Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check

doi:10.1007/s11684-019-0728-2

Front. Med.

2020, Vol. 14

Issue (3) : 273-283 https://doi.org/10.1007/s11684-019-0728-2

REVIEW

Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check

Amy Lee¹, Fa-Chyi Lee²(

)

¹. Department of Biology, University of California San Diego, San Diego, CA 92093, USA
². Division of Hematology/Oncology, Department of Internal Medicine, University of California Irvine, Orange, CA 92868, USA

Download: PDF(276 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

In terms of global cancer-related deaths, hepatocellular carcinoma (HCC) has the fourth highest mortality rate. Up until 2017, treatment of advanced HCC was largely limited to sorafenib, an oral tyrosine kinase inhibitor, with little to no success in the development of alternative treatment options. However, in the past two years, there has been an unprecedented increase in both the number and type of treatment options available for HCC. As of 2019, the US FDA has approved four oral tyrosine kinase inhibitors, two immune checkpoint inhibitors, and one anti-angiogenesis antibody for the treatment of HCC. Even with this new variety, systemic treatment of advanced HCC remains largely unsatisfactory, and the median survival rate stands at approximately one year. The expected breakthrough of using immune checkpoint inhibitors in advanced HCC did not materialize in 2019. The use of immune checkpoint inhibitors in conjunction with oral tyrosine kinase inhibitors or anti-angiogenesis medications is the current clinical research trend, the results of which are eagerly anticipated. Despite limited progress in survival, HCC research is currently experiencing a period of growth and innovation, and there is hope for significant advances in the treatment of advanced HCC as the field continues to develop.

Keywords hepatocellular carcinoma tyrosine kinase inhibitor check point inhibitor anti-angiogenesis

Corresponding Author(s): Fa-Chyi Lee

Just Accepted Date: 19 November 2019 Online First Date: 24 December 2019 Issue Date: 08 June 2020

Cite this article:

Amy Lee,Fa-Chyi Lee. Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check[J]. Front. Med., 2020, 14(3): 273-283.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0728-2
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I3/273

Fig.1 Timeline of the US FDA approval for HCC treatments. The approval of sorafenib was followed by a decade of stagnation until several treatment options were approved from 2017 to 2019. * indicates Child-Pugh Classification.

Tab.1 US FDA approval dates for use of the four oral TKIs in various cancers

Tab.2 Clinical efficacy and toxicity of the four oral TKIs in treatment for HCC

Tab.3 Main targets of the four US FDA-approved oral TKIs in HCC

Fig.2 Current treatment scheme for patients with advanced/metastatic HCC. Sorafenib/lenvantinib has replaced doxorubicin as the standard front-line treatment. Nivolumab or pembrolizumab are the most commonly used immunotherapy treatments. Other TKIs include regorafenib, cabozantinib or lenvantinib if lenvantinib was not used as the front-line treatment. Use of Ramucirumab is limited to patients with AFP≥400 ng/mL. Cytotoxic chemotherapy is listed as an “Other recommended” first-line treatment option on the NCCN Guidelines.

