Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook

References

• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33. doi:10.3322/caac.21654
   PubMed Web of Science ®Google Scholar
• Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):7.
   PubMed Web of Science ®Google Scholar
• McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021;73(Suppl 1):S4–S13.
   PubMed Web of Science ®Google Scholar
• 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(3):209–249.
   PubMed Web of Science ®Google Scholar
• Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380(15):1450–1462.
   PubMed Web of Science ®Google Scholar
• Vogel A, Martinelli E. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(6):801–805.
   PubMed Web of Science ®Google Scholar
• Maida M, Orlando E, Camma C, Cabibbo G. Staging systems of hepatocellular carcinoma: a review of literature. World J Gastroenterol. 2014;20(15):4141–4150.
   PubMed Web of Science ®Google Scholar
• Faria SC, Szklaruk J, Kaseb AO, Hassabo HM, Elsayes KM. TNM/Okuda/Barcelona/UNOS/CLIP International Multidisciplinary Classification of Hepatocellular Carcinoma: concepts, perspectives, and radiologic implications. Abdom Imaging. 2014;39(5):1070–1087.
   PubMedGoogle Scholar
• Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology. 2019;156(2):477–491.e1.
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1038/s41575-019-0186-y
   PubMed Web of Science ®Google Scholar
• Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723–750. doi:10.1002/hep.29913
   PubMed Web of Science ®Google Scholar
• Galle PR, Dufour JF, Peck-Radosavljevic M, Trojan J, Vogel A. Systemic therapy of advanced hepatocellular carcinoma. Future Oncol. 2021;17(10):1237–1251. doi:10.2217/fon-2020-0758
   PubMed Web of Science ®Google Scholar
• Bruix J, da Fonseca LG, Reig M. Insights into the success and failure of systemic therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2019;16(10):617–630. doi:10.1038/s41575-019-0179-x
   PubMed Web of Science ®Google Scholar
• Roderburg C, Ozdirik B, Wree A, Demir M, Tacke F. Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies. Hepat Oncol. 2020;7(2):HEP20. doi:10.2217/hep-2020-0004
   PubMed Web of Science ®Google Scholar
• Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa0708857
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1016/S0140-6736(18)30207-1
   PubMed Web of Science ®Google Scholar
• Bruix J, Qin S, Merle P, et al. 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. doi:10.1016/S0140-6736(16)32453-9
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018;379(1):54–63. doi:10.1056/NEJMoa1717002
   PubMed Web of Science ®Google Scholar
• Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–296. doi:10.1016/S1470-2045(18)30937-9
   PubMed Web of Science ®Google Scholar
• Flynn MJ, Sayed AA, Sharma R, Siddique A, Pinato DJ. Challenges and Opportunities in the Clinical Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma. Hepatology. 2019;69(5):2258–2270. doi:10.1002/hep.30337
   PubMed Web of Science ®Google Scholar
• Cheng H, Sun G, Chen H, et al. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res. 2019;9(8):1536–1545.
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi:10.1056/NEJMoa1915745
   PubMed Web of Science ®Google Scholar
• Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, Phase 2-3 study. Lancet Oncol. 2021;22(7):977–990. doi:10.1016/S1470-2045(21)00252-7
   PubMed Web of Science ®Google Scholar
• Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13(1):1–14. doi:10.1007/s10456-009-9160-6
   PubMed Web of Science ®Google Scholar
• Jiao Q, Bi L, Ren Y, Song S, Wang Q, Wang YS. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol Cancer. 2018;17(1):36. doi:10.1186/s12943-018-0801-5
   PubMed Web of Science ®Google Scholar
• Regad T. Targeting RTK Signaling Pathways in Cancer. Cancers. 2015;7(3):1758–1784. doi:10.3390/cancers7030860
   PubMed Web of Science ®Google Scholar
• Ghouri YA, Mian I, Rowe JH, Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog. 2017;16:1. doi:10.4103/jcar.JCar_9_16
   PubMedGoogle Scholar
• Qin S, Li A, Yi M, Yu S, Zhang M, Wu K. Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol. 2019;12(1):27. doi:10.1186/s13045-019-0718-5
   PubMed Web of Science ®Google Scholar
• 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(1):25–34. doi:10.1016/S1470-2045(08)70285-7
   PubMed Web of Science ®Google Scholar
• Ren Z, Zhu K, Kang H, et al. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(8):894–900.
   PubMed Web of Science ®Google Scholar
• Branco F, Alencar RS, Volt F, et al. The Impact of Early Dermatologic Events in the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib. Ann Hepatol. 2017;16(2):263–268.
