Treatment of Hepatocellular Carcinoma with Combined Transarterial Chemoembolization and Systemic Therapy

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide and is frequently diagnosed at intermediate or advanced stages at which curative treatments such as surgical resection or liver transplantation are not possible. For patients with later diagnoses, transarterial chemoembolization (TACE) has become a mainstay of treatment, utilizing hepatic arterial embolotherapy to induce tumor ischemia and delivery cytotoxic chemotherapy. Despite this, because TACE is not a curative therapy, there remains further opportunity to enhance TACE outcomes by combination treatment with systemic therapies. The purpose of this article is to provide a brief primer on the various systemic therapies potentially used alongside TACE, including insights into the mechanistic foundations behind these combinations as well as a narrative literature review of representative clinical trials.

Publikationsverlauf

Artikel online veröffentlicht:
19. August 2024

• References

• 1 Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol 2015; 62 (05) 1187-1195
• 2 Balogh J, Victor III D, Asham EH. et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma 2016; 3: 41-53
• 3 Reig M, Forner A, Rimola J. et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022; 76 (03) 681-693
• 4 Fong ZV, Tanabe KK. The clinical management of hepatocellular carcinoma in the United States, Europe, and Asia: a comprehensive and evidence-based comparison and review. Cancer 2014; 120 (18) 2824-2838
• 5 Bucalau AM, Tancredi I, Verset G. In the era of systemic therapy for hepatocellular carcinoma is transarterial chemoembolization still a card to play?. Cancers (Basel) 2021; 13 (20) 5129
• 6 Vilgrain V, Sibert A, Zappa M, Belghiti J. Sequential arterial and portal vein embolization in patients with cirrhosis and hepatocellular carcinoma: the Hospital Beaujon experience. Semin Intervent Radiol 2008; 25 (02) 155-161
• 7 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
• 8 Melchiorre F, Patella F, Pescatori L. et al. DEB-TACE: a standard review. Future Oncol 2018; 14 (28) 2969-2984
• 9 Zhang H, Zhang W, Jiang L, Chen Y. Recent advances in systemic therapy for hepatocellular carcinoma. Biomark Res 2022; 10 (01) 3
• 10 da Fonseca LG, Reig M, Bruix J. Tyrosine kinase inhibitors and hepatocellular carcinoma. Clin Liver Dis 2020; 24 (04) 719-737
• 11 Zeng Z, Lu Q, Liu Y. et al. Effect of the hypoxia inducible factor on sorafenib resistance of hepatocellular carcinoma. Front Oncol 2021; 11: 641522
• 12 Li X, Wang Y, Ye X, Liang P. Locoregional combined with systemic therapies for advanced hepatocellular carcinoma: an inevitable trend of rapid development. Front Mol Biosci 2021; 8: 635243
• 13 Rini BI. Sorafenib. Expert Opin Pharmacother 2006; 7 (04) 453-461
• 14 Granito A, Forgione A, Marinelli S. et al. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol 2021; 14: 17 562848211016959
• 15 Gupta S, Kobayashi S, Phongkitkarun S, Broemeling LD, Kan Z. Effect of transcatheter hepatic arterial embolization on angiogenesis in an animal model. Invest Radiol 2006; 41 (06) 516-521
• 16 Kudo M, Imanaka K, Chida N. et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011; 47 (14) 2117-2127
• 17 Lee TY, Lin CC, Chen CY. et al. Combination of transcatheter arterial chemoembolization and interrupted dosing sorafenib improves patient survival in early-intermediate stage hepatocellular carcinoma: a post hoc analysis of the START trial. Medicine (Baltimore) 2017; 96 (37) e7655
• 18 Geschwind JF, Kudo M, Marrero JA. et al. TACE treatment in patients with sorafenib-treated unresectable hepatocellular carcinoma in clinical practice: final analysis of GIDEON. Radiology 2016; 279 (02) 630-640
• 19 Kudo M, Ueshima K, Ikeda M. et al. TACTICS: final overall survival (OS) data from a randomized, open label, multicenter, phase II trial of transcatheter arterial chemoembolization (TACE) therapy in combination with sorafenib as compared with TACE alone in patients (pts) with hepatocellular carcinoma (HCC). JCO 2021; 39 (3, Suppl): 270-270
