Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Current Translational and Clinical Challenges in Advanced Hepatocellular Carcinoma

Author(s): Melissa Frizziero, Mairéad G. McNamara, Angela Lamarca, Rille Pihlak, Roopa Kurup and Richard A. Hubner*

Volume 27, Issue 29, 2020

Page: [4789 - 4805] Pages: 17

DOI: 10.2174/0929867327666200422143847

Price: $65

Abstract

Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated deaths worldwide. Reversing this trend is complicated by the varied aetiological factors leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined with frequent presentation at advanced stage. Large-scale genomic studies have identified alterations in key signalling pathways for HCC development and progression, but these findings have not yet directly influenced patient management in the clinical setting. Despite these translational challenges, a small number of anti-angiogenic systemic therapy agents have succeeded in recent randomized trials enriching the repertoire of available treatments for advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the cusp of delivering changes to standard systemic therapy algorithms. This review focuses on recent translational and clinical developments that have advanced current practice and explores the challenges encountered in attempting to improve the outcomes and experience of patients diagnosed with advanced HCC.

Keywords: Hepatocellular carcinoma, translational research, genome profiling, targeted agents, immune checkpoint inhibition.

« Previous Next »
[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[3]
Villanueva, A. Hepatocellular Carcinoma. N. Engl. J. Med., 2019, 380(15), 1450-1462.
[http://dx.doi.org/10.1056/NEJMra1713263] [PMID: 30970190]
[4]
Balogh, J.; Victor, D., III; Asham, E.H.; Burroughs, S.G.; Boktour, M.; Saharia, A.; Li, X.; Ghobrial, R.M.; Monsour, H.P. Jr Hepatocellular carcinoma: a review. J. Hepatocell. Carcinoma, 2016, 3, 41-53.
[http://dx.doi.org/10.2147/JHC.S61146] [PMID: 27785449]
[5]
El-Serag, H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology, 2012, 142(6), 1264-1273. e1.
[http://dx.doi.org/10.1053/j.gastro.2011.12.061]
[6]
Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends--an update. Cancer Epidemiol. Biomarkers Prev., 2016, 25(1), 16-27.
[http://dx.doi.org/10.1158/1055-9965.EPI-15-0578] [PMID: 26667886]
[7]
Younossi, Z.; Stepanova, M.; Ong, J.P.; Jacobson, I.M.; Bugianesi, E.; Duseja, A. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin. Gastroenterol Hepatol, 2019, 17(4), 748-755. e3.
[http://dx.doi.org/10.1016/j.cgh.2018.05.057]
[8]
Schulze, K.; Imbeaud, S.; Letouzé, E.; Alexandrov, L.B.; Calderaro, J.; Rebouissou, S.; Couchy, G.; Meiller, C.; Shinde, J.; Soysouvanh, F.; Calatayud, A.L.; Pinyol, R.; Pelletier, L.; Balabaud, C.; Laurent, A.; Blanc, J.F.; Mazzaferro, V.; Calvo, F.; Villanueva, A.; Nault, J.C.; Bioulac-Sage, P.; Stratton, M.R.; Llovet, J.M.; Zucman-Rossi, J. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet., 2015, 47(5), 505-511.
[http://dx.doi.org/10.1038/ng.3252] [PMID: 25822088]
[9]
Li, M.; Zhao, H.; Zhang, X.; Wood, L.D.; Anders, R.A.; Choti, M.A.; Pawlik, T.M.; Daniel, H.D.; Kannangai, R.; Offerhaus, G.J.; Velculescu, V.E.; Wang, L.; Zhou, S.; Vogelstein, B.; Hruban, R.H.; Papadopoulos, N.; Cai, J.; Torbenson, M.S.; Kinzler, K.W. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet., 2011, 43(9), 828-829.
[http://dx.doi.org/10.1038/ng.903] [PMID: 21822264]
[10]
Fujimoto, A.; Totoki, Y.; Abe, T.; Boroevich, K.A.; Hosoda, F.; Nguyen, H.H.; Aoki, M.; Hosono, N.; Kubo, M.; Miya, F.; Arai, Y.; Takahashi, H.; Shirakihara, T.; Nagasaki, M.; Shibuya, T.; Nakano, K.; Watanabe-Makino, K.; Tanaka, H.; Nakamura, H.; Kusuda, J.; Ojima, H.; Shimada, K.; Okusaka, T.; Ueno, M.; Shigekawa, Y.; Kawakami, Y.; Arihiro, K.; Ohdan, H.; Gotoh, K.; Ishikawa, O.; Ariizumi, S.; Yamamoto, M.; Yamada, T.; Chayama, K.; Kosuge, T.; Yamaue, H.; Kamatani, N.; Miyano, S.; Nakagama, H.; Nakamura, Y.; Tsunoda, T.; Shibata, T.; Nakagawa, H. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat. Genet., 2012, 44(7), 760-764.
[http://dx.doi.org/10.1038/ng.2291] [PMID: 22634756]
[11]
Guichard, C.; Amaddeo, G.; Imbeaud, S.; Ladeiro, Y.; Pelletier, L.; Maad, I.B.; Calderaro, J.; Bioulac-Sage, P.; Letexier, M.; Degos, F.; Clément, B.; Balabaud, C.; Chevet, E.; Laurent, A.; Couchy, G.; Letouzé, E.; Calvo, F.; Zucman-Rossi, J. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet., 2012, 44(6), 694-698.