   PubMed Web of Science ®Google Scholar
• Abdel-Rahman O, Lamarca A. Development of sorafenib-related side effects in patients diagnosed with advanced hepatocellular carcinoma treated with sorafenib: a systematic-review and meta-analysis of the impact on survival. Expert Rev Gastroenterol Hepatol. 2017;11(1):75–83.
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24(26):4293–4300.
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK. Selection of patients with hepatocellular carcinoma for sorafenib. J Natl Compr Canc Netw. 2009;7(4):397–403.
   PubMed Web of Science ®Google Scholar
• Huitzil FD, Saltz SL, Song J, et al. Retrospective analysis of outcome in hepatocellular carcinoma (HCC) patients (pts) with hepatitis C (C+) versus B (B+) treated with sorafenib (S) [abstract]. J Clin Oncol. 2011;29:e14636.
   Web of Science ®Google Scholar
• Jackson R, Psarelli EE, Berhane S, Khan H, Johnson P. Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: a Meta-Analysis of Randomized Phase III Trials. J Clin Oncol. 2017;35(6):622–628.
   PubMed Web of Science ®Google Scholar
• Kolamunnage-Dona R, Berhane S, Potts H, et al. Sorafenib is associated with a reduced rate of tumour growth and liver function deterioration in HCV-induced hepatocellular carcinoma. J Hepatol. 2021;75(4):879–887.
   PubMed Web of Science ®Google Scholar
• Giambartolomei S, Covone F, Levrero M, Balsano C. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene. 2001;20(20):2606–2610.
   PubMed Web of Science ®Google Scholar
• 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(5):999–1008.
   PubMed Web of Science ®Google Scholar
• Chiu J, Tang YF, Yao TJ, et al. The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits. Cancer. 2012;118(21):5293–5301.
   PubMed Web of Science ®Google Scholar
• Vogel A, Saborowski A. Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treat Rev. 2020;2(82):101946.
   Web of Science ®Google Scholar
• Marrero JA, Kudo M, Venook AP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65(6):1140–1147.
   PubMed Web of Science ®Google Scholar
• Kudo M. Lenvatinib in Advanced Hepatocellular Carcinoma. Liver Cancer. 2017;6(4):253–263.
   PubMed Web of Science ®Google Scholar
• Kudo M, Finn RS, Qin S, et al. Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT). J Clin Oncol. 2019;37(Suppl 4):S186–S186.
   Web of Science ®Google Scholar
• Vogel A, Frenette C, Sung M, et al. Baseline Liver Function and Subsequent Outcomes in the Phase 3 REFLECT Study of Patients with Unresectable Hepatocellular Carcinoma. Liver Cancer. 2021;10(5):510–521.
   PubMed Web of Science ®Google Scholar
• Vogel A, Qin S, Kudo M, et al. 618O - Health-related quality of Life (HRQOL) and disease symptoms in patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib (LEN) or sorafenib (SOR). Annals of Oncology. 2017;1(28):v210.
   Google Scholar
• Vogel A, Qin S, Kudo M, et al. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2021;6(8):649–658.
   PubMed Web of Science ®Google Scholar
• Kim JJ, McFarlane T, Tully S, Wong WWL. Lenvatinib Versus Sorafenib as First-Line Treatment of Unresectable Hepatocellular Carcinoma: a Cost-Utility Analysis. Oncologist. 2020;25(3):e512–e519.
   PubMed Web of Science ®Google Scholar
• Wilhelm SM, Dumas J, Adnane L, et al. 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.
   PubMed Web of Science ®Google Scholar
• Kudo M, New A. Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib. Liver Cancer. 2017;6(3):177–184.
   PubMed Web of Science ®Google Scholar
• Finn RS, Merle P, Granito A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase III RESORCE trial. J Hepatol. 2018;69(2):353–358.
   PubMed Web of Science ®Google Scholar
• Kim HD, Bang Y, Lee MA, et al. Regorafenib in patients with advanced Child-Pugh B hepatocellular carcinoma: a multicentre retrospective study. Liver Int. 2020;40(10):2544–2552.
   PubMed Web of Science ®Google Scholar
• Bruix J, Merle P, Granito A, et al. Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib. J Clin Oncol. 2018;36(Suppl 4):S412–S412.
   Web of Science ®Google Scholar
• Bruix J, Reig M, Merle P, et al. 755P - Alpha-fetoprotein (AFP) response in patients with unresectable hepatocellular carcinoma (HCC) in the phase III RESORCE trial. Annals of Oncology. 2019;30:v291.
