Hepatocellular Carcinoma with Portal Vein Tumor Involvement: Best Management Strategies

 

 Buy Article Permissions and Reprints

Abstract

Portal vein tumor thrombosis (PVTT) commonly occurs in patients with hepatocellular carcinoma (HCC). Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months. Historically, many aspects of PVTT have impacted the theoretical and practical safety and efficacy of treatment, for example, disordered blood flow and associated impairment of liver function, heat-sink effects of blood flow in the area of the PVTT, and risk of recurrence due to tumor location in the blood vessel. The current Barcelona Clinic Liver Cancer staging system categorizes HCC patients with PVTT as advanced stage, for which the standard of care is targeted therapy with sorafenib. However, sorafenib is associated with only marginal benefits among patients with PVTT. First-line lenvatinib, which was shown to be noninferior to sorafenib, excluded patients with main portal trunk invasion. Regorafenib and nivolumab, an immune-based therapy, were recently approved in the United States for second-line therapy after sorafenib. Preliminary results for cabozantinib suggest a benefit in the second-/third-line after sorafenib failure. In addition, rapid advances in many fields (surgery, interventional radiology, nuclear medicine, and immunotherapy) have increased the potential treatment options for the management of this complex disease entity. A large portion of the emerging evidence focuses on the broader category of advanced HCC of which PVTT is a subgroup. While many of these studies show promising results, the efficacy among PVTT patients requires validation in prospective studies. Real-world data may help fill the evidence gap for patients not eligible for clinical trials due to common hepatic function requirements. The variety of new treatment advances for the heterogeneous and complex disease entity of HCC with PVTT means that personalized, multidisciplinary management may be necessary to achieve optimal outcomes. In this narrative review, we summarize the evolving management strategies for patients with HCC and PVTT.

• References

• 1 Ferlay J, Soerjomataram I, Ervik M. , et al. GLOBOCAN 2012. Estimated Cancer Incidence, Mortality and Prevalence Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. http://globocan.iarc.fr . Accessed on January 1, 2018
  PubMedGoogle Scholar
• 2 El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?. Hepatology 2014; 60 (05) 1767-1775
  CrossrefPubMedGoogle Scholar
• 3 El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365 (12) 1118-1127
  CrossrefPubMedGoogle Scholar
• 4 Llovet JM, Bustamante J, Castells A. , et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 1999; 29 (01) 62-67
  CrossrefPubMedGoogle Scholar
• 5 Minagawa M, Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol 2006; 12 (47) 7561-7567
  CrossrefPubMedGoogle Scholar
• 6 Cheung TK, Lai CL, Wong BC, Fung J, Yuen MF. Clinical features, biochemical parameters, and virological profiles of patients with hepatocellular carcinoma in Hong Kong. Aliment Pharmacol Ther 2006; 24 (04) 573-583
  CrossrefPubMedGoogle Scholar
• 7 Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer 1996; 77 (11) 2217-2222
  CrossrefPubMedGoogle Scholar
• 8 Ikai I, Arii S, Kojiro M. , et al. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey. Cancer 2004; 101 (04) 796-802
  CrossrefPubMedGoogle Scholar
• 9 Fuster J, García-Valdecasas JC, Grande L. , et al. Hepatocellular carcinoma and cirrhosis. Results of surgical treatment in a European series. Ann Surg 1996; 223 (03) 297-302
  CrossrefPubMedGoogle Scholar
• 10 Calvet X, Bruix J, Ginés P. , et al. Prognostic factors of hepatocellular carcinoma in the west: a multivariate analysis in 206 patients. Hepatology 1990; 12 (4 Pt 1): 753-760
  CrossrefPubMedGoogle Scholar
• 11 Schöniger-Hekele M, Müller C, Kutilek M, Oesterreicher C, Ferenci P, Gangl A. Hepatocellular carcinoma in Central Europe: prognostic features and survival. Gut 2001; 48 (01) 103-109
  CrossrefPubMedGoogle Scholar
• 12 Chan SL, Chong CC, Chan AW, Poon DM, Chok KS. Management of hepatocellular carcinoma with portal vein tumor thrombosis: review and update at 2016. World J Gastroenterol 2016; 22 (32) 7289-7300
  CrossrefPubMedGoogle Scholar
• 13 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018; (e-pub ahead of print) DOI: 10.1016/j.jhep.2018.03.019.
