Abstract
Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.
Similar content being viewed by others
References
Akinyemiju T, Abera S, Ahmed M, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level. JAMA Oncol. 2017;98121:1683–1691.
Ryerson AB, Eheman CR, Altekruse SF, et al. Annual report to the nation on the status of cancer, 1975–2012, featuring the increasing incidence of liver cancer. Cancer. 2016;122:1312–1337.
Mcglynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19:223–238.
Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30:1434–1440.
Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–380.
Galle PR, Forner A, Llovet JM, et al. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.
Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology. 1995;197:101–108.
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;234:961–967.
Giorgio A, Di Sarno A, De Stefano G, et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma compared to percutaneous ethanol injection in treatment of cirrhotic patients: an Italian randomized controlled trial. Anticancer Res. 2011;31:2291–2295.
Firouznia K, Ghanaati H, Alavian SM, et al. Transcatheter Arterial chemoembolization therapy for patients with unresectable hepatocellular carcinoma. Hepat Mon. 2014;14:918–925.
Katsanos K, Kitrou P, Spiliopoulos S, Maroulis I, Petsas T, Karnabatidis D. Comparative effectiveness of different transarterial embolization therapies alone or in combination with local ablative or adjuvant systemic treatments for unresectable hepatocellular carcinoma: A network meta-analysis of randomized controlled trials. PLoS One. 2017;. https://doi.org/10.1371/journal.pone.0184597.
Kumar M, Panda D. Role of supportive care for terminal stage hepatocellular carcinoma. J Clin Exp Hepatol. 2014;4:S130–S139.
Cabibbo G, Maida M, Genco C, et al. Natural history of untreatable hepatocellular carcinoma: a retrospective cohort study. World J Hepatol. 2012;4:256–261.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2016;. https://doi.org/10.1038/nrdp.2016.18.
Rao CV, Asch AS, Yamada HY. Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer. Carcinogenesis. 2017;38:2–11.
Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: an update. World J Gastroenterol. 2016;22:9069–9095.
Lee J-S. The mutational landscape of hepatocellular carcinoma. Clin Mol Hepatol. 2015;21:220–229.
Kan Z, Zheng H, Liu X, et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23:1422–1433.
Cleary SP, Jeck WR, Zhao X, et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology. 2013;58:1693–1702.
Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–1273.
Ding X-X, Zhu Q-G, Zhang S-M, et al. Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy. Oncotarget. 2017;8:55715–55730.
Kawai-Kitahata F, Asahina Y, Tanaka S, et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J Gastroenterol. 2016;51:473–486.
Xu Y, Goldkorn A. Telomere and telomerase therapeutics in cancer. Genes (Basel). 2016;. https://doi.org/10.3390/genes7060022.
Pez F, Lopez A, Kim M, Wands JR, De Fromentel CC, Merle P. Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013;59:1107–1117.
Takai A, Dang HT, Wang XW. Identification of drivers from cancer genome diversity in hepatocellular carcinoma. Int J Mol Sci. 2014;15:11142–11160.
Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152:745–761.
Alizadeh AA, Aranda V, Bardelli A, et al. Toward understanding and exploiting tumor heterogeneity. Nat Med. 2015;21:846–853.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.
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;10:25–34.
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;391:1163–1173.
Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.
Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in Patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63.
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;389:2492–2502.
Cheng A-L, Kang Y-K, Lin D-Y, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067–4075.
Cainap C, Qin S, Huang W-T, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33:172–179.
Johnson PJ, Qin S, Park J-W, et al. Brivanib versus Sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31:3517–3524.
Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: Results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509–3516.
Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of Sorafenib: the EVOLVE-1 randomized clinical trial. J Am Med Assoc. 2014;312:57–67.
Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16:859–870.
Rimassa L, Assenat E, Peck-Radosavljevic M, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;. https://doi.org/10.1016/s1470-2045(18)30146-3.
Zhu AX, Rosmorduc O, Evans TRJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of Sorafenib Plus Erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33:559–566.
