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DOI: 10.1055/s-0040-1719186
Therapy of Intermediate-Stage Hepatocellular Carcinoma: Current Evidence and Clinical Practice
Abstract
Intermediate-stage Hepatocellular Carcinoma (HCC) represents a wide range of disease burden. Patients with different levels of liver function, tumor size, and number of lesions may all have intermediate-stage disease according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Several minimally invasive image-guided locoregional therapies are available for the treatment of intermediate-stage HCC, including conventional transarterial chemoembolization (cTACE), drug-eluting bead TACE (DEB-TACE), yttrium-90 radioembolization (Y-90 RE), thermal ablation, bland embolization, and combination therapy. Available clinical evidence points to cTACE as the current gold standard for the locoregional treatment of intermediate-stage HCC. DEB-TACE is at best non-inferior to cTACE in terms of survival benefit. Y-90 RE is a maturing therapy, and some institutions have adopted it as first-line therapy for intermediate-stage HCC. Thermal ablation combined with TACE may be used in select patients, while bland embolization has only limited evidence for its use. The combination of locoregional therapy with VEGF inhibitors or immune checkpoint inhibitors has also been explored. This article will examine in detail the clinical evidence supporting available locoregional treatment options for intermediate-stage HCC.
Keywords
transarterial chemoembolization - radioembolization - ablation - hepatocellular carcinoma - Barcelona Clinic Liver CancerPublication History
Article published online:
11 December 2020
© 2020. Thieme. All rights reserved.
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References
- 1 Bolondi L, Burroughs A, Dufour J-F. et al. Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis 2012; 32 (04) 348-359
- 2 European Association for the Study of the Liver.. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018; 69 (01) 182-236
- 3 Jung YK, Jung CH, Seo YS. et al. BCLC stage B is a better designation for single large hepatocellular carcinoma than BCLC stage A. J Gastroenterol Hepatol 2016; 31 (02) 467-474
- 4 Barman PM, Su GL. Limitations of the Barcelona Clinic Liver Cancer staging system with a focus on transarterial chemoembolization as a key modality for treatment of hepatocellular carcinoma. Clin Liver Dis (Hoboken) 2016; 7 (02) 32-35
- 5 Biolato M, Gallusi G, Iavarone M. et al. Prognostic ability of BCLC-B subclassification in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Ann Hepatol 2018; 17 (01) 110-118
- 6 Dhanasekaran R, Limaye A, Cabrera R. Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepat Med 2012; 4: 19-37
- 7 El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?. Hepatology 2014; 60 (05) 1767-1775
- 8 Sohn JH, Duran R, Zhao Y. et al. Validation of the Hong Kong Liver Cancer staging system in determining prognosis of the North American patients following intra-arterial therapy. Clin Gastroenterol Hepatol 2017; 15 (05) 746-755.e4
- 9 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
- 10 Lo C-M, Ngan H, Tso W-K. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35 (05) 1164-1171
- 11 Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37 (02) 429-442
- 12 Cammà C, Schepis F, Orlando A. et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002; 224 (01) 47-54
- 13 Marrero JA, Kulik LM, Sirlin CB. et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2018; 68 (02) 723-750
- 14 Park J-W, Chen M, Colombo M. et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int 2015; 35 (09) 2155-2166
- 15 Hyun MH, Lee YS, Kim JH. et al. Hepatic resection compared to chemoembolization in intermediate- to advanced-stage hepatocellular carcinoma: a meta-analysis of high-quality studies. Hepatology 2018; 68 (03) 977-993
- 16 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 (02) 439-474
- 17 Korean Liver Cancer Study Group (KLCSG), National Cancer Center, Korea (NCC). 2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver 2015; 9 (03) 267-317
- 18 Kudo M, Matsui O, Izumi N. et al; Liver Cancer Study Group of Japan. JSH Consensus-Based Clinical Practice Guidelines for the management of hepatocellular carcinoma: 2014 update by the Liver Cancer Study Group of Japan. Liver Cancer 2014; 3 (3-4): 458-468