[http://dx.doi.org/10.1038/ng.2256] [PMID: 22561517]
[12]
Cleary, S.P.; Jeck, W.R.; Zhao, X.; Chen, K.; Selitsky, S.R.; Savich, G.L.; Tan, T.X.; Wu, M.C.; Getz, G.; Lawrence, M.S.; Parker, J.S.; Li, J.; Powers, S.; Kim, H.; Fischer, S.; Guindi, M.; Ghanekar, A.; Chiang, D.Y. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology, 2013, 58(5), 1693-1702.
[http://dx.doi.org/10.1002/hep.26540] [PMID: 23728943]
[13]
Sung, W.K.; Zheng, H.; Li, S.; Chen, R.; Liu, X.; Li, Y.; Lee, N.P.; Lee, W.H.; Ariyaratne, P.N.; Tennakoon, C.; Mulawadi, F.H.; Wong, K.F.; Liu, A.M.; Poon, R.T.; Fan, S.T.; Chan, K.L.; Gong, Z.; Hu, Y.; Lin, Z.; Wang, G.; Zhang, Q.; Barber, T.D.; Chou, W.C.; Aggarwal, A.; Hao, K.; Zhou, W.; Zhang, C.; Hardwick, J.; Buser, C.; Xu, J.; Kan, Z.; Dai, H.; Mao, M.; Reinhard, C.; Wang, J.; Luk, J.M. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet., 2012, 44(7), 765-769.
[http://dx.doi.org/10.1038/ng.2295] [PMID: 22634754]
[14]
Jiang, Z.; Jhunjhunwala, S.; Liu, J.; Haverty, P.M.; Kennemer, M.I.; Guan, Y.; Lee, W.; Carnevali, P.; Stinson, J.; Johnson, S.; Diao, J.; Yeung, S.; Jubb, A.; Ye, W.; Wu, T.D.; Kapadia, S.B.; de Sauvage, F.J.; Gentleman, R.C.; Stern, H.M.; Seshagiri, S.; Pant, K.P.; Modrusan, Z.; Ballinger, D.G.; Zhang, Z. The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients. Genome Res., 2012, 22(4), 593-601.
[http://dx.doi.org/10.1101/gr.133926.111] [PMID: 22267523]
[15]
Nakagawa, H.; Shibata, T. Comprehensive genome sequencing of the liver cancer genome. Cancer Lett., 2013, 340(2), 234-240.
[http://dx.doi.org/10.1016/j.canlet.2012.10.035] [PMID: 23142287]
[16]
Schulze, K.; Nault, J.C.; Villanueva, A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J. Hepatol., 2016, 65(5), 1031-1042.
[http://dx.doi.org/10.1016/j.jhep.2016.05.035] [PMID: 27262756]
[17]
Zucman-Rossi, J.; Villanueva, A.; Nault, J.C.; Llovet, J.M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology., 2015, 149(5), 1226-1239. e4.
[http://dx.doi.org/10.1053/j.gastro.2015.05.061]
[18]
Ahn, S.M.; Jang, S.J.; Shim, J.H.; Kim, D.; Hong, S.M.; Sung, C.O.; Baek, D.; Haq, F.; Ansari, A.A.; Lee, S.Y.; Chun, S.M.; Choi, S.; Choi, H.J.; Kim, J.; Kim, S.; Hwang, S.; Lee, Y.J.; Lee, J.E.; Jung, W.R.; Jang, H.Y.; Yang, E.; Sung, W.K.; Lee, N.P.; Mao, M.; Lee, C.; Zucman-Rossi, J.; Yu, E.; Lee, H.C.; Kong, G. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology, 2014, 60(6), 1972-1982.
[http://dx.doi.org/10.1002/hep.27198] [PMID: 24798001]
[19]
Kan, Z.; Zheng, H.; Liu, X.; Li, S.; Barber, T.D.; Gong, Z.; Gao, H.; Hao, K.; Willard, M.D.; Xu, J.; Hauptschein, R.; Rejto, P.A.; Fernandez, J.; Wang, G.; Zhang, Q.; Wang, B.; Chen, R.; Wang, J.; Lee, N.P.; Zhou, W.; Lin, Z.; Peng, Z.; Yi, K.; Chen, S.; Li, L.; Fan, X.; Yang, J.; Ye, R.; Ju, J.; Wang, K.; Estrella, H.; Deng, S.; Wei, P.; Qiu, M.; Wulur, I.H.; Liu, J.; Ehsani, M.E.; Zhang, C.; Loboda, A.; Sung, W.K.; Aggarwal, A.; Poon, R.T.; Fan, S.T.; Wang, J.; Hardwick, J.; Reinhard, C.; Dai, H.; Li, Y.; Luk, J.M.; Mao, M. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res., 2013, 23(9), 1422-1433.