Kang YK, Yau T, Park JW, et al. Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma. Ann Oncol. 2015;26:2457–2463.
Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26:2992–2998.
Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;27:843–850.
Yau T, Wong H, Chan P, et al. Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease. Investig New Drugs. 2012;30:2384–2390.
Philip PA, Mahoney MR, Holen KD, et al. Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer. Cancer. 2012;118:2424–2430.
Kaseb AO, Garrett-Mayer E, Morris JS, et al. Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial. Oncology. 2012;82:67–74.
Hsu C-H, Kang YK, Yang T-S, et al. Bevacizumab with Erlotinib as first-line therapy in asian patients with advanced hepatocellular carcinoma: a multicenter phase II study. Oncology. 2013;85:44–52.
Govindarajan R, Siegel E, Makhoul I, Williamson S. Bevacizumab and erlotinib in previously untreated inoperable and metastatic hepatocellular carcinoma. Am J Clin Oncol Cancer Clin Trials. 2013;36:254–257.
Kaseb AO, Morris JS, Iwasaki M, et al. Phase II trial of bevacizumab and erlotinib as a second-line therapy for advanced hepatocellular carcinoma. Onco Targets Ther. 2016;9:773–780.
Hubbard JM, Mahoney MR, Loui WS, et al. Phase I/II randomized trial of Sorafenib and Bevacizumab as first-line therapy in patients with locally advanced or metastatic hepatocellular carcinoma: North Central Cancer Treatment Group trial N0745 (Alliance). Target Oncol. 2017;12:201–209.
Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:1898–1903.
Sun W, Sohal D, Haller DG, et al. Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer. 2011;117:3187–3192.
Hsu CH, Yang TS, Hsu C, et al. Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br J Cancer. 2010;102:981–986.
Alberts SR, Fitch TR, Kim GP, et al. Cediranib (AZD2171) in patients with advanced hepatocellular carcinoma: a phase II north central cancer treatment group clinical trial. Am J Clin Oncol Cancer Clin Trials. 2012;35:329–333.
Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer. 2007;110:581–589.
O’Dwyer P, Giantonio B, Levy D. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group’s study E1203 [abstract]. J Clin Oncol. 2006;24:A-4143.
Asnacios A, Fartoux L, Romano O, et al. Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: Results of a multicenter phase 2 study. Cancer. 2008;112:2733–2739.
Sanoff HK, Bernard S, Goldberg RM, et al. Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma. Gastrointest Cancer Res. 2011;4:78–83.
Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer. 2007;110:1059–1067.
Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;23:6657–6663.
Pircher A, Wolf D, Heidenreich A, Hilbe W, Pichler R, Heidegger I. Synergies of targeting tumor angiogenesis and immune checkpoints in non-small cell lung cancer and renal cell cancer: From basic concepts to clinical reality. Int J Mol Sci. 2017;18:1–15.
Tsukita Y, Okazaki T, Komatsu R, et al. Effects of a combination of antiangiogenic and antilymphangiogenic therapies on a death receptor-5 mediated antitumor immunotherapy in mice. J Clin Oncol. 2017;35:2e3001.
Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18:31–41.
Rizvi NA, Antonia SJ, Shepherd FA, et al. GS: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) maintenance as monotherapy or in combination with bevacizumab (BEV) for non-small cell lung cancer (NSCLC) previously treated with chemotherapy. Int J Radiat Oncol Biol Phys. 2014;90:S32.
Chau I, Penel N, Arkenau H-T, et al. Safety and antitumor activity of ramucirumab plus pembrolizumab in treatment naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: Preliminary results from a multi-disease phase I study (JVDF). J Clin Oncol. 2018;36:101.
Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the Checkmate study 016. J Clin Oncol. 2017;35:3851–3858.
Apolo AB, Mortazavi A, Stein MN, et al. A phase I study of cabozantinib plus nivolumab (CaboNivo) and cabonivo plus ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic (m) urothelial carcinoma (UC) and other genitourinary (GU) tumors. J Clin Oncol. 2017;35:4562.
Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19:405–415.
Dudek AZ, Sica RA, Sidani A, et al. Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma: big ten cancer research consortium BTCRC-GU14–003. J Clin Oncol. 2016;34:559.
Chowdhury S, McDermott DF, Voss MH, et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2017;35:4506.
McDermott DF, Atkins MB, Motzer RJ, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). J Clin Oncol. 2017;35:431.
Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4074.
Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer. 2007;109:1384–1390.
Olweny CL, Toya T, Katongole-Mbidde E, Mugerwa J, Kyalwazi SKCH. Treatment of hepatocellular carcinoma with adriamycin. Preliminary communication. Cancer. 1975;36:1250.
Lai CL, Wu PC, Chan GC, Lok AS, Lin H. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988;62:479.
Abou-Alfa G, Johnson P, Knox JJ, Davidenko I, Lacava J, Leung T. Doxorubicin plus Sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma. JAMA. 2010;304:2154–2160.
Abou-Alfa G, Niedzwieski D, Knoxx J, Kaubisch A, Posey J. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). J Clin Oncol. 2016;34:2016–2017.
Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013;31:3501–3508.
Castells A, Bruix J, Bru C, et al. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology. 1995;109:917–922.
Group C, Programme LI. Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. Lancet. 1998;352:4–7.
Chow PK, Tai BC, Tan CK, et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology. 2002;36:1221–1226.
Colleoni M, Nelli P, Vicario G, Mastropasqua GMP. Megestrol acetate in unresectable hepatocellular carcinoma. Tumori. 1995;81:351–353.
Chao Y, Chan WK, Wang SS, et al. Phase II study of megestrol acetate in the treatment of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997;12:277–281.
Chow PKH, Machin D, Chen Y, et al. Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br J Cancer. 2011;105:945–952.
Greten TF, Forner A, Korangy F, et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer. 2010;10:209.
Brunsvig PF, Aamdal S, Gjertsen MK, et al. Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother. 2006;55:1553–1564.
Kyte JA, Gaudernack G, Dueland S, Trachsel S, Julsrud L, Aamdal S. Telomerase peptide vaccination combined with temozolomide: a clinical trial in stage IV melanoma patients. Clin Cancer Res. 2011;17:4568–4580.
Kawashima T, Kagawa S, Kobayashi N, et al. Telomerase-specific replication-selective virotherapy for human cancer. Clin Cancer Res. 2004;10:285–292.
Huang P, Watanabe M, Kaku H, et al. Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model. Cancer Gene Ther. 2008;15:315–322.
Sakakibara A, Tsukuda M, Kondo N, et al. Examination of the optimal condition on the in vitro sensitivity to telomelysin in head and neck cancer cell lines. Auris Nasus Larynx. 2011;38:589–599.
Watanabe Y, Hashimoto Y, Kagawa S, et al. Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells. Cancer Gene Ther. 2012;19:767–772.
Nemunaitis J, Tong AW, Nemunaitis M, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010;18:429–434.
Tefferi A, LaPlant BR, Begna K, et al. Imetelstat, a telomerase inhibitor, therapy for myelofibrosis: a pilot study. Blood. 2014;124:634.
Chiappori AA, Kolevska T, Spigel DR, et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol. 2015;26:354–362.
Kozloff M, Sledge GW, Benedetti FM, et al. Phase I study of imetelstat (GRN163L) in combination with paclitaxel (P) and bevacizumab (B) in patients (pts) with locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2010;28:2598.
Ratain MJ, Benedetti FM, Janisch L, et al. A phase I trial of GRN163L (GRN), a first-in-class telomerase inhibitor, in advanced solid tumors. J Clin Oncol. 2008;26:3581.
Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373:908–919.
Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, et al. Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N Engl J Med. 2015;373:920–928.
Harris MP, Sutjipto S, Wills KN, et al. Adenovirus-mediated p53 gene transfer inhibits growth of human tumor cells expressing mutant p53 protein. Cancer Gene Ther. 1996;3:121–130.
