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Semin intervent Radiol 2020; 37(05): 466-474
DOI: 10.1055/s-0040-1719187
Review Article

Therapy in Advanced Hepatocellular Carcinoma

Hanna Javan
1   Department of Radiological Sciences, University of California Irvine, Orange, California
,
Farshid Dayyani
2   Chao Comprehensive Digestive Disease Center, University of California Irvine, Orange, California
,
Nadine Abi-Jaoudeh
1   Department of Radiological Sciences, University of California Irvine, Orange, California
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Abstract

Treatment of advanced hepatocellular carcinoma (HCC) is challenging. Several randomized clinical trials are investigating the efficacy of systemic therapy, immunotherapy, and locoregional therapy as monotherapy or combined with other modalities in the treatment of HCC. Systemic therapy is the preferred treatment in advanced disease. To date, multiple first-line and second-line agents received Food and Drug Administration approval. For over a decade, sorafenib was the only first-line agent. In May 2020, combination of atezolizumab and bevacizumab has been approved as a first-line systemic regimen. Lenvatinib is another first-line agent that has multikinase activity. Second-line agents include cabozantinib, regorafenib, ramucirumab, and nivolumab. Adoptive cell transfer therapy is a highly specific immunotherapy that has shown antitumor activity against HCC. Oncolytic viruses are genetically modified viruses that infect cancer cells and induce apoptosis. Locoregional therapies such as transarterial chemoembolization and radioembolization have shown a potential benefit in selected patients with advanced HCC. In this review, we aim to summarize the treatment options available for advanced HCC.

Keywords

hepatocellular carcinoma - systemic therapies - locoregional therapies


Publication History

Article published online:
11 December 2020

© 2020. Thieme. All rights reserved.