   Web of Science ®Google Scholar
• Teufel M, Seidel H, Kochert K, et al. Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma. Gastroenterology. 2019;156(6):1731–1741.
   PubMed Web of Science ®Google Scholar
• Xiang Q, Chen W, Ren M, et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res. 2014;20(11):2959–2970.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018.
   PubMed Web of Science ®Google Scholar
• Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–2308.
   PubMed Web of Science ®Google Scholar
• Miksad R, Cicin I, Chen Y, et al. O-022 - Outcomes based on Albumin‐Bilirubin (ALBI) grade in the phase 3 CELESTIAL trial of cabozantinib versus placebo in patients with advanced hepatocellular carcinoma (HCC). Annals of Oncology. 2019;30:iv134.
   Web of Science ®Google Scholar
• Abou-Alfa GK, Meyer T, Cheng A-L, 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(Suppl 4):S207–S207.
   Web of Science ®Google Scholar
• Rimassa L, Assenat E, Peck-Radosavljevic M, et al. 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.
   PubMed Web of Science ®Google Scholar
• Kelley RK, Mollon P, Blanc JF, et al. Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma. Adv Ther. 2020;37(6):2678–2695.
   PubMed Web of Science ®Google Scholar
• Soto-perez-de-celis E, Aguiar PN, Cordon ML, Chavarri-Guerra Y, Lopes GL. Cost-Effectiveness of Cabozantinib in the Second-Line Treatment of Advanced Hepatocellular Carcinoma. J Natl Compr Canc Netw. 2019;17(6):669–675.
   PubMed Web of Science ®Google Scholar
• Rimassa L, Kelley RK, Meyer T, et al. 678PD - Outcomes based on plasma biomarkers for the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (aHCC). Annals of Oncology. 2019;1(30):v257–v258.
   Google Scholar
• Syed YY. Ramucirumab: a Review in Hepatocellular Carcinoma. Drugs. 2020;80(3):315–322.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Park JO, Ryoo BY, et al. 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.
   PubMed Web of Science ®Google Scholar
• Gilabert M, Raoul JL. Potential of ramucirumab in treating hepatocellular carcinoma patients with elevated baseline alpha-fetoprotein. J Hepatocell Carcinoma. 2018;5:91–98.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Kang Y-K, Yen C-J, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol. 2018;36(Suppl 15):S4003–S4003.
   Web of Science ®Google Scholar
• Zhu A, Finn R, Galle P, et al. LBA-001 - Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: pooled efficacy and safety across two global randomized Phase 3 studies (REACH-2 and REACH). Annals of Oncology. 2018;29:v122.
   Web of Science ®Google Scholar
• Kok B, Abraldes JG. Child-Pugh Classification: time to Abandon? Semin Liver Dis. 2019;39(1):96–103.
   PubMed Web of Science ®Google Scholar
• Brandi GKM, Kang YK, et al. OP-07 Ramucirumab for patients with hepatocellular carcinoma and elevated alpha-fetoprotein following sorafenib treatment: exploratory analysis of REACH-2 trial results by albumin-bilirubin grade and Child-Pugh score [abstract]. EASL HCC SUMMIT 2019; 2019 Feb 14-16; ePOSTER ABSTRACT PRESENTATIONS: 35.
   Google Scholar
• Kudo M, Ikeda M, Galle PR, et al. Ramucirumab in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: outcomes by treatment-emergent ascites. Hepatol Res. 2021;51(6):715–721.
   PubMed Web of Science ®Google Scholar
• Demir T, Lee SS, Kaseb AO. Systemic therapy of liver cancer. Adv Cancer Res. 2021;2(149):257–294.
   Web of Science ®Google Scholar
• Kudo M. Ramucirumab as Second-Line Systemic Therapy in Hepatocellular Carcinoma. Liver Cancer. 2018;7(4):305–311.
   PubMed Web of Science ®Google Scholar
• Li X, Qiu M, Wang S, Zhu H, Feng B, Zheng L. A Phase I dose-escalation, pharmacokinetics and food-effect study of oral donafenib in patients with advanced solid tumours. Cancer Chemother Pharmacol. 2020;85(3):593–604.
   PubMed Web of Science ®Google Scholar
• Qin S, Bi F, Gu S, et al. Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: a Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. J Clin Oncol. 2021;39(27):3002–3011.