1	CL Lai, PC Wu, GC Chan, AS Lok, HJ Lin. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 62(3): 479–483 https://doi.org/10.1002/1097-0142(19880801)62:3<479::AID-CNCR2820620306>3.0.CO;2-L pmid: 2839280
2	TS Mok, TW Leung, SD Lee, Y Chao, AT Chan, A Huang, MC Lui, W Yeo, K Chak, A Johnston, P Johnson. A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 1999; 44(4): 307–311 https://doi.org/10.1007/s002800050982 pmid: 10447578
3	RG Gish, C Porta, L Lazar, P Ruff, R Feld, A Croitoru, L Feun, K Jeziorski, J Leighton, J Gallo, GT Kennealey. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 2007; 25(21): 3069–3075 https://doi.org/10.1200/JCO.2006.08.4046 pmid: 17634485
4	U Halm, G Etzrodt, I Schiefke, F Schmidt, H Witzigmann, J Mössner, F Berr. A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma. Ann Oncol 2000; 11(1): 113–114 https://doi.org/10.1023/A:1008386822906 pmid: 10690399
5	M Schmidinger, C Wenzel, GJ Locker, F Muehlbacher, R Steininger, M Gnant, R Crevenna, AC Budinsky. Pilot study with pegylated liposomal doxorubicin for advanced or unresectable hepatocellular carcinoma. Br J Cancer 2001; 85(12): 1850–1852 https://doi.org/10.1054/bjoc.2001.2149 pmid: 11747325
6	RL Hong, YL Tseng. A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2003; 51(5): 433–438 pmid: 12736762
7	SM Wilhelm, C Carter, L Tang, D Wilkie, A McNabola, H Rong, C Chen, X Zhang, P Vincent, M McHugh, Y Cao, J Shujath, S Gawlak, D Eveleigh, B Rowley, L Liu, L Adnane, M Lynch, D Auclair, I Taylor, R Gedrich, A Voznesensky, B Riedl, LE Post, G Bollag, PA Trail. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64(19): 7099–7109 https://doi.org/10.1158/0008-5472.CAN-04-1443 pmid: 15466206
8	L Liu, Y Cao, C Chen, X Zhang, A McNabola, D Wilkie, S Wilhelm, M Lynch, C Carter. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006; 66(24): 11851–11858 https://doi.org/10.1158/0008-5472.CAN-06-1377 pmid: 17178882
9	D Strumberg, H Richly, RA Hilger, N Schleucher, S Korfee, M Tewes, M Faghih, E Brendel, D Voliotis, CG Haase, B Schwartz, A Awada, R Voigtmann, ME Scheulen, S Seeber. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005; 23(5): 965–972 https://doi.org/10.1200/JCO.2005.06.124 pmid: 15613696
10	GK Abou-Alfa, L Schwartz, S Ricci , D Amadori, A Santoro, A Figer, J De Greve, JY Douillard, C Lathia, B Schwartz, I Taylor, M Moscovici, LB Saltz. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24(26): 4293–4300 https://doi.org/DOI:10.1200/JCO.2005.01.3441 pmid: 16908937
11	JM Llovet, S Ricci, V Mazzaferro, P Hilgard, E Gane, JF Blanc, AC de Oliveira, A Santoro, JL Raoul, A Forner, M Schwartz, C Porta, S Zeuzem, L Bolondi, TF Greten, PR Galle, JF Seitz, I Borbath, D Häussinger, T Giannaris, M Shan, M Moscovici, D Voliotis, J Bruix; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378–390 https://doi.org/10.1056/NEJMoa0708857 pmid: 18650514
12	AL Cheng, YK Kang, Z Chen, CJ Tsao, S Qin, JS Kim, R Luo, J Feng, S Ye, TS Yang, J Xu, Y Sun, H Liang, J Liu, J Wang, WY Tak, H Pan, K Burock, J Zou, D Voliotis, Z Guan. 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 https://doi.org/10.1016/S1470-2045(08)70285-7 pmid: 19095497
13	H Richly, BF Henning, P Kupsch, K Passarge, M Grubert, RA Hilger, O Christensen, E Brendel, B Schwartz, M Ludwig, C Flashar, R Voigtmann, ME Scheulen, S Seeber, D Strumberg. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Ann Oncol 2006; 17(5): 866–873 https://doi.org/10.1093/annonc/mdl017 pmid: 16500908
14	H Richly, B Schultheis, IA Adamietz, P Kupsch, M Grubert, RA Hilger, M Ludwig, E Brendel, O Christensen, D Strumberg. Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial. Eur J Cancer 2009; 45(4): 579–587 https://doi.org/10.1016/j.ejca.2008.10.039 pmid: 19101137