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  • Reference

  • 1 Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol 2020; 72 (02) 250-261
    CrossrefPubMedSearch in Google Scholar
  • 2 Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42 (05) 1208-1236
    CrossrefPubMedSearch in Google Scholar
  • 3 Ocker M. Systemic therapy of advanced liver cancer. In: Liver Diseases. Springer International Publishing; 2020: 661-666
    Search in Google Scholar
  • 4 Kudo M. Immune checkpoint blockade in hepatocellular carcinoma. Liver Cancer 2015; 4 (04) 201-207
    CrossrefPubMedSearch in Google Scholar
  • 5 Cabibbo G, Enea M, Attanasio M, Bruix J, Craxì A, Cammà C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology 2010; 51 (04) 1274-1283
    CrossrefPubMedSearch in Google Scholar
  • 6 Cheng AL, Guan Z, Chen Z. et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 2012; 48 (10) 1452-1465
    CrossrefPubMedSearch in Google Scholar
  • 7 Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. Expert Rev Anticancer Ther 2009; 9 (06) 739-745
    CrossrefPubMedSearch in Google Scholar
  • 8 Cheng A, Kang Y, Chen Z. et al. Randomized phase III trial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma. J Clin Oncol 2008; 26 (15) 4509
    CrossrefPubMedSearch in Google Scholar
  • 9 Llovet JM, Ricci S, Mazzaferro V. et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (04) 378-390
    CrossrefPubMedSearch in Google Scholar
  • 10 Finn RS, Zhu AX. Evolution of systemic therapy for hepatocellular carcinoma. Hepatology 2020; . Epub ahead of print. PMID: 32380571
    CrossrefPubMedSearch in Google Scholar
  • 11 Matsuki M, Hoshi T, Yamamoto Y. et al. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med 2018; 7 (06) 2641-2653
    CrossrefPubMedSearch in Google Scholar
  • 12 Spallanzani A, Orsi G, Andrikou K. et al. Lenvatinib as a therapy for unresectable hepatocellular carcinoma. Expert Rev Anticancer Ther 2018; 18 (11) 1069-1076
    CrossrefPubMedSearch in Google Scholar
  • 13 Oikonomopoulos G, Aravind P, Sarker D. Lenvatinib: a potential breakthrough in advanced hepatocellular carcinoma?. Future Oncol 2016; 12 (04) 465-476
    CrossrefPubMedSearch in Google Scholar
  • 14 Kudo M, Finn RS, Qin S. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391 (10126): 1163-1173
    CrossrefPubMedSearch in Google Scholar
  • 15 Zeng H, Sanyal S, Mukhopadhyay D. Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively. J Biol Chem 2001; 276 (35) 32714-32719
    CrossrefPubMedSearch in Google Scholar
  • 16 Hack SP, Spahn J, Chen M. et al. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol 2020; 16 (15) 975-989
    CrossrefPubMedSearch in Google Scholar
  • 17 Ellis LM. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol 2006; 33 (05) (Suppl. 10) S1-S7
    CrossrefPubMedSearch in Google Scholar
  • 18 Doycheva I, Thuluvath PJ. Systemic therapy for advanced hepatocellular carcinoma: an update of a rapidly evolving field. J Clin Exp Hepatol 2019; 9 (05) 588-596
    CrossrefPubMedSearch in Google Scholar
  • 19 Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab, (MK-3475) Versus Lenvatinib as First-line Therapy in Participants With Advanced Hepatocellular Carcinoma (MK-7902–002/E7080–G000–311/LEAP-002) - Full Text View - ClinicalTrials.gov. Accessed July 19, 2020 at: https://clinicaltrials.gov/ct2/show/NCT03713593
  • 20 Kelley RKW, , W Oliver J, Hazra S. et al. Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design. Future Oncol 2020; 16 (21) 1525-1536
    CrossrefPubMedSearch in Google Scholar
  • 21 Abou-Alfa GK, Chan SL, Furuse J. et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol 2018; 36 (15) TPS4144
    CrossrefPubMedSearch in Google Scholar
  • 22 Abou-Alfa GK, Meyer T, Cheng A-L. et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J Clin Oncol 2018; 36 (04) 207
    CrossrefPubMedSearch in Google Scholar
  • 23 Bruix J, Qin S, Merle P. et al. RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389 (10064): 56-66
