoma: Proposal for a Subclassification to Facilitate Treatment Decisions

Luigi Bolondi; Andrew Burroughs; Jean-François Dufour; Peter R. Galle; Vincenzo Mazzaferro; Fabio Piscaglia; Jean Luc Raoul; Bruno Sangro

doi:10.1055/s-0032-1329906

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2012; 32(04): 348-359
DOI: 10.1055/s-0032-1329906

Editors' Choice

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Heterogeneity of Patients with Intermediate (BCLC B) Hepatocellular Carcinoma: Proposal for a Subclassification to Facilitate Treatment Decisions

Luigi Bolondi

¹Division of Internal Medicine, Department of Digestive Disease and Internal Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy

,

Andrew Burroughs

²The Royal Free Sheila Sherlock Liver Centre, The Royal Free Hospital and UCL Institute for Liver and Digestive Health, UCL London, London, UK

,

Jean-François Dufour

³University Clinic for Visceral Surgery and Medicine, Inselspital, Bern and Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland

,

Peter R. Galle

⁴University Medical Center, I. Medical Department, Johannes Gutenberg University, Mainz, Germany

,

Vincenzo Mazzaferro

⁵Istituto Nazionale Tumori (National Cancer Institute) IRCCS Foundation, Milan, Italy

,

Fabio Piscaglia

¹Division of Internal Medicine, Department of Digestive Disease and Internal Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy

,

Jean Luc Raoul

⁶Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France

,

Bruno Sangro

⁷Liver Unit, Clinica Universidad de Navarra, and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Pamplona, Spain

› Institutsangaben

Abstract

The intermediate stage of hepatocellular carcinoma (HCC) comprises a highly heterogeneous patient population and therefore poses unique challenges for therapeutic management, different from the early and advanced stages. Patients classified as having intermediate HCC by the Barcelona Clinic Liver Cancer (BCLC) staging system present with varying tumor burden and liver function. Transarterial chemoembolization (TACE) is currently recommended as the standard of care in this setting, but there is considerable variation in the clinical benefit patients derive from this treatment.

In April 2012, a panel of experts convened to discuss unresolved issues surrounding the application of current guidelines when managing patients with intermediate HCC. The meeting explored the applicability of a subclassification system for intermediate HCC patients to tailor therapeutic interventions based on the evidence available to date and expert opinion. The present report summarizes the proposal of the expert panel: four substages of intermediate HCC patients, B1 to B4.

Keywords

hepatocellular carcinoma - sorafenib - transarterial chemoembolization - radioembolization - Barcelona Clinic Liver Cancer