15	GK Abou-Alfa, D Niedwieski, JJ Knox, et al.. 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(4 suppl): 192 https://doi.org/10.1200/jco.2016.34.4_suppl.192
16	MJ Blivet-Van Eggelpoël, H Chettouh, L Fartoux, L Aoudjehane, V Barbu, C Rey, S Priam, C Housset, O Rosmorduc, C Desbois-Mouthon. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol 2012; 57(1): 108–115 https://doi.org/10.1016/j.jhep.2012.02.019 pmid: 22414764
17	AX Zhu, O Rosmorduc, TR Evans, PJ Ross, A Santoro, FJ Carrilho, J Bruix, S Qin, PJ Thuluvath, JM Llovet, MA Leberre, M Jensen, G Meinhardt, YK Kang. 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(6): 559–566 https://doi.org/10.1200/JCO.2013.53.7746 pmid: 25547503
18	S Faivre, C Delbaldo, K Vera, C Robert, S Lozahic, N Lassau, C Bello, S Deprimo, N Brega, G Massimini, JP Armand, P Scigalla, E Raymond. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24(1): 25–35 https://doi.org/10.1200/JCO.2005.02.2194 pmid: 16314617
19	AL Cheng, YK Kang, DY Lin, JW Park, M Kudo, S Qin, HC Chung, X Song, J Xu, G Poggi, M Omata, S Pitman Lowenthal, S Lanzalone, L Yang, MJ Lechuga, E Raymond. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013; 31(32): 4067–4075 https://doi.org/10.1200/JCO.2012.45.8372 pmid: 24081937
20	RS Bhide, LJ Lombardo, JT Hunt, ZW Cai, JC Barrish, S Galbraith, R Jeyaseelan Sr, S Mortillo, BS Wautlet, B Krishnan, D Kukral, H Malone, AC Lewin, BJ Henley, J Fargnoli. The antiangiogenic activity in xenograft models of brivanib, a dual inhibitor of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinases. Mol Cancer Ther 2010; 9(2): 369–378 https://doi.org/10.1158/1535-7163.MCT-09-0472 pmid: 20103604
21	PJ Johnson, S Qin, JW Park, RT Poon, JL Raoul, PA Philip, CH Hsu, TH Hu, J Heo, J Xu, L Lu, Y Chao, E Boucher, KH Han, SW Paik, J Robles-Aviña, M Kudo, L Yan, A Sobhonslidsuk, D Komov, T Decaens, WY Tak, LB Jeng, D Liu, R Ezzeddine, I Walters, AL Cheng. 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(28): 3517–3524 https://doi.org/10.1200/JCO.2012.48.4410 pmid: 23980084
22	JM Llovet, T Decaens, JL Raoul, E Boucher, M Kudo, C Chang, YK Kang, E Assenat, HY Lim, V Boige, P Mathurin, L Fartoux, DY Lin, J Bruix, RT Poon, M Sherman, JF Blanc, RS Finn, WY Tak, Y Chao, R Ezzeddine, D Liu, I Walters, JW Park. 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(28): 3509–3516 https://doi.org/10.1200/JCO.2012.47.3009 pmid: 23980090
23	A Grothey, E Van Cutsem, A Sobrero, S Siena, A Falcone, M Ychou, Y Humblet, O Bouché, L Mineur, C Barone, A Adenis, J Tabernero, T Yoshino, HJ Lenz, RM Goldberg, DJ Sargent, F Cihon, L Cupit, A Wagner, D Laurent; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381(9863): 303–312 https://doi.org/10.1016/S0140-6736(12)61900-X pmid: 23177514
24	G Goel. Evolution of regorafenib from bench to bedside in colorectal cancer: is it an attractive option or merely a “me too” drug? Cancer Manag Res 2018; 10: 425–437 https://doi.org/10.2147/CMAR.S88825 pmid: 29563833
25	J Bruix, S Qin, P Merle, A Granito, YH Huang, G Bodoky, M Pracht, O Yokosuka, O Rosmorduc, V Breder, R Gerolami, G Masi, PJ Ross, T Song, JP Bronowicki, I Ollivier-Hourmand, M Kudo, AL Cheng, JM Llovet, RS Finn, MA LeBerre, A Baumhauer, G Meinhardt, G Han; 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 https://doi.org/10.1016/S0140-6736(16)32453-9 pmid: 27932229
26	J Matsui, Y Yamamoto, Y Funahashi, A Tsuruoka, T Watanabe, T Wakabayashi, T Uenaka, M Asada. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008; 122(3): 664–671 https://doi.org/10.1002/ijc.23131 pmid: 17943726