[http://dx.doi.org/10.1101/gr.154492.113] [PMID: 23788652]
[20]
Totoki, Y.; Tatsuno, K.; Covington, K.R.; Ueda, H.; Creighton, C.J.; Kato, M.; Tsuji, S.; Donehower, L.A.; Slagle, B.L.; Nakamura, H.; Yamamoto, S.; Shinbrot, E.; Hama, N.; Lehmkuhl, M.; Hosoda, F.; Arai, Y.; Walker, K.; Dahdouli, M.; Gotoh, K.; Nagae, G.; Gingras, M.C.; Muzny, D.M.; Ojima, H.; Shimada, K.; Midorikawa, Y.; Goss, J.A.; Cotton, R.; Hayashi, A.; Shibahara, J.; Ishikawa, S.; Guiteau, J.; Tanaka, M.; Urushidate, T.; Ohashi, S.; Okada, N.; Doddapaneni, H.; Wang, M.; Zhu, Y.; Dinh, H.; Okusaka, T.; Kokudo, N.; Kosuge, T.; Takayama, T.; Fukayama, M.; Gibbs, R.A.; Wheeler, D.A.; Aburatani, H.; Shibata, T. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet., 2014, 46(12), 1267-1273.
[http://dx.doi.org/10.1038/ng.3126] [PMID: 25362482]
[21]
Huang, J.; Deng, Q.; Wang, Q.; Li, K.Y.; Dai, J.H.; Li, N.; Zhu, Z.D.; Zhou, B.; Liu, X.Y.; Liu, R.F.; Fei, Q.L.; Chen, H.; Cai, B.; Zhou, B.; Xiao, H.S.; Qin, L.X.; Han, Z.G. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat. Genet., 2012, 44(10), 1117-1121.
[http://dx.doi.org/10.1038/ng.2391] [PMID: 22922871]
[22]
Li, S.; Mao, M. Next generation sequencing reveals genetic landscape of hepatocellular carcinomas. Cancer Lett., 2013, 340(2), 247-253.
[http://dx.doi.org/10.1016/j.canlet.2012.09.027] [PMID: 23063663]
[23]
Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Campbell, P.J.; Stratton, M.R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep., 2013, 3(1), 246-259.
[http://dx.doi.org/10.1016/j.celrep.2012.12.008] [PMID: 23318258]
[24]
Childs, A.; Ross, P.; Hossen-Mamode, A.; Ma, Y.T.; O’Rourke, J.; Hubner, R.; Hockenhull, K.; Swinson, D.; Palmer, D.; Bracconi, C.; Iwinji, C.; Shalbak, A.; Darby, S.; Roques, T.; Meyer, T. A United Kingdom audit of Hepatocellular Carcinoma patients undergoing biopsy for sorafenib therapy. Hepatocellular Carcinoma UK Annual Meeting,, 2019.
[25]
An, F.Q.; Matsuda, M.; Fujii, H.; Tang, R.F.; Amemiya, H.; Dai, Y.M.; Matsumoto, Y. Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 AND beta-catenin. Int. J. Cancer, 2001, 93(4), 468-474.
[http://dx.doi.org/10.1002/ijc.1367] [PMID: 11477549]
[26]
Friemel, J.; Frick, L.; Weber, A. Intratumor heterogeneity in HCC. Aging (Albany NY), 2015, 7(6), 350-351.
[http://dx.doi.org/10.18632/aging.100760] [PMID: 26081519]
[27]
Ling, S.; Hu, Z.; Yang, Z.; Yang, F.; Li, Y.; Lin, P.; Chen, K.; Dong, L.; Cao, L.; Tao, Y.; Hao, L.; Chen, Q.; Gong, Q.; Wu, D.; Li, W.; Zhao, W.; Tian, X.; Hao, C.; Hungate, E.A.; Catenacci, D.V.; Hudson, R.R.; Li, W.H.; Lu, X.; Wu, C.I. Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc. Natl. Acad. Sci. USA, 2015, 112(47), E6496-E6505.
[http://dx.doi.org/10.1073/pnas.1519556112] [PMID: 26561581]
[28]
Lin, D.C.; Mayakonda, A.; Dinh, H.Q.; Huang, P.; Lin, L.; Liu, X.; Ding, L.W.; Wang, J.; Berman, B.P.; Song, E.W.; Yin, D.; Koeffler, H.P. Genomic and epigenomic heterogeneity of hepatocellular carcinoma. Cancer Res., 2017, 77(9), 2255-2265.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2822] [PMID: 28302680]
[29]
Zheng, H.; Pomyen, Y.; Hernandez, M.O.; Li, C.; Livak, F.; Tang, W.; Dang, H.; Greten, T.F.; Davis, J.L.; Zhao, Y.; Mehta, M.; Levin, Y.; Shetty, J.; Tran, B.; Budhu, A.; Wang, X.W. Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma. Hepatology, 2018, 68(1), 127-140.
[http://dx.doi.org/10.1002/hep.29778] [PMID: 29315726]
[30]
Kurebayashi, Y.; Ojima, H.; Tsujikawa, H.; Kubota, N.; Maehara, J.; Abe, Y.; Kitago, M.; Shinoda, M.; Kitagawa, Y.; Sakamoto, M. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology, 2018, 68(3), 1025-1041.