    CrossrefPubMedSearch in Google Scholar
  • 24 Zhu AX, Kang YK, Yen CJ. et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol 2018; 36 (15) 4003
    CrossrefPubMedSearch in Google Scholar
  • 25 Kudo M. A new era of systemic therapy for hepatocellular carcinoma with regorafenib and lenvatinib. Liver Cancer 2017; 6 (03) 177-184
    CrossrefPubMedSearch in Google Scholar
  • 26 Finn RS, Merle P, Granito A. et al. Outcomes with sorafenib (SOR) followed by regorafenib (REG) or placebo (PBO) for hepatocellular carcinoma (HCC): Results of the international, randomized phase 3 RESORCE trial. J Clin Oncol 2017; 35 (04) 344
    CrossrefPubMedSearch in Google Scholar
  • 27 Ettrich TJ, Seufferlein T. Regorafenib. Recent Results Cancer Res 2014; 201: 185-196
    CrossrefPubMedSearch in Google Scholar
  • 28 B Peters ML, Miksad RA. Cabozantinib in the treatment of hepatocellular carcinoma. Future Oncol 2017; 13 (22) 1915-1929
    CrossrefPubMedSearch in Google Scholar
  • 29 Abou-Alfa GK, Meyer T, Cheng AL. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379 (01) 54-63
    CrossrefPubMedSearch in Google Scholar
  • 30 Kudo M. Cabozantinib for advanced hepatocellular carcinoma. Hepatobiliary Surg Nutr 2019; 8 (02) 153-156
    CrossrefPubMedSearch in Google Scholar
  • 31 Gilabert M, Raoul JL. Potential of ramucirumab in treating hepatocellular carcinoma patients with elevated baseline alpha-fetoprotein. J Hepatocell Carcinoma 2018; 5: 91-98
    CrossrefPubMedSearch in Google Scholar
  • 32 Reig M, da Fonseca LG, Faivre S. New trials and results in systemic treatment of HCC. J Hepatol 2018; 69 (02) 525-533
    CrossrefPubMedSearch in Google Scholar
  • 33 Greten TF, Manns MP, Korangy F. Immunotherapy of HCC. Rev Recent Clin Trials 2008; 3 (01) 31-39
    CrossrefPubMedSearch in Google Scholar
  • 34 Robainas M, Otano R, Bueno S, Ait-Oudhia S. Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy. OncoTargets Ther 2017; 10: 1803-1807
    CrossrefPubMedSearch in Google Scholar
  • 35 Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39 (01) 98-106
    CrossrefPubMedSearch in Google Scholar
  • 36 Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology 2017; 93 (01) (Suppl. 01) 147-159
    CrossrefPubMedSearch in Google Scholar
  • 37 Kudo M, Finn RS, Edeline J. et al. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2020; 38 (04) 518
    CrossrefPubMedSearch in Google Scholar
  • 38 Phase III CheckMate 459 Trial in Unresectable HCC Misses Primary Endpoint | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways. Accessed July 14, 2020 at: https://www.targetedonc.com/view/phase-iii-checkmate-459-trial-in-unresectable-hcc-misses-primary-endpoint
  • 39 Sangro B, Park J-W, Dela Cruz CM. et al. A randomized, multicenter, phase 3 study of nivolumab vs sorafenib as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): CheckMate-459. J Clin Oncol 2016; 34 (15) TPS4147
    CrossrefPubMedSearch in Google Scholar
  • 40 Patienten S, Therapie N. PAKT inhibitor may promote better responses to abiraterone in mCRPC. Onclive 2020; 7: 1-7
    PubMedSearch in Google Scholar
  • 41 Zhu AX, Finn RS, Edeline J. et al. KEYNOTE-224 Investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19 (07) 940-952
    CrossrefPubMedSearch in Google Scholar
  • 42 Finn RS, Ryoo BY, Merle P. et al. KEYNOTE-240 Investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol 2020; 38 (03) 193-202
    CrossrefPubMedSearch in Google Scholar
  • 43 Yau T, Kang Y-K, Kim T-Y. et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol 2019; 37 (15) 4012
    CrossrefPubMedSearch in Google Scholar
  • 44 Mizukoshi E, Kaneko S. Immune cell therapy for hepatocellular carcinoma. J Hematol Oncol 2019; 12 (01) 52
    CrossrefPubMedSearch in Google Scholar
  • 45 Zhang R, Zhang Z, Liu Z. et al. Adoptive cell transfer therapy for hepatocellular carcinoma. Frontiers Med 2019; 13: 3-11
    CrossrefPubMedSearch in Google Scholar
  • 46 Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood) 2011; 236 (05) 567-579