- 19 Tacher V, Radaelli A, Lin M, Geschwind J-F. How I do it: cone-beam CT during transarterial chemoembolization for liver cancer. Radiology 2015; 274 (02) 320-334
- 20 Miyayama S, Yamashiro M, Hattori Y. et al. Efficacy of cone-beam computed tomography during transcatheter arterial chemoembolization for hepatocellular carcinoma. Jpn J Radiol 2011; 29 (06) 371-377
- 21 Wallace MJ. C-arm computed tomography for guiding hepatic vascular interventions. Tech Vasc Interv Radiol 2007; 10 (01) 79-86
- 22 Yu L, Vrieze TJ, Bruesewitz MR. et al. Dose and image quality evaluation of a dedicated cone-beam CT system for high-contrast neurologic applications. AJR Am J Roentgenol 2010; 194 (02) W193-W201
- 23 Lin M, Loffroy R, Noordhoek N. et al. Evaluating tumors in transcatheter arterial chemoembolization (TACE) using dual-phase cone-beam CT. Minim Invasive Ther Allied Technol 2011; 20 (05) 276-281
- 24 Ning R, Chen B, Yu R, Conover D, Tang X, Ning Y. Flat panel detector-based cone-beam volume CT angiography imaging: system evaluation. IEEE Trans Med Imaging 2000; 19 (09) 949-963
- 25 Miyayama S, Yamashiro M, Hashimoto M. et al. Identification of small hepatocellular carcinoma and tumor-feeding branches with cone-beam CT guidance technology during transcatheter arterial chemoembolization. J Vasc Interv Radiol 2013; 24 (04) 501-508
- 26 Iwazawa J, Ohue S, Mitani T. et al. Identifying feeding arteries during TACE of hepatic tumors: comparison of C-arm CT and digital subtraction angiography. AJR Am J Roentgenol 2009; 192 (04) 1057-1063
- 27 Loffroy R, Lin M, Yenokyan G. et al. Intraprocedural C-arm dual-phase cone-beam CT: can it be used to predict short-term response to TACE with drug-eluting beads in patients with hepatocellular carcinoma?. Radiology 2013; 266 (02) 636-648
- 28 Toyoda H, Kumada T, Sone Y. Impact of a unified CT angiography system on outcome of patients with hepatocellular carcinoma. AJR Am J Roentgenol 2009; 192 (03) 766-774
- 29 Kakeda S, Korogi Y, Ohnari N. et al. Usefulness of cone-beam volume CT with flat panel detectors in conjunction with catheter angiography for transcatheter arterial embolization. J Vasc Interv Radiol 2007; 18 (12) 1508-1516
- 30 Idée J-M, Guiu B. Use of Lipiodol as a drug-delivery system for transcatheter arterial chemoembolization of hepatocellular carcinoma: a review. Crit Rev Oncol Hematol 2013; 88 (03) 530-549
- 31 van Breugel JMM, Geschwind J-F, Mirpour S. et al. Theranostic application of lipiodol for transarterial chemoembolization in a VX2 rabbit liver tumor model. Theranostics 2019; 9 (13) 3674-3686
- 32 Kan Z, Sato M, Ivancev K. et al. Distribution and effect of iodized poppy seed oil in the liver after hepatic artery embolization: experimental study in several animal species. Radiology 1993; 186 (03) 861-866
- 33 Kan Z, McCuskey PA, Wright KC, Wallace S. Role of Kupffer cells in iodized oil embolization. Invest Radiol 1994; 29 (11) 990-993
- 34 Okayasu I, Hatakeyama S, Yoshida T. et al. Selective and persistent deposition and gradual drainage of iodized oil, Lipiodol in the hepatocellular carcinoma after injection into the feeding hepatic artery. Am J Clin Pathol 1988; 90 (05) 536-544
- 35 Mondazzi L, Bottelli R, Brambilla G. et al. Transarterial oily chemoembolization for the treatment of hepatocellular carcinoma: a multivariate analysis of prognostic factors. Hepatology 1994; 19 (05) 1115-1123
- 36 Dumortier J, Chapuis F, Borson O. et al. Unresectable hepatocellular carcinoma: survival and prognostic factors after lipiodol chemoembolisation in 89 patients. Dig Liver Dis 2006; 38 (02) 125-133
- 37 Brown DB, Pilgram TK, Darcy MD. et al. Hepatic arterial chemoembolization for hepatocellular carcinoma: comparison of survival rates with different embolic agents. J Vasc Interv Radiol 2005; 16 (12) 1661-1666
- 38 Lee SH, Lin CY, Hsu YC, Liu YS, Chuang MT, Ou MC. Comparison of the efficacy of two microsphere embolic agents for transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Res Treat 2020; 52 (01) 24-30
- 39 Schicho A, Pereira PL, Haimerl M. et al. Transarterial chemoembolization (TACE) with degradable starch microspheres (DSM) in hepatocellular carcinoma (HCC): multi-center results on safety and efficacy. Oncotarget 2017; 8 (42) 72613-72620