[http://dx.doi.org/10.1002/hep.29904] [PMID: 29603348]
[31]
Losic, B.; Craig, A.J.; Villacorta-Martin, C.; Martins-Filho, S.N.; Akers, N.; Chen, X.; Ahsen, M.E.; von Felden, J.; Labgaa, I. DʹAvola, D.; Allette, K.; Lira, S.A.; Furtado, G.C.; Garcia-Lezana, T.; Restrepo, P.; Stueck, A.; Ward, S.C.; Fiel, M.I.; Hiotis, S.P.; Gunasekaran, G.; Sia, D.; Schadt, E.E.; Sebra, R.; Schwartz, M.; Llovet, J.M.; Thung, S.; Stolovitzky, G.; Villanueva, A. Intratumoral heterogeneity and clonal evolution in liver cancer. Nat. Commun., 2020, 11(1), 291.
[http://dx.doi.org/10.1038/s41467-019-14050-z] [PMID: 31941899]
[32]
Li, Q.; Wang, J.; Juzi, J.T.; Sun, Y.; Zheng, H.; Cui, Y.; Li, H.; Hao, X. Clonality analysis for multicentric origin and intrahepatic metastasis in recurrent and primary hepatocellular carcinoma. J. Gastrointest. Surg., 2008, 12(9), 1540-1547.
[http://dx.doi.org/10.1007/s11605-008-0591-y] [PMID: 18629593]
[33]
Morimoto, O.; Nagano, H.; Sakon, M.; Fujiwara, Y.; Yamada, T.; Nakagawa, H.; Miyamoto, A.; Kondo, M.; Arai, I.; Yamamoto, T.; Ota, H.; Dono, K.; Umeshita, K.; Nakamori, S.; Sasaki, Y.; Ishikawa, O.; Imaoka, S.; Monden, M. Diagnosis of intrahepatic metastasis and multicentric carcinogenesis by microsatellite loss of heterozygosity in patients with multiple and recurrent hepatocellular carcinomas. J. Hepatol., 2003, 39(2), 215-221.
[http://dx.doi.org/10.1016/S0168-8278(03)00233-2] [PMID: 12873818]
[34]
Furuta, M.; Ueno, M.; Fujimoto, A.; Hayami, S.; Yasukawa, S.; Kojima, F.; Arihiro, K.; Kawakami, Y.; Wardell, C.P.; Shiraishi, Y.; Tanaka, H.; Nakano, K.; Maejima, K.; Sasaki-Oku, A.; Tokunaga, N.; Boroevich, K.A.; Abe, T.; Aikata, H.; Ohdan, H.; Gotoh, K.; Kubo, M.; Tsunoda, T.; Miyano, S.; Chayama, K.; Yamaue, H.; Nakagawa, H. Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. J. Hepatol., 2017, 66(2), 363-373.
[http://dx.doi.org/10.1016/j.jhep.2016.09.021] [PMID: 27742377]
[35]
Kgatle, M.M.; Setshedi, M.; Hairwadzi, H.N. Hepatoepigenetic alterations in viral and nonviral-induced hepatocellular carcinoma. BioMed Res. Int., 2016, 20163956485
[http://dx.doi.org/10.1155/2016/3956485] [PMID: 28105421]
[36]
Hlady, R.A.; Zhou, D.; Puszyk, W.; Roberts, L.R.; Liu, C.; Robertson, K.D. Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer. Epigenetics, 2017, 12(3), 215-225.
[http://dx.doi.org/10.1080/15592294.2016.1277297] [PMID: 28059585]
[37]
Zhao, Z.H.; Fan, Y.C.; Yang, Y.; Wang, K. Association between Ras association domain family 1A promoter methylation and hepatocellular carcinoma: a meta-analysis. World J. Gastroenterol., 2013, 19(41), 7189-7196.
[http://dx.doi.org/10.3748/wjg.v19.i41.7189] [PMID: 24222965]
[38]
Li, C.P.; Cai, M.Y.; Jiang, L.J.; Mai, S.J.; Chen, J.W.; Wang, F.W.; Liao, Y.J.; Chen, W.H.; Jin, X.H.; Pei, X.Q.; Guan, X.Y.; Zeng, M.S.; Xie, D. CLDN14 is epigenetically silenced by EZH2-mediated H3K27ME3 and is a novel prognostic biomarker in hepatocellular carcinoma. Carcinogenesis, 2016, 37(6), 557-566.
[http://dx.doi.org/10.1093/carcin/bgw036] [PMID: 27207647]
[39]
Lambert, M.P.; Paliwal, A.; Vaissière, T.; Chemin, I.; Zoulim, F.; Tommasino, M.; Hainaut, P.; Sylla, B.; Scoazec, J.Y.; Tost, J.; Herceg, Z. Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. J. Hepatol., 2011, 54(4), 705-715.
[http://dx.doi.org/10.1016/j.jhep.2010.07.027] [PMID: 21146512]
[40]
Shen, J.; Wang, S.; Zhang, Y.J.; Kappil, M.; Wu, H.C.; Kibriya, M.G.; Wang, Q.; Jasmine, F.; Ahsan, H.; Lee, P.H.; Yu, M.W.; Chen, C.J.; Santella, R.M. Genome-wide DNA methylation profiles in hepatocellular carcinoma. Hepatology, 2012, 55(6), 1799-1808.