    CrossrefPubMedSearch in Google Scholar
  • 47 Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348 (6230): 62-68
    CrossrefPubMedSearch in Google Scholar
  • 48 Pan QZ, Wang QJ, Dan JQ. et al. A nomogram for predicting the benefit of adjuvant cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma. Sci Rep 2015; 5: 9202
    CrossrefPubMedSearch in Google Scholar
  • 49 Yuan BH, Li RH, Yuan WP. et al. Harms and benefits of adoptive immunotherapy for postoperative hepatocellular carcinoma: an updated review. Oncotarget 2017; 8 (11) 18537-18549
    CrossrefPubMedSearch in Google Scholar
  • 50 June CH, O'Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359 (6382): 1361-1365
    CrossrefPubMedSearch in Google Scholar
  • 51 Gao H, Li K, Tu H, Pan X. et al. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res 2014; 20: 6418-6428
    CrossrefPubMedSearch in Google Scholar
  • 52 Katz SC, Burga RA, McCormack E. et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin Cancer Res 2015; 21 (14) 3149-3159
    CrossrefPubMedSearch in Google Scholar
  • 53 Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 2018; 15 (01) 31-46
    CrossrefPubMedSearch in Google Scholar
  • 54 Twumasi-Boateng K, Pettigrew JL, Kwok YYE, Bell JC, Nelson BH. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer 2018; 18 (07) 419-432
    CrossrefPubMedSearch in Google Scholar
  • 55 Muik A, Stubbert LJ, Jahedi RZ. et al. Re-engineering vesicular stomatitis virus to abrogate neurotoxicity, circumvent humoral immunity, and enhance oncolytic potency. Cancer Res 2014; 74 (13) 3567-3578
    CrossrefPubMedSearch in Google Scholar
  • 56 Yamada T, Hamano Y, Hasegawa N. et al. Oncolytic virotherapy and gene therapy strategies for hepatobiliary cancers. Curr Cancer Drug Targets 2018; 18 (02) 188-201
    CrossrefPubMedSearch in Google Scholar
  • 57 Moehler M, Heo J, Lee HC. et al. Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE). OncoImmunology 2019; 8 (08) 1615817
    CrossrefPubMedSearch in Google Scholar
  • 58 Phase 3 Trial for Oncolytic Viral Therapy Pexa-Vec in Advanced Liver Cancer Terminated Early - Cancer Therapy Advisor. Accessed July 15, 2020 at: https://www.cancertherapyadvisor.com/home/cancer-topics/general-oncology/phase-3-trial-for-oncolytic-viral-therapy-pexa-vec-in-advanced-liver-cancer-terminated-early/
  • 59 Palmer DH, Malagari K, Kulik LM. Role of locoregional therapies in the wake of systemic therapy. J Hepatol 2020; 72 (02) 277-287
    CrossrefPubMedSearch in Google Scholar
  • 60 Kim KM, Kim JH, Park IS. et al. Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion. J Gastroenterol Hepatol 2009; 24 (05) 806-814
    CrossrefPubMedSearch in Google Scholar
  • 61 Georgiades CS, Hong K, D'Angelo M, Geschwind JFH. Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 2005; 16 (12) 1653-1659
    CrossrefPubMedSearch in Google Scholar
  • 62 Zhang XB, Wang JH, Yan ZP, Qian S, Liu R. Hepatocellular carcinoma invading the main portal vein: treatment with transcatheter arterial chemoembolization and portal vein stenting. Cardiovasc Intervent Radiol 2009; 32 (01) 52-61
    CrossrefPubMedSearch in Google Scholar
  • 63 Chung GE, Lee JH, Kim HY. et al. Transarterial chemoembolization can be safely performed in patients with hepatocellular carcinoma invading the main portal vein and may improve the overall survival. Radiology 2011; 258 (02) 627-634
    CrossrefPubMedSearch in Google Scholar
  • 64 Lee HS, Kim JS, Choi IJ, Chung JW, Park JH, Kim CY. The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. A prospective controlled study. Cancer 1997; 79 (11) 2087-2094
    CrossrefPubMedSearch in Google Scholar
  • 65 Yoo DJ, Kim KM, Jin YJ. et al. Clinical outcome of 251 patients with extrahepatic metastasis at initial diagnosis of hepatocellular carcinoma: does transarterial chemoembolization improve survival in these patients?. J Gastroenterol Hepatol 2011; 26 (01) 145-154
    CrossrefPubMedSearch in Google Scholar