   PubMed Web of Science ®Google Scholar
• Yen CJ, Kim TY, Feng YH, et al. A Phase I/Randomized Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nintedanib versus Sorafenib in Asian Patients with Advanced Hepatocellular Carcinoma. Liver Cancer. 2018;7(2):165–178.
   PubMed Web of Science ®Google Scholar
• Cheng AL, Thongprasert S, Lim HY, et al. Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2016;64(3):774–784.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Decaens T, Raoul JL, et al. 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.
   PubMed Web of Science ®Google Scholar
• Hsu C, Yang TS, Huo TI, et al. Vandetanib in patients with inoperable hepatocellular carcinoma: a Phase II, randomized, double-blind, placebo-controlled study. J Hepatol. 2012;56(5):1097–1103.
   PubMed Web of Science ®Google Scholar
• Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;23(27):6657–6663.
   PubMed Web of Science ®Google Scholar
• Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33(2):172–179.
   PubMed Web of Science ®Google Scholar
• Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol. 2009;10(8):794–800.
   PubMed Web of Science ®Google Scholar
• Turpin A, de Baere T, Heurgue A, et al. Liver transarterial chemoembolization and sunitinib for unresectable hepatocellular carcinoma: results of the PRODIGE 16 study. Clin Res Hepatol Gastroenterol. 2021;45(2):101464.
   PubMed Web of Science ®Google Scholar
• Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–630.
   PubMed Web of Science ®Google Scholar
• Pickup M, Novitskiy S, Moses HL. The roles of TGFbeta in the tumour microenvironment. Nat Rev Cancer. 2013;13(11):788–799.
   PubMed Web of Science ®Google Scholar
• Faivre S, Santoro A, Kelley RK, et al. Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. Liver Int. 2019;39(8):1468–1477.
   PubMed Web of Science ®Google Scholar
• Kasprzak A, Adamek A. Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy. Int J Mol Sci. 2018;19(12):3887.
   PubMed Web of Science ®Google Scholar
• Duffy AG, Ma C, Ulahannan SV, et al. Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma. Clin Cancer Res. 2017;23(16):4633–4641.
   PubMed Web of Science ®Google Scholar
• Alqahtani A, Khan Z, Alloghbi A, Said ahmed TS, Ashraf M, Hammouda DM. Hepatocellular Carcinoma: molecular Mechanisms and Targeted Therapies. Medicina. 2019;55(9):526.
   PubMed Web of Science ®Google Scholar
• Zhu YJ, Zheng B, Wang HY, Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 2017;38(5):614–622.
   PubMed Web of Science ®Google Scholar
• Garlich JR, De P, Dey N, et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res. 2008;68(1):206–215.
   PubMed Web of Science ®Google Scholar
• Singh AR, Joshi S, Burgoyne AM, et al. Single Agent and Synergistic Activity of the “First-in-Class” Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma. Mol Cancer Ther. 2016;15(11):2553–2562.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312(1):57–67.
   PubMed Web of Science ®Google Scholar
• Koeberle D, Dufour JF, Demeter G, et al. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann Oncol. 2016;27(5):856–861.
   PubMed Web of Science ®Google Scholar
• Hwang YH, Choi JY, Kim S, et al. Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res. 2004;29(2):113–121.
   PubMed Web of Science ®Google Scholar
• Chen L, Shi Y, Jiang CY, Wei LX, Wang YL, Dai GH. Expression and prognostic role of pan-Ras, Raf-1, pMEK1 and pERK1/2 in patients with hepatocellular carcinoma. Eur J Surg Oncol. 2011;37(6):513–520.
   PubMed Web of Science ®Google Scholar
• Tai WM, Yong WP, Lim C, et al. A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC). Ann Oncol. 2016;27(12):2210–2215.
   PubMed Web of Science ®Google Scholar
• Lim HY, Merle P, Weiss KH, et al. Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma. Clin Cancer Res. 2018;24(19):4650–4661.