27	K Ikeda, M Kudo, S Kawazoe, Y Osaki, M Ikeda, T Okusaka, T Tamai, T Suzuki, T Hisai, S Hayato, K Okita, H Kumada. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol 2017; 52(4): 512–519 https://doi.org/10.1007/s00535-016-1263-4 pmid: 27704266
28	M Kudo, RS Finn, S Qin, KH Han, K Ikeda, F Piscaglia, A Baron, JW Park, G Han, J Jassem, JF Blanc, A Vogel, D Komov, TRJ Evans, C Lopez, C Dutcus, M Guo, K Saito, S Kraljevic, T Tamai, M Ren, AL Cheng. 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 https://doi.org/10.1016/S0140-6736(18)30207-1 pmid: 29433850
29	FM Yakes, J Chen, J Tan, K Yamaguchi, Y Shi, P Yu, F Qian, F Chu, F Bentzien, B Cancilla, J Orf, A You, AD Laird, S Engst, L Lee, J Lesch, YC Chou, AH Joly. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011; 10(12): 2298–2308 https://doi.org/10.1158/1535-7163.MCT-11-0264 pmid: 21926191
30	RK Kelley, C Verslype, AL Cohn, TS Yang, WC Su, H Burris, F Braiteh, N Vogelzang, A Spira, P Foster, Y Lee, E Van Cutsem. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol 2017; 28(3): 528–534 https://doi.org/10.1093/annonc/mdw651 pmid: 28426123
31	GK Abou-Alfa, T Meyer, AL Cheng, AB El-Khoueiry, L Rimassa, BY Ryoo, I Cicin, P Merle, Y Chen, JW Park, JF Blanc, L Bolondi, HJ Klümpen, SL Chan, V Zagonel, T Pressiani, MH Ryu, AP Venook, C Hessel, AE Borgman-Hagey, G Schwab, RK Kelley. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379(1): 54–63 https://doi.org/10.1056/NEJMoa1717002 pmid: 29972759
32	LM Ellis. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol 2006; 33(5 Suppl 10): S1–S7 https://doi.org/10.1053/j.seminoncol.2006.08.002 pmid: 17145519
33	P Fang, JH Hu, ZG Cheng, ZF Liu, JL Wang, SC Jiao. Efficacy and safety of bevacizumab for the treatment of advanced hepatocellular carcinoma: a systematic review of phase II trials. PLoS One 2012; 7(12): e49717 https://doi.org/10.1371/journal.pone.0049717 pmid: 23284624
34	JM Hubbard, MR Mahoney, WS Loui, LR Roberts, TC Smyrk, Z Gatalica, M Borad, S Kumar, SR Alberts. Phase I/II random-ized 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(2): 201–209 https://doi.org/10.1007/s11523-016-0467-0 pmid: 27943153
35	T Torimura, H Iwamoto, T Nakamura, M Abe, Y Ikezono, F Wada, T Sakaue, H Masuda, O Hashimoto, H Koga, T Ueno, H Yano. Antiangiogenic and antitumor activities of aflibercept, a soluble VEGF receptor-1 and -2, in a mouse model of hepatocellular carcinoma. Neoplasia 2016; 18(7): 413–424 https://doi.org/10.1016/j.neo.2016.05.001 pmid: 27435924
36	JL Sprat;om, RB Cohen, M Eadens, et al.. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 2010; 28: 780–787
37	AX Zhu, JO Park, BY Ryoo, CJ Yen, R Poon, D Pastorelli, JF Blanc, HC Chung, AD Baron, TE Pfiffer, T Okusaka, K Kubackova, J Trojan, J Sastre, I Chau, SC Chang, PB Abada, L Yang, JD Schwartz, M Kudo; REACH Trial Investigators. 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(7): 859–870 https://doi.org/10.1016/S1470-2045(15)00050-9 pmid: 26095784
38	AX Zhu, YK Kang, CJ Yen, RS Finn, PR Galle, JM Llovet, E Assenat, G Brandi, M Pracht, HY Lim, KM Rau, K Motomura, I Ohno, P Merle, B Daniele, DB Shin, G Gerken, C Borg, JB Hiriart, T Okusaka, M Morimoto, Y Hsu, PB Abada, M Kudo; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20(2): 282–296 https://doi.org/10.1016/S1470-2045(18)30937-9 pmid: 30665869
39	JM Llovet, R Montal, D Sia, RS Finn. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018; 15(10): 599–616 https://doi.org/10.1038/s41571-018-0073-4 pmid: 30061739