• 20 Kudo M, Cheng AL, Park JW. et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol Hepatol 2018; 3 (01) 37-46
• 21 Kudo M, Han G, Finn RS. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology 2014; 60 (05) 1697-1707
• 22 Choi NR, Kim JY, Hong JH. et al. Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis. BMC Gastroenterol 2022; 22 (01) 135
• 23 Peng Z, Fan W, Zhu B, Li J, Kuang M. Lenvatinib combined with transarterial chemoembolization as first-line treatment of advanced hepatocellular carcinoma: a phase 3, multicenter, randomized controlled trial. JCO 2022; 40 (4, Suppl): 380-380
• 24 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
• 25 Cosgrove DP, Reyes DK, Pawlik TM, Feng AL, Kamel IR, Geschwind JFH. Open-label single-arm phase II trial of sorafenib therapy with drug-eluting bead transarterial chemoembolization in patients with unresectable hepatocellular carcinoma: clinical results. Radiology 2015; 277 (02) 594-603
• 26 Onuma AE, Zhang H, Huang H, Williams TM, Noonan A, Tsung A. Immune checkpoint inhibitors in hepatocellular cancer: current understanding on mechanisms of resistance and biomarkers of response to treatment. Gene Expr 2020; 20 (01) 53-65
• 27 Chapiro J, Wood LD, Lin M. et al. Radiologic-pathologic analysis of contrast-enhanced and diffusion-weighted MR imaging in patients with HCC after TACE: diagnostic accuracy of 3D quantitative image analysis. Radiology 2014; 273 (03) 746-758
• 28 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
• 29 Duffy AG, Ulahannan SV, Makorova-Rusher O. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017; 66 (03) 545-551
• 30 Fulgenzi CAM, Cortellini A, D'Alessio A. et al. A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL. JCO 2022; 40 (16, Suppl): e16195-e16195
• 31 Saborowski A, Waldschmidt D, Hinrichs J. et al. IMMUTACE: a biomarker-orientated phase II, single-arm, open-label AIO study of transarterial chemoembolization (TACE) in combination with nivolumab performed for intermediate-stage hepatocellular carcinoma (HCC; AIO-HEP-0217)—updated efficacy results. JCO 2022; 40 (16, Suppl): 4116-4116
• 32 Kloeckner R, Galle PR, Bruix J. Local and regional therapies for hepatocellular carcinoma. Hepatology 2021; 73 (Suppl. 01) 137-149
• 33 Sangro B, Kudo M, Qin S. et al. P-347 A phase 3, randomized, double-blind, placebo-controlled study of transarterial chemoembolization combined with durvalumab or durvalumab plus bevacizumab therapy in patients with locoregional hepatocellular carcinoma: EMERALD-1. Ann Oncol 2020; 31: S202-S203
• 34 Yasuda S, Sho M, Yamato I. et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol 2013; 172 (03) 500-506
• 35 El-Khoueiry AB, Llovet JM, Vogel A. et al. LEAP-012 trial in progress: transarterial chemoembolization (TACE) with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma (HCC). JCO 2022; 40 (4, Suppl): TPS494-TPS494
• 36 Kudo M, Guo Y, Hua Y. et al. TALENTACE: a phase III, open-label, randomized study of on-demand transarterial chemoembolization combined with atezolizumab + bevacizumab or on-demand transarterial chemoembolization alone in patients with untreated hepatocellular carcinoma. JCO 2022; 40 (4, Suppl): TPS487-TPS487
• 37 Ben Khaled N, Seidensticker M, Ricke J. et al. Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol. Future Oncol 2022; 18 (12) 1423-1435
• 38 Ponziani FR, Santopaolo F, Posa A. et al. SIRT in 2025. Cardiovasc Intervent Radiol 2022; 45 (11) 1622-1633
• 39 Lencioni R. et al. EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. Journal of Clinical Oncology 2024;42(03):suppl. Doi.org/10.1200/JCO.2024.42.3_suppl.LBA432
• 40 Chao Y, Chung YH, Han G. et al. The combination of transcatheter arterial chemoembolization and sorafenib is well tolerated and effective in Asian patients with hepatocellular carcinoma: final results of the START trial. Int J Cancer 2015; 136 (06) 1458-1467
• 41 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