   PubMed Web of Science ®Google Scholar
• Bitzer M, Horger M, Giannini EG, et al. Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study. J Hepatol. 2016;65(2):280–288. doi:10.1016/j.jhep.2016.02.043
   PubMed Web of Science ®Google Scholar
• Bollard J, Miguela V, Ruiz de Galarreta M, et al. Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut. 2017;66(7):1286–1296. doi:10.1136/gutjnl-2016-312268
   PubMed Web of Science ®Google Scholar
• Reiter FP, Denk G, Ziesch A, et al. Predictors of ribociclib-mediated antitumour effects in native and sorafenib-resistant human hepatocellular carcinoma cells. Cell Oncol. 2019;42(5):705–715. doi:10.1007/s13402-019-00458-8
   PubMed Web of Science ®Google Scholar
• Yoo C, Kang J, Lim HY, et al. Phase I Dose-Finding Study of OPB-111077, a Novel STAT3 Inhibitor, in Patients with Advanced Hepatocellular Carcinoma. Cancer Res Treat. 2019;51(2):510–518. doi:10.4143/crt.2018.226
   PubMed Web of Science ®Google Scholar
• Zhu H, Wang DD, Yuan T, et al. Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis. Cancer Res. 2018;78(14):3995–4006. doi:10.1158/0008-5472.CAN-17-1548
   PubMed Web of Science ®Google Scholar
• Eatrides J, Wang E, Kothari N, Kim R. Role of Systemic Therapy and Future Directions for Hepatocellular Carcinoma. Cancer Control. 2017;24(3):1073274817729243. doi:10.1177/1073274817729243
   Web of Science ®Google Scholar
• Johnson PJ. Are there indications for chemotherapy in hepatocellular carcinoma? Surg Oncol Clin N Am. 2003;12(1):127–134. doi:10.1016/S1055-3207(02)00075-3
   PubMedGoogle Scholar
• Huang CC, Wu MC, Xu GW, et al. Overexpression of the MDR1 gene and P-glycoprotein in human hepatocellular carcinoma. J Natl Cancer Inst. 1992;84(4):262–264. doi:10.1093/jnci/84.4.262
   PubMedGoogle Scholar
• Chou YY, Cheng AL, Hsu HC. Expression of P-glycoprotein and p53 in advanced hepatocellular carcinoma treated by single agent chemotherapy: clinical correlation. J Gastroenterol Hepatol. 1997;12(8):569–575. doi:10.1111/j.1440-1746.1997.tb00487.x
   PubMed Web of Science ®Google Scholar
• Abouelezz K, Khanapara D, Batiha GE, Ahmed EA, Hetta HF, Cytotoxic Chemotherapy as an Alternative for Systemic Treatment of Advanced Hepatocellular Carcinoma in Developing Countries. Cancer Manag Res. 2020;12:12239–12248. doi:10.2147/CMAR.S280631
   PubMed Web of Science ®Google Scholar
• Johnson PJ, Dobbs N, Kalayci C, et al. Clinical efficacy and toxicity of standard dose Adriamycin in hyperbilirubinaemic patients with hepatocellular carcinoma: relation to liver tests and pharmacokinetic parameters. Br J Cancer. 1992;65(5):751–755. doi:10.1038/bjc.1992.158
   PubMed Web of Science ®Google Scholar
• Chlebowski RT, Brzechwa-Adjukiewicz A, Cowden A, Block JB, Tong M, Chan KK. Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results. Cancer Treat Rep. 1984;68(3):487–491.
   PubMedGoogle Scholar
• 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. doi:10.1002/1097-0142(19880801)62:3<479::AID-CNCR2820620306>3.0.CO;2-L
   PubMed Web of Science ®Google Scholar
• Patt YZ, Hassan MM, Aguayo A, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004;101(3):578–586. doi:10.1002/cncr.20368
   PubMed Web of Science ®Google Scholar
• Brandi G, de Rosa F, Agostini V, et al. Metronomic capecitabine in advanced hepatocellular carcinoma patients: a phase II study. Oncologist. 2013;18(12):1256–1257. doi:10.1634/theoncologist.2013-0093
   PubMed Web of Science ®Google Scholar
• Trevisani F, Brandi G, Garuti F, et al. Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. J Cancer Res Clin Oncol. 2018;144(2):403–414. doi:10.1007/s00432-017-2556-6
   PubMed Web of Science ®Google Scholar
• Xia Y, Qiu Y, Li J, et al. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol. 2010;17(12):3137–3144. doi:10.1245/s10434-010-1148-3
   PubMed Web of Science ®Google Scholar
• Ravaioli M, Cucchetti A, Pinna AD, et al. The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation. Sci Rep. 2017;7(1):11305. doi:10.1038/s41598-017-11810-z
   PubMed Web of Science ®Google Scholar