40	A Santoro, L Rimassa, I Borbath, B Daniele, S Salvagni, JL Van Laethem, H Van Vlierberghe, J Trojan, FT Kolligs, A Weiss, S Miles, A Gasbarrini, M Lencioni, L Cicalese, M Sherman, C Gridelli, P Buggisch, G Gerken, RM Schmid, C Boni, N Personeni, Z Hassoun, G Abbadessa, B Schwartz, R Von Roemeling, ME Lamar, Y Chen, C Porta. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013; 14(1): 55–63 https://doi.org/10.1016/S1470-2045(12)70490-4 pmid: 23182627
41	L Rimassa, E Assenat, M Peck-Radosavljevic, M Pracht, V Zagonel, P Mathurin, E Rota Caremoli, C Porta, B Daniele, L Bolondi, V Mazzaferro, W Harris, N Damjanov, D Pastorelli, M Reig, J Knox, F Negri, J Trojan, C López López, N Personeni, T Decaens, M Dupuy, W Sieghart, G Abbadessa, B Schwartz, M Lamar, T Goldberg, D Shuster, A Santoro, J Bruix. 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; 19(5): 682–693 https://doi.org/10.1016/S1470-2045(18)30146-3 pmid: 29625879
42	Y Hoshida, SM Nijman, M Kobayashi, JA Chan, JP Brunet, DY Chiang, A Villanueva, P Newell, K Ikeda, M Hashimoto, G Watanabe, S Gabriel, SL Friedman, H Kumada, JM Llovet, TR Golub. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009; 69(18): 7385–7392 https://doi.org/10.1158/0008-5472.CAN-09-1089 pmid: 19723656
43	S Boyault, DS Rickman, A de Reyniès, C Balabaud, S Rebouissou, E Jeannot, A Hérault, J Saric, J Belghiti, D Franco, P Bioulac-Sage, P Laurent-Puig, J Zucman-Rossi. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007; 45(1): 42–52 https://doi.org/10.1002/hep.21467 pmid: 17187432
44	AB El-Khoueiry, B Sangro, T Yau, TS Crocenzi, M Kudo, C Hsu, TY Kim, SP Choo, J Trojan, TH Welling 3rd, T Meyer, YK Kang, W Yeo, A Chopra, J Anderson, C Dela Cruz, L Lang, J Neely, H Tang, HB Dastani, I Melero. 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 https://doi.org/10.1016/S0140-6736(17)31046-2 pmid: 28434648
45	AX Zhu, RS Finn, J Edeline, S Cattan, S Ogasawara, D Palmer, C Verslype, V Zagonel, L Fartoux, A Vogel, D Sarker, G Verset, SL Chan, J Knox, B Daniele, AL Webber, SW Ebbinghaus, J Ma, AB Siegel, AL Cheng, M Kudo; 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(7): 940–952 https://doi.org/10.1016/S1470-2045(18)30351-6 pmid: 29875066
46	RS Finn, BY Ryoo, P Merle, et al.. Results of Keynote-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J Clin Oncol 2019; 37 (suppl) : 4004
47	K Lee, C HSU, MS Lee, et al.. Atezolizumab+ Bevacizumab in hepatocellular carcinoma (HCC): safety and clinical activity results from a Phase 1b study. Ann Oncol 2018; 29 (suppl_9): mdy432 https://doi.org/Doi:10.1093/annonc/mdy432
48	J Xu, Y Zhang, R Jia, C Yue, L Chang, R Liu, G Zhang, C Zhao, Y Zhang, C Chen, Y Wang, X Yi, Z Hu, J Zou, Q Wang. Anti-PD-1 antibody SHR-1210 combined with Apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res 2019; 25(2): 515–523 https://doi.org/10.1158/1078-0432.CCR-18-2484 pmid: 30348638
49	TC Yau, V Tang, J Chan, et al.. Outcomes of tyrosine kinase inhibitors (TKI) after immunotherapy in unresectable or advanced hepatocellular carcinoma (HCC) patients. J Clin Oncol 2019;39(4)_suppl.361
50	X Liu, S Qin. Immune Checkpoint inhibitors in hepatocellular carcinoma: opportunities and challenges. Oncologist 2019; 24(Suppl 1): S3–S10 https://doi.org/10.1634/theoncologist.2019-IO-S1-s01 pmid: 30819826
51	N Abdel-Wahab, H Safa, A Abudayyeh, DH Johnson, VA Trinh, CM Zobniw, H Lin, MK Wong, M Abdelrahim, AO Gaber, ME Suarez-Almazor, A Diab. Checkpoint inhibitors therapy for cancer in solid organ transplantation recipients: an institutional experience and a systemic review of the literature. J Immunother Cancer 2019; 7(1): 106 https://doi.org/10.1186/s40425-019-0585-1 pmid: PMID:30992053
52	S Munker, EN De Toni. Use of checkpoint inhibitors in liver transplant recipients. United European Gastroenterol J 2018; 6(7): 970–973 https://doi.org/10.1177/2050640618774631 pmid: 30228883
