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

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

References

[1] Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 62(3): 479–483

[2] Mok TS, Leung TW, Lee SD, Chao Y, Chan AT, Huang A, Lui MC, Yeo W, Chak K, Johnston A, Johnson P. 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

[3] Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, Feun L, Jeziorski K, Leighton J, Gallo J, Kennealey GT. 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

[4] Halm U, Etzrodt G, Schiefke I, Schmidt F, Witzigmann H, Mössner J, Berr F. A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma. Ann Oncol 2000; 11(1): 113–114

[5] Schmidinger M, Wenzel C, Locker GJ, Muehlbacher F, Steininger R, Gnant M, Crevenna R, Budinsky AC. Pilot study with pegylated liposomal doxorubicin for advanced or unresectable hepatocellular carcinoma. Br J Cancer 2001; 85(12): 1850–1852

[6] Hong RL, Tseng YL. A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2003; 51(5): 433–438

[7] Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. 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

[8] Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. 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

[9] Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, Faghih M, Brendel E, Voliotis D, Haase CG, Schwartz B, Awada A, Voigtmann R, Scheulen ME, Seeber S. 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

[10] Abou-Alfa GK, Schwartz L, Ricci S , Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24(26): 4293–4300

[11] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, 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

[12] Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, 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

[13] Richly H, Henning BF, Kupsch P, Passarge K, Grubert M, Hilger RA, Christensen O, Brendel E, Schwartz B, Ludwig M, Flashar C, Voigtmann R, Scheulen ME, Seeber S, Strumberg D. 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

[14] Richly H, Schultheis B, Adamietz IA, Kupsch P, Grubert M, Hilger RA, Ludwig M, Brendel E, Christensen O, Strumberg D. 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

[15] Abou-Alfa GK, Niedwieski D, Knox JJ, . 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

[16] Blivet-Van Eggelpoël MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, Priam S, Housset C, Rosmorduc O, Desbois-Mouthon C. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol 2012; 57(1): 108–115

[17] Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, Bruix J, Qin S, Thuluvath PJ, Llovet JM, Leberre MA, Jensen M, Meinhardt G, Kang YK. 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

[18] Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E. 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

[19] Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G, Omata M, Pitman Lowenthal S, Lanzalone S, Yang L, Lechuga MJ, Raymond E. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013; 31(32): 4067–4075

[20] Bhide RS, Lombardo LJ, Hunt JT, Cai ZW, Barrish JC, Galbraith S, Jeyaseelan R Sr, Mortillo S, Wautlet BS, Krishnan B, Kukral D, Malone H, Lewin AC, Henley BJ, Fargnoli J. 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

[21] Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng 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(28): 3517–3524

[22] Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. 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

[23] Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; 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

[24] Goel G. 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

[25] Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, 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

[26] Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, Uenaka T, Asada M. 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

[27] Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, Tamai T, Suzuki T, Hisai T, Hayato S, Okita K, Kumada H. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol 2017; 52(4): 512–519

[28] Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng 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

[29] Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011; 10(12): 2298–2308

[30] Kelley RK, Verslype C, Cohn AL, Yang TS, Su WC, Burris H, Braiteh F, Vogelzang N, Spira A, Foster P, Lee Y, Van Cutsem E. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol 2017; 28(3): 528–534

[31] Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379(1): 54–63

[32] Ellis LM. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol 2006; 33(5 Suppl 10): S1–S7

[33] Fang P, Hu JH, Cheng ZG, Liu ZF, Wang JL, Jiao SC. 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

[34] Hubbard JM, Mahoney MR, Loui WS, Roberts LR, Smyrk TC, Gatalica Z, Borad M, Kumar S, Alberts SR. 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

[35] Torimura T, Iwamoto H, Nakamura T, Abe M, Ikezono Y, Wada F, Sakaue T, Masuda H, Hashimoto O, Koga H, Ueno T, Yano H. 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

[36] Sprat;om JL, Cohen RB, Eadens M, . 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] Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M; 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