[http://dx.doi.org/10.1002/hep.25569] [PMID: 22234943]
[41]
Villanueva, A.; Portela, A.; Sayols, S.; Battiston, C.; Hoshida, Y.; Méndez-González, J.; Imbeaud, S.; Letouzé, E.; Hernandez-Gea, V.; Cornella, H.; Pinyol, R.; Solé, M.; Fuster, J.; Zucman-Rossi, J.; Mazzaferro, V.; Esteller, M.; Llovet, J.M. HEPTROMIC Consortium. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology, 2015, 61(6), 1945-1956.
[http://dx.doi.org/10.1002/hep.27732] [PMID: 25645722]
[42]
Qiu, J.; Peng, B.; Tang, Y.; Qian, Y.; Guo, P.; Li, M.; Luo, J.; Chen, B.; Tang, H.; Lu, C.; Cai, M.; Ke, Z.; He, W.; Zheng, Y.; Xie, D.; Li, B.; Yuan, Y. CpG methylation signature predicts recurrence in early-stage hepatocellular carcinoma: results from a multicenter study. J. Clin. Oncol., 2017, 35(7), 734-742.
[http://dx.doi.org/10.1200/JCO.2016.68.2153] [PMID: 28068175]
[43]
Revill, K.; Wang, T.; Lachenmayer, A.; Kojima, K.; Harrington, A.; Li, J. Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma. Gastroenterology, 2013, 145(6), 1424-1435. e1-25.
[http://dx.doi.org/10.1053/j.gastro.2013.08.055]
[44]
Hardy, T.; Mann, D.A. Epigenetics in liver disease: from biology to therapeutics. Gut, 2016, 65(11), 1895-1905.
[http://dx.doi.org/10.1136/gutjnl-2015-311292] [PMID: 27624887]
[45]
Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; de Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; Schwartz, M.; Porta, C.; Zeuzem, S.; Bolondi, L.; Greten, T.F.; Galle, P.R.; Seitz, J.F.; Borbath, I.; Häussinger, D.; Giannaris, T.; Shan, M.; Moscovici, M.; Voliotis, D.; Bruix, J. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359(4), 378-390.
[http://dx.doi.org/10.1056/NEJMoa0708857] [PMID: 18650514]
[46]
Cheng, A.L.; Kang, Y.K.; Chen, Z.; Tsao, C.J.; Qin, S.; Kim, J.S.; Luo, R.; Feng, J.; Ye, S.; Yang, T.S.; Xu, J.; Sun, Y.; Liang, H.; Liu, J.; Wang, J.; Tak, W.Y.; Pan, H.; Burock, K.; Zou, J.; Voliotis, D.; Guan, Z. 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.
[http://dx.doi.org/10.1016/S1470-2045(08)70285-7] [PMID: 19095497]
[47]
Zhu, A.X. Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? Oncologist, 2006, 11(7), 790-800.
[http://dx.doi.org/10.1634/theoncologist.11-7-790] [PMID: 16880238]
[48]
Llovet, J.M.; Montal, R.; Sia, D.; Finn, R.S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol., 2018, 15(10), 599-616.
[http://dx.doi.org/10.1038/s41571-018-0073-4] [PMID: 30061739]
[49]
Brizzi, M.P.; Pignataro, D.; Tampellini, M.; Scagliotti, G.V.; Di Maio, M. Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs? Expert Rev. Anticancer Ther., 2016, 16(10), 1053-1062.
[http://dx.doi.org/10.1080/14737140.2016.1227706] [PMID: 27548441]
[50]
Reig, M.; Rimola, J.; Torres, F.; Darnell, A.; Rodriguez-Lope, C.; Forner, A.; Llarch, N.; Ríos, J.; Ayuso, C.; Bruix, J. Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design. Hepatology, 2013, 58(6), 2023-2031.
[http://dx.doi.org/10.1002/hep.26586] [PMID: 23787822]
[51]
Bruix, J.; Qin, S.; Merle, P.; Granito, A.; Huang, Y.H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Breder, V.; Gerolami, R.; Masi, G.; Ross, P.J.; Song, T.; Bronowicki, J.P.; Ollivier-Hourmand, I.; Kudo, M.; Cheng, A.L.; Llovet, J.M.; Finn, R.S.; LeBerre, M.A.; Baumhauer, A.; Meinhardt, G.; Han, G. 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.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[52]
Abou-Alfa, G.K.; Meyer, T.; Cheng, A.L.; El-Khoueiry, A.B.; Rimassa, L.; Ryoo, B.Y.; Cicin, I.; Merle, P.; Chen, Y.; Park, J.W.; Blanc, J.F.; Bolondi, L.; Klümpen, H.J.; Chan, S.L.; Zagonel, V.; Pressiani, T.; Ryu, M.H.; Venook, A.P.; Hessel, C.; Borgman-Hagey, A.E.; Schwab, G.; Kelley, R.K. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med., 2018, 379(1), 54-63.