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Referenzen

References
1 National Cancer Institute. SEER Stat Fact Sheets: Liver and Intrahepatic Bile Duct. Available at: http://seer.cancer.gov/statfacts/html/livibd.html . Accessed August 24, 2012.
2 Berrino F, De Angelis R, Sant M , et al; EUROCARE Working group. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995-99: results of the EUROCARE-4 study. Lancet Oncol 2007; 8 (9) 773-783
3 Verdecchia A, Francisci S, Brenner H , et al; EUROCARE-4 Working Group. Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol 2007; 8 (9) 784-796
4 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379 (9822) 1245-1255
5 Marrero JA, Fontana RJ, Barrat A , et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005; 41 (4) 707-716
6 Cillo U, Vitale A, Grigoletto F , et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol 2006; 44 (4) 723-731
7 Guglielmi A, Ruzzenente A, Pachera S , et al. Comparison of seven staging systems in cirrhotic patients with hepatocellular carcinoma in a cohort of patients who underwent radiofrequency ablation with complete response. Am J Gastroenterol 2008; 103 (3) 597-604
8 Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53 (3) 1020-1022
9 European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56 (4) 908-943
10 Schwartz M, Roayaie S, Konstadoulakis M. Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol 2007; 4 (7) 424-432
11 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362 (9399) 1907-1917
12 Clark HP, Carson WF, Kavanagh PV, Ho CP, Shen P, Zagoria RJ. Staging and current treatment of hepatocellular carcinoma. Radiographics 2005; 25 (Suppl. 01) S3-S23
13 Llovet JM. Treatment of Hepatocellular Carcinoma. Curr Treat Options Gastroenterol 2004; 7 (6) 431-441
14 Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37 (2) 429-442
15 Piscaglia F, Bolondi L. The intermediate hepatocellular carcinoma stage: Should treatment be expanded?. Dig Liver Dis 2010; 42 (Suppl. 03) S258-S263
16 D'Avola D, Iñarrairaegui M, Pardo F , et al. Prognosis of hepatocellular carcinoma in relation to treatment across BCLC stages. Ann Surg Oncol 2011; 18 (7) 1964-1971
17 Marelli L, Stigliano R, Triantos C , et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007; 30 (1) 6-25
18 Tsochatzis EA, Germani G, Burroughs AK. Transarterial chemoembolization, transarterial chemotherapy, and intra-arterial chemotherapy for hepatocellular carcinoma treatment. Semin Oncol 2010; 37 (2) 89-93
19 Terzi E, Golfieri R, Piscaglia F , et al. Response rate and clinical outcome of HCC after first and repeated cTACE performed “on demand”. J Hepatol 2012; ; Epub ahead of print
20 Takayasu K, Arii S, Kudo M , et al. Superselective transarterial chemoembolization for hepatocellular carcinoma. Validation of treatment algorithm proposed by Japanese guidelines. J Hepatol 2012; 56 (4) 886-892
21 Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011; (3) CD004787
22 Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30 (1) 52-60
23 Gillmore R, Stuart S, Kirkwood A , et al. EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization. J Hepatol 2011; 55 (6) 1309-1316
24 Cammà C, Schepis F, Orlando A , et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002; 224 (1) 47-54
25 Raoul JL, Sangro B, Forner A , et al. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev 2011; 37 (3) 212-220
26 Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology 2010; 52 (2) 762-773
27 Meyer T, Roughton M, Yu D , et al. A randomized phase II/III trial of three weekly cisplatin based transarterial chemoembolization (TACE) versus embolization (TAE) alone for hepatocellular cancer (HCC) [Abstract 4025]. J Clin Oncol 2010; 28 (suppl): 15s
28 Llovet JM, Real MI, Montaña X , et al; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359 (9319) 1734-1739
29 Golfieri R, Cappelli A, Cucchetti A , et al. Efficacy of selective transarterial chemoembolization in inducing tumor necrosis in small (<5 cm) hepatocellular carcinomas. Hepatology 2011; 53 (5) 1580-1589
30 Varela M, Real MI, Burrel M , et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46 (3) 474-481
31 Lammer J, Malagari K, Vogl T , et al; PRECISION V Investigators. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010; 33 (1) 41-52
32 Malagari K, Pomoni M, Kelekis A , et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 2010; 33 (3) 541-551
33 Grieco A, Marcoccia S, Miele L , et al. Transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma in cirrhotics: functional hepatic reserve and survival. Hepatogastroenterology 2003; 50 (49) 207-212
34 Saccheri S, Lovaria A, Sangiovanni A , et al. Segmental transcatheter arterial chemoembolization treatment in patients with cirrhosis and inoperable hepatocellular carcinomas. J Vasc Interv Radiol 2002; 13 (10) 995-999
35 Lu W, Li Y, He X, Chen Y. Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with cirrhosis: evaluation of two kinds of dosages of anticancer drugs and analysis of prognostic factors. Hepatogastroenterology 2003; 50 (54) 2079-2083
36 Ikeda K, Kumada H, Saitoh S, Arase Y, Chayama K. Effect of repeated transcatheter arterial embolization on the survival time in patients with hepatocellular carcinoma. An analysis by the Cox proportional hazard model. Cancer 1991; 68 (10) 2150-2154
37 Herber SC, Otto G, Schneider J , et al. Transarterial chemoembolization in patients not eligible for liver transplantation: single-center results. AJR Am J Roentgenol 2008; 190 (4) 1035-1042
38 Ernst O, Sergent G, Mizrahi D, Delemazure O, Paris JC, L'Herminé C. Treatment of hepatocellular carcinoma by transcatheter arterial chemoembolization: comparison of planned periodic chemoembolization and chemoembolization based on tumor response. AJR Am J Roentgenol 1999; 172 (1) 59-64
39 Forner A, Ayuso C, Varela M , et al. Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?. Cancer 2009; 115 (3) 616-623
40 Llovet JM, Ricci S, Mazzaferro V , et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (4) 378-390
41 Kulik LM, Carr BI, Mulcahy MF , et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008; 47 (1) 71-81
42 Hsu CY, Hsia CY, Huang YH , et al. Comparison of surgical resection and transarterial chemoembolization for hepatocellular carcinoma beyond the Milan criteria: a propensity score analysis. Ann Surg Oncol 2012; 19 (3) 842-849