  • 66 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 (03) 868-878
    CrossrefPubMedSearch in Google Scholar
  • 67 Salem R, Lewandowski RJ, Atassi B. et al. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival. J Vasc Interv Radiol 2005; 16 (12) 1627-1639
    CrossrefPubMedSearch in Google Scholar
  • 68 Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19 (03) 329-338
    Thieme ConnectPubMedSearch in Google Scholar
  • 69 Chow PKH, Gandhi M, Tan S-B. et al. Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 2018; 36 (19) 1913-1921
    CrossrefPubMedSearch in Google Scholar
  • 70 Vilgrain V, Pereira H, Assenat E. et al. SARAH Trial Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol 2017; 18 (12) 1624-1636
    CrossrefPubMedSearch in Google Scholar
  • 71 Ricke J, Klümpen HJ, Amthauer H. et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol 2019; 71 (06) 1164-1174
    CrossrefPubMedSearch in Google Scholar
  • 72 Venerito M, Pech M, Canbay A. et al. Nemesis: non-inferiority meta-analysis of selective internal radiation therapy with yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma: a preliminary analysis. J Clin Oncol 2019; 37 (15) e15604
    CrossrefPubMedSearch in Google Scholar
  • 73 Garin E, Tzelikas L, Guiu B. et al. Major impact of personalized dosimetry using 90Y loaded glass microspheres SIRT in HCC: Final overall survival analysis of a multicenter randomized phase II study (DOSISPHERE-01). J Clin Oncol 2020; 38 (4_suppl): 516
    CrossrefPubMedSearch in Google Scholar
  • 74 Garin E, Palard X, Rolland Y. Personalised dosimetry in radioembolisation for HCC: impact on clinical outcome and on trial design. Cancers (Basel) 2020; 12 (06) 1557
    CrossrefPubMedSearch in Google Scholar
  • 75 Ren NA, Qin S, Ding L, Jia E, Xue J. Comparison of Transarterial Y90 Radioembolization and Conventional Transarterial Chemoembolization in Hepatocarcinoma Patients: A Meta-Analysis. Vol 82. OMICS International. 2020 . Accessed July 14, 2020 at: www.ijpsonline.com
    Search in Google Scholar
  • 76 Kudo M, Ueshima K, Ikeda M. et al. Randomized, open label, multicenter, phase II trial comparing transarterial chemoembolization (TACE) plus sorafenib with TACE alone in patients with hepatocellular carcinoma (HCC): TACTICS trial. J Clin Oncol 2018; 36 (04) 206
    CrossrefPubMedSearch in Google Scholar
  • 77 Dendy MS, Ludwig JM, Stein SM, Kim HS. Locoregional therapy, immunotherapy and the combination in hepatocellular carcinoma: future directions. Liver Cancer 2019; 8 (05) 326-340
    CrossrefPubMedSearch in Google Scholar
  • 78 Feng D, Hui X, Shi-Chun L. et al. Initial experience of anti-PD1 therapy with nivolumab in advanced hepatocellular carcinoma. Oncotarget 2017; 8 (57) 96649-96655
    CrossrefPubMedSearch in Google Scholar
  • 79 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
    CrossrefPubMedSearch in Google Scholar
  • 80 Sangro B, Gomez-Martin C, de la Mata M. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013; 59 (01) 81-88
    CrossrefPubMedSearch in Google Scholar
  • 81 Iñarrairaegui M, Melero I, Sangro B. Immunotherapy of hepatocellular carcinoma: Facts and hopes. Clin Cancer Res 2018; 24 (07) 1518-1524
    CrossrefPubMedSearch in Google Scholar
  • 82 Lahti S, Ludwig JM, Xing M, Sun L, Zeng D, Kim HS. In vitro biologic efficacy of sunitinib drug-eluting beads on human colorectal and hepatocellular carcinoma - a pilot study. PLoS One 2017; 12 (04) e0174539
    CrossrefPubMedSearch in Google Scholar
  • 83 Fuchs K, Duran R, Denys A, Bize PE, Borchard G, Jordan O. Drug-eluting embolic microspheres for local drug delivery - state of the art. J Control Release 2017; 262: 127-138
    CrossrefPubMedSearch in Google Scholar
  • 84 Bédouet L, Verret V, Louguet S. et al. Anti-angiogenic drug delivery from hydrophilic resorbable embolization microspheres: an in vitro study with sunitinib and bevacizumab. Int J Pharm 2015; 484 (1-2): 218-227
    CrossrefPubMedSearch in Google Scholar