[http://dx.doi.org/10.1056/NEJMoa1717002] [PMID: 29972759]
[53]
Zhu, A.X.; Kang, Y-K.; Yen, C-J.; Finn, R.S.; Galle, P.R.; Llovet, J.M.; Assenat, E.; Brandi, G.; Pracht, M.; Lim, H.Y.; Rau, K.M.; Motomura, K.; Ohno, I.; Merle, P.; Daniele, B.; Shin, D.B.; Gerken, G.; Borg, C.; Hiriart, J.B.; Okusaka, T.; Morimoto, M.; Hsu, Y.; Abada, P.B.; Kudo, M. 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.
[http://dx.doi.org/10.1016/S1470-2045(18)30937-9] [PMID: 30665869]
[54]
Kudo, M.; Finn, R.S.; Qin, S.; Han, K.H.; Ikeda, K.; Piscaglia, F.; Baron, A.; Park, J.W.; Han, G.; Jassem, J.; Blanc, J.F.; Vogel, A.; Komov, D.; Evans, T.R.J.; Lopez, C.; Dutcus, C.; Guo, M.; Saito, K.; Kraljevic, S.; Tamai, T.; Ren, M.; Cheng, A.L. 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.
[http://dx.doi.org/10.1016/S0140-6736(18)30207-1] [PMID: 29433850]
[55]
Pishvaian, M.J.; Lee, M.S.; Ryoo, B.Y.; Stein, S.; Lee, K.H.; Verret, W. Updated safety and clinical activity results from a phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol, 2018, 29(Suppl 8), viii718-viii719.
[56]
Cheng, A-L.; Qin, S.; Ikeda, M. Atezolizumuab and bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma: phase 3 results from IMbrave150. European Society of Medical Oncology (ESMO Asia Conference, November 22nd-24th, 2019Singapore 2019.
[57]
Kassel, R.; Cruise, M.W.; Iezzoni, J.C.; Taylor, N.A.; Pruett, T.L.; Hahn, Y.S. Chronically inflamed livers up-regulate expression of inhibitory B7 family members. Hepatology, 2009, 50(5), 1625-1637.
[http://dx.doi.org/10.1002/hep.23173] [PMID: 19739236]
[58]
Kalathil, S.; Lugade, A.A.; Miller, A.; Iyer, R.; Thanavala, Y. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res., 2013, 73(8), 2435-2444.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3381] [PMID: 23423978]
[59]
Kuang, D.M.; Zhao, Q.; Peng, C.; Xu, J.; Zhang, J.P.; Wu, C.; Zheng, L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med., 2009, 206(6), 1327-1337.
[http://dx.doi.org/10.1084/jem.20082173] [PMID: 19451266]
[60]
Matsui, M.; Machida, S.; Itani-Yohda, T.; Akatsuka, T. Downregulation of the proteasome subunits, transporter, and antigen presentation in hepatocellular carcinoma, and their restoration by interferon-gamma. J. Gastroenterol. Hepatol., 2002, 17(8), 897-907.
[http://dx.doi.org/10.1046/j.1440-1746.2002.02837.x] [PMID: 12164966]
[61]
Sangro, B.; Gomez-Martin, C.; de la Mata, M.; Iñarrairaegui, M.; Garralda, E.; Barrera, P.; Riezu-Boj, J.I.; Larrea, E.; Alfaro, C.; Sarobe, P.; Lasarte, J.J.; Pérez-Gracia, J.L.; Melero, I.; Prieto, J. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol., 2013, 59(1), 81-88.
[http://dx.doi.org/10.1016/j.jhep.2013.02.022] [PMID: 23466307]
[62]
El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.Y.; Choo, S.P.; Trojan, J.; Welling, T.H.; Meyer, T.; Kang, Y.K.; Yeo, W.; Chopra, A.; Anderson, J.; Dela Cruz, C.; Lang, L.; Neely, J.; Tang, H.; Dastani, H.B.; Melero, I. 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.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[63]
Yau, T.; Park, J.W.; Finn, R.S.; Cheng, A-L.; Mathurin, P.; Edeline, J.; Kudo, M.; Han, K.H.; Harding, J.J.; Merle, P.; Rosmorduc, O.; Wyrwicz, L.; Schott, E.; Choo, S.P.; Kelley, R.K.; Begic, D.; Chen, G.; Neely, J.; Anderson, J.; Sangro, B. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as firstline (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol., 2019, 30(Suppl 5), v874-v875. (abstract LBA38_PR)..
[http://dx.doi.org/10.1093/annonc/mdz394.029]
[64]
Zhu, A.X.; Finn, R.S.; Edeline, J.; Cattan, S.; Ogasawara, S.; Palmer, D.; Verslype, C.; Zagonel, V.; Fartoux, L.; Vogel, A.; Sarker, D.; Verset, G.; Chan, S.L.; Knox, J.; Daniele, B.; Webber, A.L.; Ebbinghaus, S.W.; Ma, J.; Siegel, A.B.; Cheng, A.L.; Kudo, M. 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.
[http://dx.doi.org/10.1016/S1470-2045(18)30351-6] [PMID: 29875066]
[65]
Finn, R.S.; Ryoo, B.Y.; Merle, P.; Kudo, M.; Bouattour, M.; Lim, H.Y.; Breder, V.; Edeline, J.; Chao, Y.; Ogasawara, S.; Yau, T.; Garrido, M.; Chan, S.L.; Knox, J.; Daniele, B.; Ebbinghaus, S.W.; Chen, E.; Siegel, A.B.; Zhu, A.X.; Cheng, A.L. 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(3), 193-202.