• Yang TS, Lin YC, Chen JS, Wang HM, Wang CH. Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer. 2000;89(4):750–756. doi:10.1002/1097-0142(20000815)89:4<750::AID-CNCR5>3.0.CO;2-R
   PubMed Web of Science ®Google Scholar
• Yen Y, Lim DW, Chung V, et al. Phase II study of oxaliplatin in patients with unresectable, metastatic, or recurrent hepatocellular cancer: a California Cancer Consortium Trial. Am J Clin Oncol. 2008;31(4):317–322. doi:10.1097/COC.0b013e318162f57d
   PubMed Web of Science ®Google Scholar
• Boige V, Taieb J, Hebbar M, et al. Irinotecan as first-line chemotherapy in patients with advanced hepatocellular carcinoma: a multicenter phase II study with dose adjustment according to baseline serum bilirubin level. Eur J Cancer. 2006;42(4):456–459. doi:10.1016/j.ejca.2005.09.034
   PubMed Web of Science ®Google Scholar
• Qin S, Bai Y, Lim HY, et al. 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. doi:10.1200/JCO.2012.44.5643
   PubMed Web of Science ®Google Scholar
• Qin S, Cheng Y, Liang J, et al. Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study. Oncologist. 2014;19(11):1169–1178. doi:10.1634/theoncologist.2014-0190
   PubMed Web of Science ®Google Scholar
• Dhooge M, Coriat R, Mir O, et al. Feasibility of gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma patients with Child-Pugh B cirrhosis. Oncology. 2013;84(1):32–38. doi:10.1159/000342763
   PubMed Web of Science ®Google Scholar
• Patrikidou A, Sinapi I, Regnault H, et al. Gemcitabine and oxaliplatin chemotherapy for advanced hepatocellular carcinoma after failure of anti-angiogenic therapies. Invest New Drugs. 2014;32(5):1028–1035. doi:10.1007/s10637-014-0100-y
   PubMed Web of Science ®Google Scholar
• Zaanan A, Williet N, Hebbar M, et al. Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study. J Hepatol. 2013;58(1):81–88. doi:10.1016/j.jhep.2012.09.006
   PubMed Web of Science ®Google Scholar
• Boige V, Raoul JL, Pignon JP, et al. Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial. Br J Cancer. 2007;97(7):862–867. doi:10.1038/sj.bjc.6603956
   PubMed Web of Science ®Google Scholar
• Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97(20):1532–1538. doi:10.1093/jnci/dji315
   PubMedGoogle Scholar
• Chia WK, Ong S, Toh HC, et al. Phase II trial of gemcitabine in combination with cisplatin in inoperable or advanced hepatocellular carcinoma. Ann Acad Med Singap. 2008;37(7):554–558.
   PubMed Web of Science ®Google Scholar
• Lee JO, Lee KW, Oh DY, et al. Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma. Ann Oncol. 2009;20(8):1402–1407. doi:10.1093/annonc/mdp010
   PubMed Web of Science ®Google Scholar
• Petrelli F, Coinu A, Borgonovo K, et al. Oxaliplatin-based chemotherapy: a new option in advanced hepatocellular carcinoma. a systematic review and pooled analysis. Clin Oncol. 2014;26(8):488–496. doi:10.1016/j.clon.2014.04.031
   Web of Science ®Google Scholar
• Qin LX. Inflammatory immune responses in tumor microenvironment and metastasis of hepatocellular carcinoma. Cancer Microenviron. 2012;5(3):203–209. doi:10.1007/s12307-012-0111-1
   PubMedGoogle Scholar
• Daniyan AF, Brentjens RJ. Immunotherapy: hiding in plain sight: immune escape in the era of targeted T-cell-based immunotherapies. Nat Rev Clin Oncol. 2017;14(6):333–334. doi:10.1038/nrclinonc.2017.49
   PubMed Web of Science ®Google Scholar
• Khan AA, Liu ZK, Xu X. Recent advances in immunotherapy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2021;20(6):511–520. doi:10.1016/j.hbpd.2021.06.010
   PubMed Web of Science ®Google Scholar
• Budhu A, Forgues M, Ye QH, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10(2):99–111. doi:10.1016/j.ccr.2006.06.016
   PubMed Web of Science ®Google Scholar
• Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328–2339. doi:10.1053/j.gastro.2007.03.102
   PubMed Web of Science ®Google Scholar
• Meirow Y, Kanterman J, Baniyash M, Paving the Road to Tumor Development and Spreading: myeloid-Derived Suppressor Cells are Ruling the Fate. Front Immunol. 2015;6:523. doi:10.3389/fimmu.2015.00523
   PubMed Web of Science ®Google Scholar
• Chen KJ, Lin SZ, Zhou L, et al. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS One. 2011;6(9):e24671. doi:10.1371/journal.pone.0024671