Foster BA, Coffey HA, Morin MJ, Rastinejad R. Pharmacological rescue of mutant p53 conformation and function. Science. 1999;286:2507–2510.
Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med. 1997;3:639–645.
Stokłosa T. Goła̧b J: prospects for p53-based cancer therapy. Acta Biochim Pol. 2005;52:321–328.
Tazawa H, Kagawa S, Fujiwara T. Advances in adenovirus-mediated p53 cancer gene therapy. Expert Opin Biol Ther. 2013;13:1569–1583.
Guan Y-S. p53 gene in treatment of hepatic carcinoma: Status quo. World J Gastroenterol. 2007;13:985.
Fricker J. Hepatocellular carcinoma and p53 gene therapy. Mol Med Today. 1996;2:361.
Shen A, Liu S, Yu W, Deng H, Li Q. p53 gene therapy-based transarterial chemoembolization for unresectable hepatocellular carcinoma: a prospective cohort study. J Gastroenterol Hepatol. 2015;30:1651–1656.
Guan Y-S. p53 gene therapy in combination with transcatheter arterial chemoembolization for HCC: one-year follow-up. World J Gastroenterol. 2011;17:2143.
Tian G, Liu J, Zhou JSR, Chen W. Multiple hepatic arterial injections of recombinant adenovirus p53 and 5-fluorouracil after transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a pilot phase II trial. Anticancer Drugs. 2009;20:389–395.
Yang Z, Wang D, Wang G, et al. Clinical study of recombinant adenovirus-p53 combined with fractionated stereotactic radiotherapy for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2010;136:625–630.
Zhang X, Hao J. Development of anticancer agents targeting the wnt/β-catenin signaling. Am J Cancer Res. 2015;5:2344–2360.
Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461–1473.
Gurney A, Axelrod F, Bond CJ, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci. 2012;109:11717–11722.
Giraudet A-L, Badel J-N, Cassier P, Desuzinges C, Kriza DPD, et al. SYNFRIZZA phase Ia/Ib of a radiolabelled monoclonal AB for the treatment of relapsing synovial sarcoma. J Nucl Med. 2014;55:223.
Yeung P, Beviglia L, Cancilla B, et al. Abstract 1907: Wnt pathway antagonist OMP-54F28 (FZD8-Fc) inhibits tumor growth and reduces tumor-initiating cell frequency in patient-derived hepatocellular carcinoma and ovarian cancer xenograft models. Cancer Res. 2014;74:1907.
Handeli S, Simon JA. A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPAR and PPAR activities. Mol Cancer Ther. 2008;7:521–529.
Ko AH, Chiorean EG, Kwak EL, et al. Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX. J Clin Oncol. 2016;34:e15721.
Bendell J, Eckhardt GS, Hochster HS, et al. Initial results from a phase 1a/b study of OMP-131R10, a first-in-class anti-RSPO3 antibody, in advanced solid tumors and previously treated metastatic colorectal cancer (CRC). Eur J Cancer. 2016;69:29–30.
Shih YL, Hsieh CB, Lai HC, et al. SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway. Int J Cancer. 2007;121:1028–1035.
Nambotin SB, Lefrancois L, Sainsily X, Berthillon P. Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma. J Hepatol. 2011;54:288–299.
Chang L, Chang M, Chang HM, Chang F. Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol. 2018;26:e15–e21.
Cortes-Ciriano I, Lee S, Park WY, Kim TM, Park PJ. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:1–12.
Goumard C, Desbois-Mouthon C, Wendum D, et al. Low levels of microsatellite instability at simple repeated sequences commonly occur in human hepatocellular carcinoma. Cancer Genom Proteom. 2017;14:329–339.
Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:1–14.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Saffo, S., Taddei, T.H. Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies. Dig Dis Sci 64, 1016–1029 (2019). https://doi.org/10.1007/s10620-019-05582-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-019-05582-x