[http://dx.doi.org/10.1200/JCO.19.01307] [PMID: 31790344]
[66]
Feng, Y.; Hong, Y.; Sun, H.; Zhang, B.; Wu, H.; Li, K.; Liu, X.; Liu, Y. The molecular binding mechanism of tislelizumab, an investigational anti-PD-1 antibody, is differentiated from pembrolizumab and nivolumab. American Association for Cancer Research (AACR) Annual Meeting, 2019. March 29th-April 3rd, 2019Atlanta
[67]
Zhang, T.; Song, X.; Xu, L.; Ma, J.; Zhang, Y.; Gong, W.; Zhang, Y.; Zhou, X.; Wang, Z.; Wang, Y.; Shi, Y.; Bai, H.; Liu, N.; Yang, X.; Cui, X.; Cao, Y.; Liu, Q.; Song, J.; Li, Y.; Tang, Z.; Guo, M.; Wang, L.; Li, K. The binding of an anti-PD-1 antibody to FcγRI has a profound impact on its biological functions. Cancer Immunol. Immunother., 2018, 67(7), 1079-1090.
[http://dx.doi.org/10.1007/s00262-018-2160-x] [PMID: 29687231]
[68]
Roland, C.L.; Lynn, K.D.; Toombs, J.E.; Dineen, S.P.; Udugamasooriya, D.G.; Brekken, R.A. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS One, 2009, 4(11), e7669.
[http://dx.doi.org/10.1371/journal.pone.0007669] [PMID: 19888452]
[69]
Voron, T.; Colussi, O.; Marcheteau, E.; Pernot, S.; Nizard, M.; Pointet, A.L.; Latreche, S.; Bergaya, S.; Benhamouda, N.; Tanchot, C.; Stockmann, C.; Combe, P.; Berger, A.; Zinzindohoue, F.; Yagita, H.; Tartour, E.; Taieb, J.; Terme, M. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med., 2015, 212(2), 139-148.
[http://dx.doi.org/10.1084/jem.20140559] [PMID: 25601652]
[70]
Kimura, T.; Kato, Y.; Ozawa, Y.; Kodama, K.; Ito, J.; Ichikawa, K.; Yamada, K.; Hori, Y.; Tabata, K.; Takase, K.; Matsui, J.; Funahashi, Y.; Nomoto, K. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci., 2018, 109(12), 3993-4002.
[http://dx.doi.org/10.1111/cas.13806] [PMID: 30447042]
[71]
Llovet, J.; Finn, R.S.; Ikeda, M.; Sung, M.; Baron, A.D.; Kudo, M.; Okusaka, T.; Kobayashi, M.; Kumada, H.; Kaneko, S.; Pracht, M.; Mamontov, K.; Meyer, T.; Mody, K.; Kubota, T.; Dutcus, C.E.; Saito, K.; Siegel, A.B.; Dubrovsky, L.; Zhu, A.X. A Phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results. Ann. Oncol., 2019, 30(Suppl. 5), v253-v324.
[http://dx.doi.org/10.1093/annonc/mdz247.073]
[72]
Motzer, R.J.; Rini, B.I.; McDermott, D.F.; Arén Frontera, O.; Hammers, H.J.; Carducci, M.A.; Salman, P.; Escudier, B.; Beuselinck, B.; Amin, A.; Porta, C.; George, S.; Neiman, V.; Bracarda, S.; Tykodi, S.S.; Barthélémy, P.; Leibowitz-Amit, R.; Plimack, E.R.; Oosting, S.F.; Redman, B.; Melichar, B.; Powles, T.; Nathan, P.; Oudard, S.; Pook, D.; Choueiri, T.K.; Donskov, F.; Grimm, M.O.; Gurney, H.; Heng, D.Y.C.; Kollmannsberger, C.K.; Harrison, M.R.; Tomita, Y.; Duran, I.; Grünwald, V.; McHenry, M.B.; Mekan, S.; Tannir, N.M. CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol., 2019, 20(10), 1370-1385.
[http://dx.doi.org/10.1016/S1470-2045(19)30413-9] [PMID: 31427204]
[73]
Hellmann, M.D.; Ciuleanu, T.E.; Pluzanski, A.; Lee, J.S.; Otterson, G.A.; Audigier-Valette, C.; Minenza, E.; Linardou, H.; Burgers, S.; Salman, P.; Borghaei, H.; Ramalingam, S.S.; Brahmer, J.; Reck, M.; O’Byrne, K.J.; Geese, W.J.; Green, G.; Chang, H.; Szustakowski, J.; Bhagavatheeswaran, P.; Healey, D.; Fu, Y.; Nathan, F.; Paz-Ares, L. Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med., 2018, 378(22), 2093-2104.
[http://dx.doi.org/10.1056/NEJMoa1801946] [PMID: 29658845]
[74]
Hodi, F.S.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Rutkowski, P.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; Ferrucci, P.F.; Smylie, M.; Hill, A.; Hogg, D.; Marquez-Rodas, I.; Jiang, J.; Rizzo, J.; Larkin, J.; Wolchok, J.D. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol., 2018, 19(11), 1480-1492.