   PubMed Web of Science ®Google Scholar
• Degroote H, Van Dierendonck A, Geerts A, Van Vlierberghe H, Devisscher L. Preclinical and Clinical Therapeutic Strategies Affecting Tumor-Associated Macrophages in Hepatocellular Carcinoma. J Immunol Res. 2018;2018:7819520. doi:10.1155/2018/7819520
   PubMed Web of Science ®Google Scholar
• Sangro B, Sarobe P, Hervas-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(8):525–543. doi:10.1038/s41575-021-00438-0
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1016/S0140-6736(17)31046-2
   PubMed Web of Science ®Google Scholar
• Yau T, Park JW, Finn RS, et al. LBA38_PR - CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Annals of Oncology. 2019;1(30):v874–v875. doi:10.1093/annonc/mdz394.029
   Google Scholar
• Lleo A, Rimassa L, Colombo M. Hepatotoxicity of immune check point inhibitors: approach and management. Dig Liver Dis. 2019;51(8):1074–1078. doi:10.1016/j.dld.2019.06.017
   PubMedGoogle Scholar
• Kuo YH, Yen YH, Chen YY, et al. Nivolumab Versus Regorafenib in Patients With Hepatocellular Carcinoma After Sorafenib Failure. Front Oncol. 2021;11:683341. doi:10.3389/fonc.2021.683341
   PubMed Web of Science ®Google Scholar
• Lee CH, Lee YB, Kim MA, et al. Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment. Clin Mol Hepatol. 2020;26(3):328–339. doi:10.3350/cmh.2019.0049n
   PubMed Web of Science ®Google Scholar
• 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(3):600–609. doi:10.1016/j.jhep.2021.04.047
   PubMed Web of Science ®Google Scholar
• Fessas P, Kaseb A, Wang Y, et al. Post-registration experience of nivolumab in advanced hepatocellular carcinoma: an international study. J Immunother Cancer. 2020;8(2):e001033. doi:10.1136/jitc-2020-001033
   PubMed Web of Science ®Google Scholar
• Choi WM, Lee D, Shim JH, et al. Effectiveness and Safety of Nivolumab in Child-Pugh B Patients with Hepatocellular Carcinoma: a Real-World Cohort Study. Cancers. 2020;12(7):1968. doi:10.3390/cancers12071968
   PubMed Web of Science ®Google Scholar
• El-Khoueiry AB, Melero I, Yau TC, et al. Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): subanalyses of CheckMate-040. J Clin Oncol. 2018;36(Suppl 4):S475–S475. doi:10.1200/JCO.2018.36.4_suppl.475
   Web of Science ®Google Scholar
• Sangro B, Melero I, Wadhawan S, et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol. 2020;73(6):1460–1469. doi:10.1016/j.jhep.2020.07.026
   PubMed Web of Science ®Google Scholar
• Teng W, Lin CC, Ho MM, et al. Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma. Am J Cancer Res. 2021;11(5):2319–2330.
   PubMed Web of Science ®Google Scholar
• Rapposelli IG, De Matteis S, Lanuti P, et al. Heterogeneity of Response and Immune System Activity during Treatment with Nivolumab in Hepatocellular Carcinoma: results from a Single-Institution Retrospective Analysis. Cancers. 2021;13(2):213. doi:10.3390/cancers13020213
   PubMed Web of Science ®Google Scholar
• Zhu AX, Finn RS, Edeline J, et al. 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. doi:10.1016/S1470-2045(18)30351-6
   PubMed Web of Science ®Google Scholar
• Finn RS, Ryoo BY, Merle P, et al. 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. doi:10.1200/JCO.19.01307
   PubMed Web of Science ®Google Scholar
• Qin S, Chen Z, Fang W, et al. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): phase 3 KEYNOTE-394 study. J Clin Oncol. 2022;40(Suppl 4):S383–S383. doi:10.1200/JCO.2022.40.4_suppl.383
   Web of Science ®Google Scholar
• Vogel A, Merle P, Verslype C, et al. ALBI score and outcomes in patients with hepatocellular carcinoma: post hoc analysis of the randomized controlled trial KEYNOTE-240. Ther Adv Med Oncol. 2021;13:17588359211039928. doi:10.1177/17588359211039928
   Web of Science ®Google Scholar
• Ryoo BY, Merle P, Kulkarni AS, et al. Health-related quality-of-life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: KEYNOTE-240. Cancer. 2021;127(6):865–874. doi:10.1002/cncr.33317
   PubMed Web of Science ®Google Scholar