53	CM Ho, HL Chen, RH Hu, PH Lee. Harnessing immunotherapy for liver recipients with hepatocellular carcinoma: a review from a transplant oncology perspective. Ther Adv Med Oncol 2019; 11: 1758835919843463 https://doi.org/10.1177/1758835919843463 pmid: 31065295
54	S Qin, Y Bai, HY Lim, S Thongprasert, Y Chao, J Fan, TS Yang, V Bhudhisawasdi, WK Kang, Y Zhou, JH Lee, Y Sun. 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(28): 3501–3508 https://doi.org/10.1200/JCO.2012.44.5643 pmid: 23980077
55	DW Lee, KH Lee, HJ Kim, TY Kim, JS Kim, SW Han, DY Oh, JH Kim, SA Im, TY Kim. A phase II trial of S-1 and oxaliplatin in patients with advanced hepatocellular carcinoma. BMC Cancer 2018; 18(1): 252 https://doi.org/10.1186/s12885-018-4039-9 pmid: 29506478
56	M Reig, Z Mariño, C Perelló, M Iñarrairaegui, A Ribeiro, S Lens, A Díaz, R Vilana, A Darnell, M Varela, B Sangro, JL Calleja, X Forns, J Bruix. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65(4): 719–726 https://doi.org/10.1016/j.jhep.2016.04.008 pmid: 27084592
57	F Conti, F Buonfiglioli, A Scuteri, C Crespi, L Bolondi, P Caraceni, FG Foschi, M Lenzi, G Mazzella, G Verucchi, P Andreone, S Brillanti. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65(4): 727–733 https://doi.org/10.1016/j.jhep.2016.06.015 pmid: 27349488
58	H Nagata, M Nakagawa, Y Asahina, A Sato, Y Asano, T Tsunoda, M Miyoshi, S Kaneko, S Otani, F Kawai-Kitahata, M Murakawa, S Nitta, Y Itsui, S Azuma, S Kakinuma, T Nouchi, H Sakai, M Tomita, M Watanabe; Ochanomizu Liver Conference Study Group. Effect of interferon-based and-free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol 2017; 67(5): 933–939 https://doi.org/10.1016/j.jhep.2017.05.028 pmid: 28627363
59	AG Singal, NE Rich, N Mehta, A Branch, A Pillai, M Hoteit, M Volk, M Odewole, S Scaglione, J Guy, A Said, JJ Feld, BV John, C Frenette, P Mantry, AS Rangnekar, O Oloruntoba, M Leise, JH Jou, KR Bhamidimarri, L Kulik, T Tran, H Samant, R Dhanasekaran, A Duarte-Rojo, R Salgia, S Eswaran, P Jalal, A Flores, SK Satapathy, R Wong, A Huang, S Misra, M Schwartz, R Mitrani, S Nakka, W Noureddine, C Ho, VR Konjeti, A Dao, K Nelson, K Delarosa, U Rahim, M Mavuram, JJ Xie, CC Murphy, ND Parikh. Direct-acting antiviral therapy no associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study. Gastroenterology 2019; 156(6): 1683–1692.e1 https://doi.org/10.1053/j.gastro.2019.01.027 pmid: 30660729
60	M Guarino, A Sessa, V Cossiga, F Morando, N Caporaso, F Morisco; Special Interest Group on “Hepatocellular carcinoma and new anti-HCV therapies” of the Italian Association for the Study of the Liver. Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: a few lights and many shadows. World J Gastroenterol 2018; 24(24): 2582–2595 https://doi.org/10.3748/wjg.v24.i24.2582 pmid: 29962815
61	M Guarino, L Viganò, FR Ponziani, EG Giannini, Q Lai, F Morisco; Special Interest Group on Hepatocellular carcinoma and new anti-HCV therapies” of the Italian Association for the Study of the Liver. Recurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: literature review and risk analysis. Dig Liver Dis 2018; 50(11): 1105–1114 https://doi.org/10.1016/j.dld.2018.08.001 pmid: 30170908
62	YQ Zhang, JS Guo. Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2015; 21(13): 3860–3866 https://doi.org/10.3748/wjg.v21.i13.3860 pmid: 25852270
63	M Pazgan-Simon, KA Simon, E Jarowicz, K Rotter, A Szymanek-Pasternak, J Zuwała-Jagiełło. Hepatitis B virus treatment in hepatocellular carcinoma patients prolongs survival and reduces the risk of cancer recurrence. Clin Exp Hepatol 2018; 4(3): 210–216 https://doi.org/10.5114/ceh.2018.78127 pmid: 30324148