- 40 Pelletier G, Ducreux M, Gay F. et al; Groupe CHC. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. J Hepatol 1998; 29 (01) 129-134
- 41 Lewandowski RJ, Mulcahy MF, Kulik LM. et al. Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort. Radiology 2010; 255 (03) 955-965
- 42 Lencioni R, de Baere T, Soulen MC, Rilling WS, Geschwind JF. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology 2016; 64 (01) 106-116
- 43 de Baere T, Arai Y, Lencioni R. et al. Treatment of liver tumors with lipiodol TACE: technical recommendations from experts opinion. Cardiovasc Intervent Radiol 2016; 39 (03) 334-343
- 44 Namur J, Wassef M, Millot JM, Lewis AL, Manfait M, Laurent A. Drug-eluting beads for liver embolization: concentration of doxorubicin in tissue and in beads in a pig model. J Vasc Interv Radiol 2010; 21 (02) 259-267
- 45 Lewis AL, Gonzalez MV, Lloyd AW. et al. DC bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 2006; 17 (2, Pt 1): 335-342
- 46 Hong K, Khwaja A, Liapi E, Torbenson MS, Georgiades CS, Geschwind JF. New intra-arterial drug delivery system for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 2006; 12 (08) 2563-2567
- 47 Zhang S, Huang C, Li Z. et al. Comparison of pharmacokinetics and drug release in tissues after transarterial chemoembolization with doxorubicin using diverse lipiodol emulsions and CalliSpheres Beads in rabbit livers. Drug Deliv 2017; 24 (01) 1011-1017
- 48 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 (01) 41-52
- 49 Golfieri R, Giampalma E, Renzulli M. et al; PRECISION ITALIA STUDY GROUP. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014; 111 (02) 255-264
- 50 Monier A, Guiu B, Duran R. et al. Liver and biliary damages following transarterial chemoembolization of hepatocellular carcinoma: comparison between drug-eluting beads and lipiodol emulsion. Eur Radiol 2017; 27 (04) 1431-1439
- 51 Guiu B, Deschamps F, Aho S. et al. Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol vs. drug-eluting beads. J Hepatol 2012; 56 (03) 609-617
- 52 Facciorusso A, Di Maso M, Muscatiello N. Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: a meta-analysis. Dig Liver Dis 2016; 48 (06) 571-577
- 53 Zou JH, Zhang L, Ren ZG, Ye SL. Efficacy and safety of cTACE versus DEB-TACE in patients with hepatocellular carcinoma: a meta-analysis. J Dig Dis 2016; 17 (08) 510-517
- 54 Zhou X, Tang Z, Wang J. et al. Doxorubicin-eluting beads versus conventional transarterial chemoembolization for the treatment of hepatocellular carcinoma: a meta-analysis. Int J Clin Exp Med 2014; 7 (11) 3892-3903
- 55 Ashrafi K, Tang Y, Britton H. et al. Characterization of a novel intrinsically radiopaque drug-eluting bead for image-guided therapy: DC Bead LUMI™. J Control Release 2017; 250: 36-47
- 56 Brown KT, Do RK, Gonen M. et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol 2016; 34 (17) 2046-2053
- 57 Dancey JE, Shepherd FA, Paul K. et al. Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres. J Nucl Med 2000; 41 (10) 1673-1681
- 58 Salem R, Miller FH, Yaghmai V, Lewandowski RJ. Response assessment methodologies in hepatocellular carcinoma: complexities in the era of local and systemic treatments. J Hepatol 2013; 58 (06) 1260-1262
- 59 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 (01) 71-81
- 60 Salem R, Gilbertsen M, Butt Z. et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin Gastroenterol Hepatol 2013; 11 (10) 1358-1365.e1
- 61 Salem R, Lewandowski RJ, Kulik L. et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2011; 140 (02) 497-507.e2
- 62 Salem R, Gordon AC, Mouli S. et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2016; 151 (06) 1155-1163.e2
- 63 Kolligs FT, Bilbao JI, Jakobs T. et al. Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. Liver Int 2015; 35 (06) 1715-1721
- 64 Salem R, Gabr A, Riaz A. et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. Hepatology 2018; 68 (04) 1429-1440
- 65 Sugimori K, Nozawa A, Morimoto M. et al. Extension of radiofrequency ablation of the liver by transcatheter arterial embolization with iodized oil and gelatin sponge: results in a pig model. J Vasc Interv Radiol 2005; 16 (06) 849-856
- 66 Morimoto M, Numata K, Kondou M, Nozaki A, Morita S, Tanaka K. Midterm outcomes in patients with intermediate-sized hepatocellular carcinoma: a randomized controlled trial for determining the efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization. Cancer 2010; 116 (23) 5452-5460