[38] Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, 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

[39] Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018; 15(10): 599–616

[40] Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S, Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z, Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y, Porta C. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013; 14(1): 55–63

[41] Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, López López C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J. 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

[42] Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, Newell P, Ikeda K, Hashimoto M, Watanabe G, Gabriel S, Friedman SL, Kumada H, Llovet JM, Golub TR. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009; 69(18): 7385–7392

[43] Boyault S, Rickman DS, de Reyniès A, Balabaud C, Rebouissou S, Jeannot E, Hérault A, Saric J, Belghiti J, Franco D, Bioulac-Sage P, Laurent-Puig P, Zucman-Rossi J. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007; 45(1): 42–52

[44] El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH 3rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, 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

[45] Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, 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

[46] Finn RS, Ryoo BY, Merle P, . 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] Lee K, HSU C, Lee MS, . Atezolizumab+ Bevacizumab in hepatocellular carcinoma (HCC): safety and clinical activity results from a Phase 1b study. Ann Oncol 2018; 29 (suppl_9): mdy432

[48] Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, Zhang G, Zhao C, Zhang Y, Chen C, Wang Y, Yi X, Hu Z, Zou J, Wang Q. 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

[49] Yau TC, Tang V, Chan J, . 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] Liu X, Qin S. Immune Checkpoint inhibitors in hepatocellular carcinoma: opportunities and challenges. Oncologist 2019; 24(Suppl 1): S3–S10

[51] Abdel-Wahab N, Safa H, Abudayyeh A, Johnson DH, Trinh VA, Zobniw CM, Lin H, Wong MK, Abdelrahim M, Gaber AO, Suarez-Almazor ME, Diab A. 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

[52] Munker S, De Toni EN. Use of checkpoint inhibitors in liver transplant recipients. United European Gastroenterol J 2018; 6(7): 970–973

[53] Ho CM, Chen HL, Hu RH, Lee PH. Harnessing immunotherapy for liver recipients with hepatocellular carcinoma: a review from a transplant oncology perspective. Ther Adv Med Oncol 2019; 11: 1758835919843463

[54] Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. 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

[55] Lee DW, Lee KH, Kim HJ, Kim TY, Kim JS, Han SW, Oh DY, Kim JH, Im SA, Kim TY. A phase II trial of S-1 and oxaliplatin in patients with advanced hepatocellular carcinoma. BMC Cancer 2018; 18(1): 252

[56] Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, Díaz A, Vilana R, Darnell A, Varela M, Sangro B, Calleja JL, Forns X, Bruix J. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65(4): 719–726

[57] Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65(4): 727–733

[58] Nagata H, Nakagawa M, Asahina Y, Sato A, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Nouchi T, Sakai H, Tomita M, Watanabe M; 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

[59] Singal AG, Rich NE, Mehta N, Branch A, Pillai A, Hoteit M, Volk M, Odewole M, Scaglione S, Guy J, Said A, Feld JJ, John BV, Frenette C, Mantry P, Rangnekar AS, Oloruntoba O, Leise M, Jou JH, Bhamidimarri KR, Kulik L, Tran T, Samant H, Dhanasekaran R, Duarte-Rojo A, Salgia R, Eswaran S, Jalal P, Flores A, Satapathy SK, Wong R, Huang A, Misra S, Schwartz M, Mitrani R, Nakka S, Noureddine W, Ho C, Konjeti VR, Dao A, Nelson K, Delarosa K, Rahim U, Mavuram M, Xie JJ, Murphy CC, Parikh ND. 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

[60] Guarino M, Sessa A, Cossiga V, Morando F, Caporaso N, Morisco F; 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

[61] Guarino M, Viganò L, Ponziani FR, Giannini EG, Lai Q, Morisco F; 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

[62] Zhang YQ, Guo JS. Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2015; 21(13): 3860–3866

[63] Pazgan-Simon M, Simon KA, Jarowicz E, Rotter K, Szymanek-Pasternak A, Zuwała-Jagiełło J. 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

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