[1]	Ching-Hon Pui. Precision medicine in acute lymphoblastic leukemia[J]. Front. Med., 2020, 14(6): 689-700.
[2]	Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao. Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects[J]. Front. Med., 2019, 13(4): 427-437.
[3]	Xiaojun Huang, Qian Jiang, Jianda Hu, Jianyong Li, Jie Jin, Fanyi Meng, Zhixiang Shen, Ting Liu, Depei Wu, Jianmin Wang, Jianxiang Wang. Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety[J]. Front. Med., 2019, 13(3): 344-353.
[4]	Renyu Zhang, Zhao Zhang, Zekun Liu, Ding Wei, Xiaodong Wu, Huijie Bian, Zhinan Chen. Adoptive cell transfer therapy for hepatocellular carcinoma[J]. Front. Med., 2019, 13(1): 3-11.
[5]	Shasha Zhu, Huimin Zhang, Li Bai. NKT cells in liver diseases[J]. Front. Med., 2018, 12(3): 249-261.
[6]	Guangbiao Zhou, Xinchun Zhao. Carcinogens that induce the A:T>T:A nucleotide substitutions in the genome[J]. Front. Med., 2018, 12(2): 236-238.
[7]	Min Yu, Zonghai Li. Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches[J]. Front. Med., 2017, 11(4): 509-521.
[8]	Zhen He,Cheng Hu,Weiping Jia. miRNAs in non-alcoholic fatty liver disease[J]. Front. Med., 2016, 10(4): 389-396.
[9]	Shuhang Wang,Yongping Song,Feifei Yan,Delong Liu. Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors[J]. Front. Med., 2016, 10(4): 383-388.
[10]	Xinsen Xu,Yanyan Zhou,Runchen Miao,Wei Chen,Kai Qu,Qing Pang,Chang Liu. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis[J]. Front. Med., 2016, 10(2): 183-190.
[11]	Zhi Xu,Chunxiang Cao,Haiyan Xia,Shujing Shi,Lingzhi Hong,Xiaowei Wei,Dongying Gu,Jianmin Bian,Zijun Liu,Wenbin Huang,Yixin Zhang,Song He,Nikki Pui-Yue Lee,Jinfei Chen. Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma[J]. Front. Med., 2016, 10(1): 52-60.
[12]	Felice Ho-Ching Tsang,Sandy Leung-Kuen Au,Lai Wei,Dorothy Ngo-Yin Fan,Joyce Man-Fong Lee,Carmen Chak-Lui Wong,Irene Oi-Lin Ng,Chun-Ming Wong. MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility[J]. Front. Med., 2015, 9(3): 331-343.
[13]	Farhad Sahebjam,John M. Vierling. Autoimmune hepatitis[J]. Front. Med., 2015, 9(2): 187-219.
[14]	Guanghua Rong,Wenlin Bai,Zheng Dong,Chunping Wang,Yinying Lu,Zhen Zeng,Jianhui Qu,Min Lou,Hong Wang,Xudong Gao,Xiujuan Chang,Linjing An,Yan Chen,Yongping Yang. Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases[J]. Front. Med., 2015, 9(1): 63-71.
[15]	Kai Qu,Ting Lin,Zhixin Wang,Sinan Liu,Hulin Chang,Xinsen Xu,Fandi Meng,Lei Zhou,Jichao Wei,Minghui Tai,Yafeng Dong,Chang Liu. Reactive oxygen species generation is essential for cisplatin-induced accelerated senescence in hepatocellular carcinoma[J]. Front. Med., 2014, 8(2): 227-235.

Viewed

Full text

Abstract

Cited

Shared

Discussed