  CrossrefPubMedGoogle Scholar
• 14 Heimbach JK, Kulik LM, Finn RS. , et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018; 67 (01) 358-380
  CrossrefPubMedGoogle Scholar
• 15 Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19 (03) 329-338
  Article in Thieme ConnectPubMedGoogle Scholar
• 16 Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391 (10127): 1301-1314
  CrossrefPubMedGoogle Scholar
• 17 Jeong SW, Jang JY, Shim KY. , et al. Practical effect of sorafenib monotherapy on advanced hepatocellular carcinoma and portal vein tumor thrombosis. Gut Liver 2013; 7 (06) 696-703
  CrossrefPubMedGoogle Scholar
• 18 Cillo U, Vitale A, Bassanello M. , et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004; 239 (02) 150-159
  CrossrefPubMedGoogle Scholar
• 19 Gondolesi GE, Roayaie S, Muñoz L. , et al. Adult living donor liver transplantation for patients with hepatocellular carcinoma: extending UNOS priority criteria. Ann Surg 2004; 239 (02) 142-149
  CrossrefPubMedGoogle Scholar
• 20 Shimada M, Takenaka K, Gion T. , et al. Prognosis of recurrent hepatocellular carcinoma: a 10-year surgical experience in Japan. Gastroenterology 1996; 111 (03) 720-726
  CrossrefPubMedGoogle Scholar
• 21 Shi J, Lai EC, Li N. , et al. Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus. Ann Surg Oncol 2010; 17 (08) 2073-2080
  CrossrefPubMedGoogle Scholar
• 22 Kumada K, Ozawa K, Okamoto R. , et al. Hepatic resection for advanced hepatocellular carcinoma with removal of portal vein tumor thrombi. Surgery 1990; 108 (05) 821-827
  PubMedGoogle Scholar
• 23 Yamaoka Y, Kumada K, Ino K. , et al. Liver resection for hepatocellular carcinoma (HCC) with direct removal of tumor thrombi in the main portal vein. World J Surg 1992; 16 (06) 1172-1176 , discussion 1177
  CrossrefPubMedGoogle Scholar
• 24 Chok KS, Cheung TT, Chan SC, Poon RT, Fan ST, Lo CM. Surgical outcomes in hepatocellular carcinoma patients with portal vein tumor thrombosis. World J Surg 2014; 38 (02) 490-496
  CrossrefPubMedGoogle Scholar
• 25 Wu CC, Hsieh SR, Chen JT. , et al. An appraisal of liver and portal vein resection for hepatocellular carcinoma with tumor thrombi extending to portal bifurcation. Arch Surg 2000; 135 (11) 1273-1279
  CrossrefPubMedGoogle Scholar
• 26 Yin J, Bo WT, Sun J. , et al. New evidence and perspectives on the management of hepatocellular carcinoma with portal vein tumor thrombus. J Clin Transl Hepatol 2017; 5 (02) 169-176
  PubMedGoogle Scholar
• 27 Jiang JF, Lao YC, Yuan BH. , et al. Treatment of hepatocellular carcinoma with portal vein tumor thrombus: advances and challenges. Oncotarget 2017; 8 (20) 33911-33921
  CrossrefPubMedGoogle Scholar
• 28 Kokudo T, Hasegawa K, Matsuyama Y. , et al; Liver Cancer Study Group of Japan. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol 2016; 65 (05) 938-943
  CrossrefPubMedGoogle Scholar
• 29 Hasegawa K, Kokudo N, Makuuchi M. , et al. Comparison of resection and ablation for hepatocellular carcinoma: a cohort study based on a Japanese nationwide survey. J Hepatol 2013; 58 (04) 724-729
  CrossrefPubMedGoogle Scholar
• 30 Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014; 146 (07) 1691-700.e3
  CrossrefPubMedGoogle Scholar
• 31 Adhoute X, Penaranda G, Bronowicki JP, Raoul JL. Usefulness of the HKLC vs. the BCLC staging system in a European HCC cohort. J Hepatol 2015; 62 (02) 492-493
  CrossrefPubMedGoogle Scholar
• 32 Liu PH, Hsu CY, Lee YH. , et al. Hong Kong Liver Cancer Staging System is associated with better performance for hepatocellular carcinoma: special emphasis on viral etiology. Medicine (Baltimore) 2015; 94 (41) e1772
  CrossrefPubMedGoogle Scholar
• 33 Kolly P, Reeves H, Sangro B, Knöpfli M, Candinas D, Dufour JF. Assessment of the Hong Kong Liver Cancer Staging System in Europe. Liver Int 2016; 36 (06) 911-917
  CrossrefPubMedGoogle Scholar
• 34 Fontana RJ, Hamidullah H, Nghiem H. , et al. Percutaneous radiofrequency thermal ablation of hepatocellular carcinoma: a safe and effective bridge to liver transplantation. Liver Transpl 2002; 8 (12) 1165-1174
  CrossrefPubMedGoogle Scholar
• 35 Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg 2009; 249 (01) 20-25
  CrossrefPubMedGoogle Scholar
• 36 N'Kontchou G, Mahamoudi A, Aout M. , et al. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology 2009; 50 (05) 1475-1483
  CrossrefPubMedGoogle Scholar
• 37 Han K, Kim JH, Ko GY, Gwon DI, Sung KB. Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: a comprehensive review. World J Gastroenterol 2016; 22 (01) 407-416
  CrossrefPubMedGoogle Scholar
• 38 Duffy AG, Ulahannan SV, Makorova-Rusher O. , et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017; 66 (03) 545-551
  CrossrefPubMedGoogle Scholar
• 39 Lo CM, Ngan H, Tso WK. , et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35 (05) 1164-1171
  CrossrefPubMedGoogle Scholar
• 40 Llovet JM, Real MI, Montaña X. , et al; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359 (9319): 1734-1739
  CrossrefPubMedGoogle Scholar
• 41 Takayasu K, Arii S, Kudo M. , et al. Superselective transarterial chemoembolization for hepatocellular carcinoma. Validation of treatment algorithm proposed by Japanese guidelines. J Hepatol 2012; 56 (04) 886-892
  CrossrefPubMedGoogle Scholar
• 42 Burrel M, Reig M, Forner A. , et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol 2012; 56 (06) 1330-1335
  CrossrefPubMedGoogle Scholar
• 43 Omata M, Cheng AL, Kokudo N. , et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017; 11 (04) 317-370
  CrossrefPubMedGoogle Scholar
• 44 Silva JP, Berger NG, Tsai S. , et al. Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis. HPB 2017; 19 (08) 659-666
  CrossrefPubMedGoogle Scholar
• 45 Yamada R, Sato M, Kawabata M, Nakatsuka H, Nakamura K, Takashima S. Hepatic artery embolization in 120 patients with unresectable hepatoma. Radiology 1983; 148 (02) 397-401
  CrossrefPubMedGoogle Scholar
• 46 Quirk M, Kim YH, Saab S, Lee EW. Management of hepatocellular carcinoma with portal vein thrombosis. World J Gastroenterol 2015; 21 (12) 3462-3471
  CrossrefPubMedGoogle Scholar
• 47 Luo J, Guo RP, Lai EC. , et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study. Ann Surg Oncol 2011; 18 (02) 413-420
  CrossrefPubMedGoogle Scholar
• 48 Niu ZJ, Ma YL, Kang P. , et al. Transarterial chemoembolization compared with conservative treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus: using a new classification. Med Oncol 2012; 29 (04) 2992-2997
  CrossrefPubMedGoogle Scholar
• 49 Lawrence TS, Robertson JM, Anscher MS, Jirtle RL, Ensminger WD, Fajardo LF. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995; 31 (05) 1237-1248
  CrossrefPubMedGoogle Scholar
• 50 Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 2005; 15 (04) 279-283
  CrossrefPubMedGoogle Scholar
• 51 Krishnan S, Dawson LA, Seong J. , et al. Radiotherapy for hepatocellular carcinoma: an overview. Ann Surg Oncol 2008; 15 (04) 1015-1024
  CrossrefPubMedGoogle Scholar
• 52 Tse RV, Guha C, Dawson LA. Conformal radiotherapy for hepatocellular carcinoma. Crit Rev Oncol Hematol 2008; 67 (02) 113-123
  CrossrefPubMedGoogle Scholar
• 53 Hoffe SE, Finkelstein SE, Russell MS, Shridhar R. Nonsurgical options for hepatocellular carcinoma: evolving role of external beam radiotherapy. Cancer Contr 2010; 17 (02) 100-110
  PubMedGoogle Scholar
• 54 Jiang W, Zeng ZC. Is it time to adopt external beam radiotherapy in the NCCN guidelines as a therapeutic strategy for intermediate/advanced hepatocellular carcinoma?. Oncology 2013; 84 (Suppl. 01) 69-74
  CrossrefPubMedGoogle Scholar
• 55 Klein J, Dawson LA. Hepatocellular carcinoma radiation therapy: review of evidence and future opportunities. Int J Radiat Oncol Biol Phys 2013; 87 (01) 22-32
  CrossrefPubMedGoogle Scholar
• 56 Dawson LA. Overview: where does radiation therapy fit in the spectrum of liver cancer local-regional therapies?. Semin Radiat Oncol 2011; 21 (04) 241-246
  CrossrefPubMedGoogle Scholar
• 57 Chen SC, Lian SL, Chang WY. The effect of external radiotherapy in treatment of portal vein invasion in hepatocellular carcinoma. Cancer Chemother Pharmacol 1994; 33 (Suppl): S124-S127
  CrossrefPubMedGoogle Scholar
• 58 Im JH, Yoon SM, Park HC. , et al. Radiotherapeutic strategies for hepatocellular carcinoma with portal vein tumour thrombosis in a hepatitis B endemic area. Liver Int 2017; 37 (01) 90-100
  PubMedGoogle Scholar
• 59 Liapi E, Geschwind JF. Intra-arterial therapies for hepatocellular carcinoma: where do we stand?. Ann Surg Oncol 2010; 17 (05) 1234-1246
  CrossrefPubMedGoogle Scholar
• 60 Kennedy A, Nag S, Salem R. , et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007; 68 (01) 13-23
  CrossrefPubMedGoogle Scholar
• 61 Sato K, Lewandowski RJ, Bui JT. , et al. Treatment of unresectable primary and metastatic liver cancer with yttrium-90 microspheres (TheraSphere): assessment of hepatic arterial embolization. Cardiovasc Intervent Radiol 2006; 29 (04) 522-529
  CrossrefPubMedGoogle Scholar
• 62 Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J Vasc Interv Radiol 2006; 17 (08) 1251-1278
  CrossrefPubMedGoogle Scholar
• 63 Coldwell D, Sangro B, Wasan H, Salem R, Kennedy A. General selection criteria of patients for radioembolization of liver tumors: an international working group report. Am J Clin Oncol 2011; 34 (03) 337-341
  CrossrefPubMedGoogle Scholar
• 64 Salem R, Lewandowski RJ, Mulcahy MF. , et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010; 138 (01) 52-64
  CrossrefPubMedGoogle Scholar
• 65 Lau WY, Sangro B, Chen PJ. , et al. Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90. Oncology 2013; 84 (05) 311-318
  CrossrefPubMedGoogle Scholar
• 66 Sangro B, Iñarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol 2012; 56 (02) 464-473
  CrossrefPubMedGoogle Scholar
• 67 Sangro B, Rodriguez M. Radioembolization for hepatocellular carcinoma: gaining insight on a personalized approach. Liver Int 2017; 37 (01) 32-34
  CrossrefPubMedGoogle Scholar
• 68 Hilgard P, Hamami M, Fouly AE. , et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 2010; 52 (05) 1741-1749
  CrossrefPubMedGoogle Scholar
• 69 Sangro B, Carpanese L, Cianni R. , et al; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011; 54 (03) 868-878
  CrossrefPubMedGoogle Scholar
• 70 She WH, Cheung TT, Yau TC. , et al. Survival analysis of transarterial radioembolization with yttrium-90 for hepatocellular carcinoma patients with HBV infection. Hepatobiliary Surg Nutr 2014; 3 (04) 185-193
  PubMedGoogle Scholar
• 71 Chow PKH, Gandhi M, Tan SB. , et al; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 2018; (e-pub ahead of print) DOI: 10.1200/JCO.2017.76.0892.
  CrossrefPubMedGoogle Scholar
• 72 Ricke J, Sangro B, Amthauer H. , et al. LBO-005 - The impact of combining Selective Internal Radiation Therapy (SIRT) with Sorafenib on overall survival in patients with advanced hepatocellular carcinoma: the Soramic trial palliative cohort. J Hepatol 2018; 68 (Suppl. 01) S102
  PubMedGoogle Scholar
• 73 Nerenstone SR, Ihde DC, Friedman MA. Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treat Rev 1988; 15 (01) 1-31
  CrossrefPubMedGoogle Scholar
• 74 Okada S, Okazaki N, Nose H, Yoshimori M, Aoki K. Prognostic factors in patients with hepatocellular carcinoma receiving systemic chemotherapy. Hepatology 1992; 16 (01) 112-117
  CrossrefPubMedGoogle Scholar
• 75 Chan SL, Yeo W. Targeted therapy of hepatocellular carcinoma: present and future. J Gastroenterol Hepatol 2012; 27 (05) 862-872
  CrossrefPubMedGoogle Scholar
• 76 Castells A, Bruix J, Brú C. , et al. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology 1995; 109 (03) 917-922
  CrossrefPubMedGoogle Scholar
• 77 Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology 2004; 40 (06) 1361-1369
  CrossrefPubMedGoogle Scholar
• 78 Llovet JM, Ricci S, Mazzaferro V. , et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (04) 378-390
  CrossrefPubMedGoogle Scholar
• 79 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 (01) 25-34
  CrossrefPubMedGoogle Scholar
• 80 Bruix J, Qin S, Merle P. , et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389 (10064): 56-66
  CrossrefPubMedGoogle Scholar
• 81 Kudo M, Finn RS, Qin S. , et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391 (10126): 1163-1173
  CrossrefPubMedGoogle Scholar
• 82 Abou-Alfa GK, Meyer T, Cheng AL. , et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial. J Clin Oncol 2018; 36 (04) 207
  CrossrefPubMedGoogle Scholar
• 83 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 (12) 1898-1903
  CrossrefPubMedGoogle Scholar
• 84 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 (18) 2992-2998
  CrossrefPubMedGoogle Scholar
• 85 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 (06) 843-850
  CrossrefPubMedGoogle Scholar
• 86 Bruix J, Raoul JL, Sherman M. , et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012; 57 (04) 821-829
  CrossrefPubMedGoogle Scholar
• 87 Cheng AL, Guan Z, Chen Z. , et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 2012; 48 (10) 1452-1465
  CrossrefPubMedGoogle Scholar
• 88 Bruix J, Cheng AL, 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 (05) 999-1008
  CrossrefPubMedGoogle Scholar
• 89 Reig M, Torres F, Rodriguez-Lope C. , et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 2014; 61 (02) 318-324
  CrossrefPubMedGoogle Scholar
• 90 Rimola J, Díaz-González Á, Darnell A. , et al. Complete response under sorafenib in patients with hepatocellular carcinoma: relationship with dermatologic adverse events. Hepatology 2017; (e-pub ahead of print) DOI: 10.1002/hep.29515.
  CrossrefPubMedGoogle Scholar
• 91 Giorgio A, Merola MG, Montesarchio L. , et al. Sorafenib combined with radio-frequency ablation compared with sorafenib alone in treatment of hepatocellular carcinoma invading portal vein: a western randomized controlled trial. Anticancer Res 2016; 36 (11) 6179-6183
  CrossrefPubMedGoogle Scholar
• 92 Nakazawa T, Hidaka H, Shibuya A. , et al. Overall survival in response to sorafenib versus radiotherapy in unresectable hepatocellular carcinoma with major portal vein tumor thrombosis: propensity score analysis. BMC Gastroenterol 2014; 14: 84
  CrossrefPubMedGoogle Scholar
• 93 Song DS, Song MJ, Bae SH. , et al. A comparative study between sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. J Gastroenterol 2015; 50 (04) 445-454
  CrossrefPubMedGoogle Scholar
• 94 Gerbes A, Zoulim F, Tilg H. , et al. Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma. Gut 2018; 67 (02) 380-388
  CrossrefPubMedGoogle Scholar
• 95 Kudo M. Lenvatinib in advanced hepatocellular carcinoma. Liver Cancer 2017; 6 (04) 253-263
  CrossrefPubMedGoogle Scholar
• 96 Ramucirumab Improves Survival in Second-Line HCC. https://www.onclive.com/web-exclusives/ramucirumab-improves-survival-in-secondline-hcc . Accessed April 25, 2018
  PubMed
• 97 Phase 3 REACH-2 Study in Second-Line Hepatocellular Carcinoma Patients Met Overall Survival Endpoint. https://investor.lilly.com/news-releases/news-release-details/lilly-announces-cyramzar-ramucirumab-phase-3-reach-2-study . Accessed April 25, 2018
  PubMed
• 98 Greten TF, Manns MP, Korangy F. Immunotherapy of hepatocellular carcinoma. J Hepatol 2006; 45 (06) 868-878
  CrossrefPubMedGoogle Scholar
• 99 Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol 2017; (e-pub ahead of print) DOI: 10.1016/j.jhep.2017.09.007.
  CrossrefPubMedGoogle Scholar
• 100 Inarrairaegui M, Melero I, Sangro B. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin Cancer Res 2018; 24 (07) 1518-1524
  CrossrefPubMedGoogle Scholar
• 101 Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology 2017; 93 (Suppl. 01) 147-159
  CrossrefPubMedGoogle Scholar
• 102 Sangro B, Gomez-Martin C, de la Mata M. , et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013; 59 (01) 81-88
  CrossrefPubMedGoogle Scholar
• 103 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 (10088): 2492-2502
  CrossrefPubMedGoogle Scholar
• 104 Crocenzi TS, El-Khoueiry AB, Yau TC. , et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. J Clin Oncol 2017; 35 (15) 4013
  CrossrefPubMedGoogle Scholar
• 105 Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; 378 (02) 158-168
  CrossrefPubMedGoogle Scholar
• 106 Postow MA, Chesney J, Pavlick AC. , et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372 (21) 2006-2017
  CrossrefPubMedGoogle Scholar
• 107 Larkin J, Chiarion-Sileni V, Gonzalez R. , et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373 (01) 23-34
  CrossrefPubMedGoogle Scholar
• 108 Barone C, Koeberle D, Metselaar H, Parisi G, Sansonno D, Spinzi G. Multidisciplinary approach for HCC patients: hepatology for the oncologists. Ann Oncol 2013; 24 (Suppl. 02) ii15-ii23
  CrossrefPubMedGoogle Scholar
• 109 Sherman M, Burak K, Maroun J. , et al. Multidisciplinary Canadian consensus recommendations for the management and treatment of hepatocellular carcinoma. Curr Oncol 2011; 18 (05) 228-240
  PubMedGoogle Scholar
• 110 Guy J, Kelley RK, Roberts J, Kerlan R, Yao F, Terrault N. Multidisciplinary management of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2012; 10 (04) 354-362
  CrossrefPubMedGoogle Scholar
• 111 Chang TT, Sawhney R, Monto A. , et al. Implementation of a multidisciplinary treatment team for hepatocellular cancer at a Veterans Affairs Medical Center improves survival. HPB 2008; 10 (06) 405-411
  CrossrefPubMedGoogle Scholar