43 Zhang ZM, Guo JX, Zhang ZC, Jiang N, Zhang ZY, Pan LJ. Therapeutic options for intermediate-advanced hepatocellular carcinoma. World J Gastroenterol 2011; 17 (13) 1685-1689
44 Silva MF, Sherman M. Criteria for liver transplantation for HCC: what should the limits be?. J Hepatol 2011; 55 (5) 1137-1147
45 Mazzaferro V, Llovet JM, Miceli R , et al; Metroticket Investigator Study Group. 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
46 Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A. OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012; 13 (1) e11-e22
47 Jelic S, Sotiropoulos GC. ESMO Guidelines Working Group. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 05) v59-v64
48 Ravaioli M, Grazi GL, Piscaglia F , et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008; 8 (12) 2547-2557
49 Vibert E, Azoulay D, Hoti E , et al. Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor. Am J Transplant 2010; 10 (1) 129-137
50 Yao FY, Kerlan Jr RK, 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
51 Llovet JM, Ricci S, Mazzaferro V , et al. Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a Phase III randomized placebo-controlled trial (SHARP trial). Paper presented at: American Society of Clinical Oncology Annual Meeting; June 1–5, 2007; Chicago, IL
52 Cheng AL, Kang YK, 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
53 Bruix J, Raoul JL, Sherman M , et al. Efficacy and safety of sorafenib in patients with hepatocellular carcinoma (HCC): Subanalysis of SHARP trial based on Barcelona Clinic Liver Cancer (BCLC) stage. J Hepatol 2009; 50 (Suppl. 01) S28-S29
54 Lencioni R, Venook AP, Marrero JA , et al. Second Interim Results of the GIDEON (Global Investigation of Therapeutic DEcisions in HCC and of Its Treatment With SorafeNib) Study - Barcelona-Clinic Liver Cancer (BCLC) Stage Subgroup Analysis. Abs 6500. Abstract presented at: The European Multidisciplinary Cancer Congress; September 23–27, 2011; Stockholm, Sweden
55 Marrero JA, Lencioni R, Kudo M , et al. Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON) second interim analysis in more than 1,500 patients: Clinical findings in patients with liver dysfunction. J Clin Oncol 2011; 29: 4001
56 Iavarone M, Cabibbo G, Piscaglia F , et al; SOFIA (SOraFenib Italian Assessment) study group. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology 2011; 54 (6) 2055-2063
57 Piscaglia F, Trimarchi C, Terzi E , et al. The rate of HCC patients in Child-Pugh B untreatable with effective strategies according to AASLD guidelines increases with the progression of specific Child-Pugh score. Hepatology 2010; 52: 1168A
58 Burrel M, Reig M, Forner A , et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using drug eluting beads. Implications for clinical practice and trial design. J Hepatol 2012; 56 (6) 1330-1335
59 Salem R, Lewandowski RJ, Mulcahy MF , et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010; 138 (1) 52-64
60 Hilgard P, Hamami M, Fouly AE , et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 2010; 52 (5) 1741-1749
61 Sangro B, Carpanese L, Cianni R , et al; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011; 54 (3) 868-878
62 Sangro B, Iñarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol 2012; 56 (2) 464-473
63 Andreana L, Isgrò G, Marelli L , et al. Treatment of hepatocellular carcinoma (HCC) by intra-arterial infusion of radio-emitter compounds: trans-arterial radio-embolisation of HCC. Cancer Treat Rev 2012; 38 (6) 641-649
64 Iñarrairaegui M, Pardo F, Bilbao JI , et al. Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. Eur J Surg Oncol 2012; 38 (7) 594-601
65 Lewandowski RJ, Kulik LM, Riaz A , et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009; 9 (8) 1920-1928
66 Lencioni R. Management of hepatocellular carcinoma with transarterial chemoembolization in the era of systemic targeted therapy. Crit Rev Oncol Hematol 2012; 83 (2) 216-224
67 Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004; 10 (19) 2878-2882
68 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407 (6801) 249-257
69 Dufour JF, Hoppe H, Heim MH , et al. Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist 2010; 15 (11) 1198-1204
70 Chung Y, Kim B, Chen C , et al. Study in Asia of the combination of transcatheter arterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma (HCC) trial (START): Second interim safety and efficacy analysis. J Clin Oncol 2010; 28: 4026
71 Lencioni R, Llovet JM, Han G , et al. Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial. . [Abstract LBA154] J Clin Oncol 2012; 30 (suppl)
72 Akamatsu M, Yoshida H, Obi S , et al. Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial. Liver Int 2004; 24 (6) 625-629
73 Bartolozzi C, Lencioni R, Caramella D , et al. Treatment of large HCC: transcatheter arterial chemoembolization combined with percutaneous ethanol injection versus repeated transcatheter arterial chemoembolization. Radiology 1995; 197 (3) 812-818
74 Becker G, Soezgen T, Olschewski M, Laubenberger J, Blum HE, Allgaier HP. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol 2005; 11 (39) 6104-6109
75 Marelli L, Stigliano R, Triantos C , et al. Treatment outcomes for hepatocellular carcinoma using chemoembolization in combination with other therapies. Cancer Treat Rev 2006; 32 (8) 594-606
76 Cheung TT, Ng KK, Chok KS , et al. Combined resection and radiofrequency ablation for multifocal hepatocellular carcinoma: prognosis and outcomes. World J Gastroenterol 2010; 16 (24) 3056-3062
77 NCCN. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2012. Available at: www.nccn.org . Accessed August 24, 2012
78 Kudo M, Izumi N, Kokudo N , et al; HCC Expert Panel of Japan Society of Hepatology. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis 2011; 29 (3) 339-364
79 Omata M, Lesmana LA, Tateishi R , et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010; 4 (2) 439-474
80 Tournoux-Facon C, Paoletti X, Barbare JC , et al. Development and validation of a new prognostic score of death for patients with hepatocellular carcinoma in palliative setting. J Hepatol 2011; 54 (1) 108-114
81 Llovet JM, 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
82 Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004; 127 (5) (Suppl. 01) S179-S188