- 67 Lu Z, Wen F, Guo Q, Liang H, Mao X, Sun H. Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: a meta-analysis of randomized-controlled trials. Eur J Gastroenterol Hepatol 2013; 25 (02) 187-194
- 68 Ni J-Y, Liu S-S, Xu L-F, Sun H-L, Chen Y-T. Meta-analysis of radiofrequency ablation in combination with transarterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol 2013; 19 (24) 3872-3882
- 69 Shibata T, Isoda H, Hirokawa Y, Arizono S, Shimada K, Togashi K. Small hepatocellular carcinoma: is radiofrequency ablation combined with transcatheter arterial chemoembolization more effective than radiofrequency ablation alone for treatment?. Radiology 2009; 252 (03) 905-913
- 70 Zhang L, Wang J-N, Tang J-M. et al. VEGF is essential for the growth and migration of human hepatocellular carcinoma cells. Mol Biol Rep 2012; 39 (05) 5085-5093
- 71 Li X, Feng G-S, Zheng C-S, Zhuo C-K, 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
- 72 Shim JH, Park JW, Kim JH. et al. Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci 2008; 99 (10) 2037-2044
- 73 Marrero JA, Kudo M, Venook AP. et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol 2016; 65 (06) 1140-1147
- 74 Meyer T, Fox R, Ma YT. et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 2017; 2 (08) 565-575
- 75 Lencioni R, Llovet JM, Han G. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. J Hepatol 2016; 64 (05) 1090-1098
- 76 Kim MJ, Jang JW, Oh BS. et al. Change in inflammatory cytokine profiles after transarterial chemotherapy in patients with hepatocellular carcinoma. Cytokine 2013; 64 (02) 516-522
- 77 Takaki H, Imai N, Contessa TT. et al. Peripheral blood regulatory T-cell and type 1 helper T-cell population decrease after hepatic artery embolization. J Vasc Interv Radiol 2016; 27 (10) 1561-1568
- 78 Liao Y, Wang B, Huang Z-L. et al. Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study. PLoS One 2013; 8 (04) e60444
- 79 El-Khoueiry AB, Sangro B, Yau T. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389 (10088): 2492-2502
- 80 Transarterial Chemoembolization in Combination with Nivolumab Performed for Intermediate Stage Hepatocellular Carcinoma (IMMUTACE), ClinicalTrialsgov. Accessed October 17, 2020 at: https://clinicaltrialsgov/ct2/show/NCT03572582
- 81 The Effect of CTLA-4/PD-L1 Blockade Following Drug-eluting Bead Transarterial Chemoembolization (DEB-TACE) in Patients With Intermediate Stage of HCC Using Durvalumab, (MEDI4736) and Tremelimumab, ClinicalTrialsgov. Accessed October 17, 2020 at: https://clinicaltrialsgov/ct2/show/study/NCT03638141
- 82 Vaidya S, Tozer KR, Chen J. An overview of embolic agents. Semin Intervent Radiol 2008; 25 (03) 204-215
- 83 Sacco R, Bargellini I, Bertini M. et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011; 22 (11) 1545-1552
- 84 van Malenstein H, Maleux G, Vandecaveye V. et al. A randomized phase II study of drug-eluting beads versus transarterial chemoembolization for unresectable hepatocellular carcinoma. Onkologie 2011; 34 (07) 368-376
- 85 Dekervel J, van Malenstein H, Vandecaveye V. et al. Transcatheter arterial chemoembolization with doxorubicin-eluting superabsorbent polymer microspheres in the treatment of hepatocellular carcinoma: midterm follow-up. J Vasc Interv Radiol 2014; 25 (02) 248-55.e1
- 86 Richter G, Radeleff B, Stroszczynski C. et al. Safety and feasibility of chemoembolization with doxorubicin-loaded small calibrated microspheres in patients with hepatocellular carcinoma: results of the MIRACLE I prospective multicenter study. Cardiovasc Intervent Radiol 2018; 41 (04) 587-593
- 87 Malagari K, Kiakidis T, Pomoni M. et al. Pharmacokinetics, safety, and efficacy of chemoembolization with doxorubicin-loaded tightly calibrated small microspheres in patients with hepatocellular carcinoma. Cardiovasc Intervent Radiol 2016; 39 (10) 1379-1391
- 88 Reicher J, Mafeld S, Priona G. et al. Early experience of trans-arterial chemo-embolisation for hepatocellular carcinoma with a novel radiopaque bead. Cardiovasc Intervent Radiol 2019; 42 (11) 1563-1570
- 89 DC Bead LUMI (TM) Loaded With Doxorubicin for Intermediate Hepatocellular Carcinoma, (HCC), ClinicalTrialsgov. Accessed October 17, 2020 at: https://clinicaltrialsgov/ct2/show/NCT03474354