[http://dx.doi.org/10.1016/S1470-2045(18)30700-9] [PMID: 30361170]
[75]
Yau, T.; Kang, Y-K.; Kim, T-Y.; El-Khoueiry, A.B.; Santoro, A.; Sangro, B.; Melero, I.; Kudo, M.; Hou, M-M.; Matilla, A.; Tovoli, F.; Knox, J.J.; He, A.R.; El-Rayes, B.F.; Acosta-Rivera, M.; Neely, J.; Shen, Y. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J. Clin. Oncol, 2019, 37(Suppl 15)
[76]
El-Khoueiry, A.B.; Hsu, C.; Kang, Y-K.; Kim, T-Y.; Santoro, A.; Sangro, B.; Melero, I.; Kudo, M.; Hou, M-M.; Matilla, A.; Tovoli, F.; Knox, J.J.; He, A.R.; El-Rayes, B.; Acosta-Rivera, M.; Neely, J.; Shen, Y.; Anderson, J.; Yau, T. Safety profile of Nivolumab (nivo) plus Ipilimumab (ipi) combination therapy in patients (pts) with advanced hepatocellular carcinoma (HCC) in the checkmate 040 study. 13th International Liver Cancer Association (ILCA Annual Conference,, September 20th-22nd, 2019Chicago, IL (US)2019.
[77]
Tohyama, O.; Matsui, J.; Kodama, K.; Hata-Sugi, N.; Kimura, T.; Okamoto, K.; Minoshima, Y.; Iwata, M.; Funahashi, Y. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J. Thyroid Res., 2014, 2014638747
[http://dx.doi.org/10.1155/2014/638747]] [PMID: 25295214]
[78]
Yamamoto, Y.; Matsui, J.; Matsushima, T.; Obaishi, H.; Miyazaki, K.; Nakamura, K.; Tohyama, O.; Semba, T.; Yamaguchi, A.; Hoshi, S.S.; Mimura, F.; Haneda, T.; Fukuda, Y.; Kamata, J.I.; Takahashi, K.; Matsukura, M.; Wakabayashi, T.; Asada, M.; Nomoto, K.I.; Watanabe, T.; Dezso, Z.; Yoshimatsu, K.; Funahashi, Y.; Tsuruoka, A. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc. Cell, 2014, 6, 18.
[http://dx.doi.org/10.1186/2045-824X-6-18] [PMID: 25197551]
[79]
Reig, M.; Bruix, J. Lenvatinib: can a non-inferiority trial change clinical practice? Lancet, 2018, 391(10126), 1123-1124.
[http://dx.doi.org/10.1016/S0140-6736(18)30208-3] [PMID: 29433849]
[80]
Wilhelm, S.M.; Dumas, J.; Adnane, L.; Lynch, M.; Carter, C.A.; Schütz, G.; Thierauch, K.H.; Zopf, D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int. J. Cancer, 2011, 129(1), 245-255.
[http://dx.doi.org/10.1002/ijc.25864] [PMID: 21170960]
[81]
Abou-Elkacem, L.; Arns, S.; Brix, G.; Gremse, F.; Zopf, D.; Kiessling, F.; Lederle, W. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol. Cancer Ther., 2013, 12(7), 1322-1331.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-1162] [PMID: 23619301]
[82]
Bruix, J.; Cheng, A.L.; Meinhardt, G.; Nakajima, K.; De Sanctis, Y.; Llovet, J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J. Hepatol., 2017, 67(5), 999-1008.
[http://dx.doi.org/10.1016/j.jhep.2017.06.026] [PMID: 28687477]
[83]
Yamashita, T.; Forgues, M.; Wang, W.; Kim, J.W.; Ye, Q.; Jia, H.; Budhu, A.; Zanetti, K.A.; Chen, Y.; Qin, L.X.; Tang, Z.Y.; Wang, X.W. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res., 2008, 68(5), 1451-1461.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-6013] [PMID: 18316609]
[84]
Shan, Y.F.; Huang, Y.L.; Xie, Y.K.; Tan, Y.H.; Chen, B.C.; Zhou, M.T.; Shi, H.Q.; Yu, Z.P.; Song, Q.T.; Zhang, Q.Y. Angiogenesis and clinicopathologic characteristics in different hepatocellular carcinoma subtypes defined by EpCAM and α-fetoprotein expression status. Med. Oncol., 2019, 28(4), 1012-1016.
[85]
Fung, A.S.; Tam, V.C.; Meyers, D.E.; Sim, H-W.; Knox, J.J.; Zaborska, V.O.; Davies, J.M.; Ko, Y-J.; Batuyong, E.; Cheung, W.Y.; Samawi, H.; Lee-Ying, R.M. Real world eligibility for cabozantinib (C), regorafenib (Reg), and ramucirumab (Ram) in hepatocellular carcinoma (HCC) patients after sorafenib (S). J. Clin. Oncol, 2019, 37 Suppl 4 (abstract 422).

Rights & Permissions Print Cite
Article Metrics
50
3
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy