Evaluation and Management of Unresectable Hepatocellular Carcinoma: Multidisciplinary Indian Consensus Statements from a Delphi Panel

Abstract

Background

India, like many parts of Asia, likely faces a high burden of hepatocellular carcinoma (HCC), though large-scale data on etiology, presentation, and outcomes are lacking. There appears to be a predominance of unresectable, advanced-stage HCC at presentation in India with variable level of expertise in India to manage these scenarios. This publication summarizes the latest evidence with cognizance of the unique challenges faced in India by treating clinicians.

Methods

A multidisciplinary panel of medical oncologists, gastroenterologists, hepatologists, interventional radiologists, and hepatobiliary surgical oncologists held a meeting in June 2022 and reviewed the evidence available for management of HCC. The meeting concentrated on the recognition and management of HCC not amenable to surgical approaches in the Indian context. A literature review of these aspects of management was conducted and consensus statements with level of evidence and grades of recommendation were prepared by individual specialists in each field. Statements were evaluated by the modified Delphi method.

Key Content and Findings

The panel comprising 22 experts formulated 40 consensus statements with regard to defining unresectable HCC, optimization of underlying conditions prior to management, rationale use of various liver-directed therapies (LDTs) in unresectable HCC, and systemic therapeutic options in this group of patients.

Conclusion

Our consensus statements offer practical, yet evidence-based management guidelines for treating unresectable HCC in the Indian context. There is an emphasis on the crucial need for combining available approaches for LDT, even if less well studied though possibly effective, with standard systemic therapy.

Keywords

HCC - hepatocellular carcinoma - Indian consensus - MDT - multidisciplinary tumor board

Publikationsverlauf

Eingereicht: 28. Oktober 2023

Angenommen: 26. Juni 2024

Artikel online veröffentlicht:
22. Juli 2024

• References

• 1 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
• 2 Shetty VV, Kellarai A. Comprehensive review of hepatocellular carcinoma in India: current challenges and future directions. JCO Glob Oncol 2022; 8: e2200118
• 3 Lingiah VA, Niazi M, Olivo R, Paterno F, Guarrera JV, Pyrsopoulos NT. Liver transplantation beyond Milan Criteria. J Clin Transl Hepatol 2020; 8 (01) 69-75
• 4 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
• 5 Abou-Alfa GK, Lau G, Kudo M. et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid 2022; 1 (08) EVIDa2100070
• 6 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
• 7 Reig M, Forner A, Rimola J. et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022; 76 (03) 681-693
• 8 Yau T, Tang VYF, Yao TJ, Fan ST, Lo CM, Poon RTP. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014; 146 (07) 1691-700.e3
• 9 Fidelman N, Kerlan Jr RK. Transarterial chemoembolization and (90)Y radioembolization for hepatocellular carcinoma: review of current applications beyond intermediate-stage disease. AJR Am J Roentgenol 2015; 205 (04) 742-752
• 10 Brown AM, Kassab I, Massani M. et al. TACE versus TARE for patients with hepatocellular carcinoma: overall and individual patient level meta analysis. Cancer Med 2023; 12 (03) 2590-2599
• 11 Bhandare MS, Patkar S, Shetty N. et al. Liver resection for HCC outside the BCLC criteria. Langenbecks Arch Surg 2018; 403 (01) 37-44
• 12 Pamecha V, Sinha PK, Rajendran V. et al. Living donor liver transplantation for hepatocellular carcinoma in Indian patients- is the scenario different?. Indian J Gastroenterol 2021; 40 (03) 295-302
• 13 Khan AR, Khan S, Zimmerman V, Baddour LM, Tleyjeh IM. Quality and strength of evidence of the Infectious Diseases Society of America clinical practice guidelines. Clin Infect Dis 2010; 51 (10) 1147-1156
• 14 D'Avola D, Granito A, Torre-Aláez M, Piscaglia F. The importance of liver functional reserve in the non-surgical treatment of hepatocellular carcinoma. J Hepatol 2022; 76 (05) 1185-1198
• 15 Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16 (10) 589-604
• 16 El-Khateeb E, Darwich AS, Achour B, Athwal V, Rostami-Hodjegan A. Review article: time to revisit Child-Pugh score as the basis for predicting drug clearance in hepatic impairment. Aliment Pharmacol Ther 2021; 54 (04) 388-401
• 17 Wang YY, Zhong JH, Su ZY. et al. Albumin-bilirubin versus Child-Pugh score as a predictor of outcome after liver resection for hepatocellular carcinoma. Br J Surg 2016; 103 (06) 725-734
• 18 Pinato DJ, Sharma R, Allara E. et al. The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma. J Hepatol 2017; 66 (02) 338-346
• 19 Hickey R, Mouli S, Kulik L. et al. Independent analysis of albumin-bilirubin grade in a 765-patient cohort treated with transarterial locoregional therapy for hepatocellular carcinoma. J Vasc Interv Radiol 2016; 27 (06) 795-802
• 20 Vos JJ, Wietasch JKG, Absalom AR, Hendriks HGD, Scheeren TWL. Green light for liver function monitoring using indocyanine green? An overview of current clinical applications. Anaesthesia 2014; 69 (12) 1364-1376
• 21 Erdogan D, Heijnen BHM, Bennink RJ. et al. Preoperative assessment of liver function: a comparison of 99mTc-Mebrofenin scintigraphy with indocyanine green clearance test. Liver Int 2004; 24 (02) 117-123
• 22 de Graaf W, van Lienden KP, Dinant S. et al. Assessment of future remnant liver function using hepatobiliary scintigraphy in patients undergoing major liver resection. J Gastrointest Surg 2010; 14 (02) 369-378
• 23 Fung J, Poon RTP, Yu WC. et al. Use of liver stiffness measurement for liver resection surgery: correlation with indocyanine green clearance testing and post-operative outcome. PLoS One 2013; 8 (08) e72306
• 24 Cescon M, Colecchia A, Cucchetti A. et al. Value of transient elastography measured with FibroScan in predicting the outcome of hepatic resection for hepatocellular carcinoma. Ann Surg 2012; 256 (05) 706-712 , discussion 712–713
• 25 Galle PR, Forner A, Llovet JM. et al; European Association for the Study of the Liver. Electronic address: [e-mail], European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018; 69 (01) 182-236
• 26 Laube R, Sabih AH, Strasser SI, Lim L, Cigolini M, Liu K. Palliative care in hepatocellular carcinoma. J Gastroenterol Hepatol 2021; 36 (03) 618-628
• 27 Shukla A, Patkar S, Sundaram S. et al. Clinical profile, patterns of care & adherence to guidelines in patients with hepatocellular carcinoma: prospective multi-center study. J Clin Exp Hepatol 2022; 12 (06) 1463-1473
• 28 Tohra S, Duseja A, Taneja S. et al. Experience with changing etiology and nontransplant curative treatment modalities for hepatocellular carcinoma in a real-life setting-a retrospective descriptive analysis. J Clin Exp Hepatol 2021; 11 (06) 682-690
• 29 Peng CY, Chien RN, Liaw YF. Hepatitis B virus-related decompensated liver cirrhosis: benefits of antiviral therapy. J Hepatol 2012; 57 (02) 442-450
• 30 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 (03) 210-216
• 31 Giri S, Agrawal D, Afzalpurkar S, Gopan A, Angadi S, Sundaram S. Tenofovir versus entecavir for tertiary prevention of hepatocellular carcinoma in chronic hepatitis B infection after curative therapy: a systematic review and meta-analysis. J Viral Hepat 2023; 30 (02) 108-115
• 32 Pawlotsky JM, Negro F, Aghemo A. et al; European Association for the Study of the Liver. Electronic address: [e-mail], Clinical Practice Guidelines Panel: Chair, EASL Governing Board representative, Panel members. EASL recommendations on treatment of hepatitis C: final update of the series^☆ . J Hepatol 2020; 73 (05) 1170-1218
• 33 Singal AG, Rich NE, Mehta N. et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 2019; 157 (05) 1253-1263.e2
• 34 Singal AG, Rich NE, Mehta N. et al. Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study. Gastroenterology 2019; 156 (06) 1683-1692.e1
• 35 Guglielmi A, Ruzzenente A, Conci S, Valdegamberi A, Iacono C. How much remnant is enough in liver resection?. Dig Surg 2012; 29 (01) 6-17
• 36 Glantzounis GK, Tokidis E, Basourakos SP, Ntzani EE, Lianos GD, Pentheroudakis G. The role of portal vein embolization in the surgical management of primary hepatobiliary cancers. A systematic review. Eur J Surg Oncol 2017; 43 (01) 32-41 (EJSO)
• 37 Kuroda S, Tashiro H, Kobayashi T, Oshita A, Amano H, Ohdan H. Selection criteria for hepatectomy in patients with hepatocellular carcinoma classified as Child-Pugh class B. World J Surg 2011; 35 (04) 834-841
• 38 Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007; 356 (15) 1545-1559
• 39 Berzigotti A, Reig M, Abraldes JG, Bosch J, Bruix J. Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and meta-analysis. Hepatology 2015; 61 (02) 526-536
• 40 Liau KH, Ruo L, Shia J. et al. Outcome of partial hepatectomy for large (> 10 cm) hepatocellular carcinoma. Cancer 2005; 104 (09) 1948-1955
• 41 Yamashita Y, Taketomi A, Shirabe K. et al. Outcomes of hepatic resection for huge hepatocellular carcinoma (≥ 10 cm in diameter). J Surg Oncol 2011; 104 (03) 292-298
• 42 Kokudo T, Hasegawa K, Matsuyama Y. et al; Liver Cancer Study Group of Japan. Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: a Japanese nationwide survey. Hepatology 2017; 66 (02) 510-517
• 43 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
• 44 Chen ZH, Wang K, Zhang XP. et al. A new classification for hepatocellular carcinoma with hepatic vein tumor thrombus. Hepatobiliary Surg Nutr 2020; 9 (06) 717-728
• 45 Moon DB, Hwang S, Wang HJ. et al. Surgical outcomes of hepatocellular carcinoma with bile duct tumor thrombus: a Korean multicenter study. World J Surg 2013; 37 (02) 443-451
• 46 Rammohan A, Sathyanesan J, Rajendran K. et al. Bile duct thrombi in hepatocellular carcinoma: is aggressive surgery worthwhile?. HPB (Oxford) 2015; 17 (06) 508-513
• 47 Fukami Y, Kaneoka Y, Maeda A. et al; Liver Cancer Study Group of Japan. Liver resection for multiple hepatocellular carcinomas: a Japanese nationwide survey. Ann Surg 2020; 272 (01) 145-154
• 48 Li ZL, Yu JJ, Guo JW. et al. Liver resection is justified for multinodular hepatocellular carcinoma in selected patients with cirrhosis: a multicenter analysis of 1,066 patients. Eur J Surg Oncol 2019; 45 (05) 800-807
• 49 Kudo M. Adjuvant atezolizumab-bevacizumab after curative therapy for hepatocellular carcinoma. Hepatobiliary Surg Nutr 2023; 12 (03) 435-439
• 50 Yang X, Xu H, Zuo B. et al. Downstaging and resection of hepatocellular carcinoma in patients with extrahepatic metastases after stereotactic therapy. Hepatobiliary Surg Nutr 2021; 10 (04) 434-442
• 51 Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database of Systematic Reviews [Internet]. 2011 Accessed July 16, 2023 at: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004787.pub2/full
• 52 Ray Jr CE, Haskal ZJ, Geschwind JFH, Funaki BS. The use of transarterial chemoembolization in the treatment of unresectable hepatocellular carcinoma: a response to the Cochrane Collaboration review of 2011. J Vasc Interv Radiol 2011; 22 (12) 1693-1696
• 53 Liu W, Xu H, Ying X. et al. Radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) for patients with medium-to-large hepatocellular carcinoma: a retrospective analysis of long-term outcome. Med Sci Monit 2020; 26: e923263
• 54 Hirooka M, Hiraoka A, Ochi H. et al. Transcatheter arterial chemoembolization with or without radiofrequency ablation: outcomes in patients with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. AJR Am J Roentgenol 2018; 210 (04) 891-898
• 55 Song JE, Kim DY. Conventional vs drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma. World J Hepatol 2017; 9 (18) 808-814
• 56 Lammer J, Malagari K, Vogl T. et al; PRECISION V Investigators. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010; 33 (01) 41-52
• 57 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 (Oxford) 2017; 19 (08) 659-666
• 58 Garin E, Tselikas L, Guiu B. et al; DOSISPHERE-01 Study Group. Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial. Lancet Gastroenterol Hepatol 2021; 6 (01) 17-29
• 59 Bujold A, Massey CA, Kim JJ. et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 2013; 31 (13) 1631-1639
• 60 Fukuda K, Okumura T, Abei M. et al. Long-term outcomes of proton beam therapy in patients with previously untreated hepatocellular carcinoma. Cancer Sci 2017; 108 (03) 497-503
• 61 Bush DA, Smith JC, Slater JD. et al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys 2016; 95 (01) 477-482
• 62 Kim TH, Koh YH, Kim BH. et al. Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial. J Hepatol 2021; 74 (03) 603-612
• 63 Jang WI, Bae SH, Kim MS. et al. A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy. Cancer 2020; 126 (02) 363-372
• 64 Dawson LA, Winter K, Knox J. et al. NRG/RTOG 1112: randomized phase III study of sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC) (NCT01730937). Int J Radiat Oncol Biol Phys 2022; 114 (05) 1057
• 65 Buckstein M, Kim E, Özbek U. et al. Combination transarterial chemoembolization and stereotactic body radiation therapy for unresectable single large hepatocellular carcinoma: results from a prospective phase 2 trial. Int J Radiat Oncol Biol Phys 2022; 114 (02) 221-230
• 66 Comito T, Loi M, Franzese C. et al. Stereotactic radiotherapy after incomplete transarterial (Chemo-) embolization (TAE) versus exclusive TAE or TACE for treatment of inoperable HCC: a phase III trial (NCT02323360). Curr Oncol 2022; 29 (11) 8802-8813
• 67 Yoon SM, Ryoo BY, Lee SJ. et al. Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial. JAMA Oncol 2018; 4 (05) 661-669
• 68 Wei X, Jiang Y, Zhang X. et al. Neoadjuvant three-dimensional conformal radiotherapy for resectable hepatocellular carcinoma with portal vein tumor thrombus: a randomized, open-label, multicenter controlled study. J Clin Oncol 2019; 37 (24) 2141-2151
• 69 Lencioni R, Llovet JM, Han G. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. J Hepatol 2016; 64 (05) 1090-1098
• 70 Kudo M, Ueshima K, Ikeda M. et al; TACTICS study group. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut 2020; 69 (08) 1492-1501
• 71 Kudo M, Ueshima K, Ikeda M. et al. Final results of TACTICS: a randomized, prospective trial comparing transarterial chemoembolization plus sorafenib to transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma. Liver Cancer 2022; 11 (04) 354-367
• 72 Peng Z, Fan W, Zhu B. et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: a phase III, randomized clinical trial (LAUNCH). J Clin Oncol 2023; 41 (01) 117-127
• 73 Kudo M, Kawamura Y, Hasegawa K. et al. Management of hepatocellular carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update. Liver Cancer 2021; 10 (03) 181-223
• 74 Vilgrain V, Pereira H, Assenat E. et al; SARAH Trial Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol 2017; 18 (12) 1624-1636
• 75 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; 36 (19) 1913-1921
• 76 Ricke J, Klümpen HJ, Amthauer H. et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol 2019; 71 (06) 1164-1174
• 77 Chuma M, Uojima H, Hiraoka A. et al. Analysis of efficacy of lenvatinib treatment in highly advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein or tumor with more than 50% liver occupation: a multicenter analysis. Hepatol Res 2021; 51 (02) 201-215
• 78 Kuzuya T, Ishigami M, Ito T. et al. Sorafenib vs. lenvatinib as first-line therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Anticancer Res 2020; 40 (04) 2283-2290
• 79 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
• 80 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
• 81 Ramaswamy A, Kulkarni A, John G. et al. Survival of trial-like and non-trial-like patients with immunotherapy in advanced hepatocellular carcinoma in real world: a collaborative multicenter Indian study (IMHEP). JCO Glob Oncol 2023; 9 (09) e2300215
• 82 Ostwal V, Gupta T, Chopra S. et al. Tolerance and adverse event profile with sorafenib in Indian patients with advanced hepatocellular carcinoma. South Asian J Cancer 2017; 6 (04) 144-146
• 83 Kim BK, Cheon J, Kim H. et al. Atezolizumab/bevacizumab vs. lenvatinib as first-line therapy for unresectable hepatocellular carcinoma: a real-world, multi-center study. Cancers (Basel) 2022; 14 (07) 1747
• 84 Casadei-Gardini A, Rimini M, Tada T. et al. Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population. Eur J Cancer 2023; 180: 9-20
• 85 Yau T, Park JW, Finn RS. et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2022; 23 (01) 77-90
• 86 Finn RS, Ryoo BY, Merle P. et al; 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 (03) 193-202
• 87 Kudo M, Matilla A, Santoro A. et al. CheckMate 040 cohort 5: a phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol 2021; 75 (03) 600-609
• 88 Pressiani T, Boni C, Rimassa L. et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol 2013; 24 (02) 406-411
• 89 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
• 90 Abou-Alfa GK, Meyer T, Cheng AL. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379 (01) 54-63
• 91 Zhu AX, Kang YK, Yen CJ. et al; 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 (02) 282-296
• 92 Zhu AX, Park JO, Ryoo BY. et al; 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 (07) 859-870
• 93 Yau T, Kang YK, Kim TY. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol 2020; 6 (11) e204564