• Chiang CL, Chan SK, Lee SF, Wong IO, Choi HC. Cost-effectiveness of Pembrolizumab as a Second-Line Therapy for Hepatocellular Carcinoma. JAMA Netw Open. 2021;4(1):e2033761. doi:10.1001/jamanetworkopen.2020.33761
   PubMed Web of Science ®Google Scholar
• Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett. 2020;470:8–17. doi:10.1016/j.canlet.2019.12.002
   PubMed Web of Science ®Google Scholar
• Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21(4):571–580. doi:10.1016/S1470-2045(20)30011-5
   PubMed Web of Science ®Google Scholar
• Qin S, Finn RS, Kudo M, et al. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol. 2019;15(16):1811–1822. doi:10.2217/fon-2019-0097
   PubMed Web of Science ®Google Scholar
• Wainberg ZA, Segal NH, Jaeger D, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2017;35(Suppl 15):4071. doi:10.1200/JCO.2017.35.15_suppl.4071
   Web of Science ®Google Scholar
• Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12(12):681–700. doi:10.1038/nrgastro.2015.173
   PubMed Web of Science ®Google Scholar
• 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(1):81–88. doi:10.1016/j.jhep.2013.02.022
   PubMed Web of Science ®Google Scholar
• Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66(3):545–551. doi:10.1016/j.jhep.2016.10.029
   PubMed Web of Science ®Google Scholar
• Yau T, Kang Y-K, Kim T-Y, et al. 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):S4012–S4012. doi:10.1200/JCO.2019.37.15_suppl.4012
   Web of Science ®Google Scholar
• Lai E, Astara G, Ziranu P, et al. Introducing immunotherapy for advanced hepatocellular carcinoma patients: too early or too fast? Crit Rev Oncol Hematol. 2021;2(157):103167. doi:10.1016/j.critrevonc.2020.103167
   Web of Science ®Google Scholar
• Dovedi SJ, Elder MJ, Yang C, et al. Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1(+) Activated T Cells. Cancer Discov. 2021;11(5):1100–1117. doi:10.1158/2159-8290.CD-20-1445
   PubMed Web of Science ®Google Scholar
• Zhang R, Zhang Z, Liu Z, et al. Adoptive cell transfer therapy for hepatocellular carcinoma. Front Med. 2019;13(1):3–11. doi:10.1007/s11684-019-0684-x
   PubMed Web of Science ®Google Scholar
• Mizukoshi E, Kaneko S. Immune cell therapy for hepatocellular carcinoma. J Hematol Oncol. 2019;12(1):52. doi:10.1186/s13045-019-0742-5
   PubMed Web of Science ®Google Scholar
• Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013;13(8):525–541. doi:10.1038/nrc3565
   PubMed Web of Science ®Google Scholar
• Rochigneux P, Chanez B, De Rauglaudre B, Mitry E, Chabannon C, Gilabert M. Adoptive Cell Therapy in Hepatocellular Carcinoma: biological Rationale and First Results in Early Phase Clinical Trials. Cancers. 2021;13:2. doi:10.3390/cancers13020271
   Web of Science ®Google Scholar
• Ping Y, Liu C, Zhang Y. T-cell receptor-engineered T cells for cancer treatment: current status and future directions. Protein Cell. 2018;9(3):254–266. doi:10.1007/s13238-016-0367-1
   PubMed Web of Science ®Google Scholar
• Tan AT, Yang N, Lee Krishnamoorthy T, et al. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy. Gastroenterology. 2019;156(6):1862–1876.e9. doi:10.1053/j.gastro.2019.01.251
   PubMed Web of Science ®Google Scholar
• Qasim W, Brunetto M, Gehring AJ, et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol. 2015;62(2):486–491. doi:10.1016/j.jhep.2014.10.001
   PubMed Web of Science ®Google Scholar
• Sun L, Guo H, Jiang R, Lu L, Liu T, He X. Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma. Tumour Biol. 2016;37(1):799–806. doi:10.1007/s13277-015-3845-9
   PubMedGoogle Scholar
• Dargel C, Bassani-Sternberg M, Hasreiter J, et al. T Cells Engineered to Express a T-Cell Receptor Specific for Glypican-3 to Recognize and Kill Hepatoma Cells In Vitro and in Mice. Gastroenterology. 2015;149(4):1042–1052. doi:10.1053/j.gastro.2015.05.055
   PubMed Web of Science ®Google Scholar
• June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359(6382):1361–1365. doi:10.1126/science.aar6711
   PubMed Web of Science ®Google Scholar
• Shi D, Shi Y, Kaseb AO, et al. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: results of Phase I Trials. Clin Cancer Res. 2020;26(15):3979–3989. doi:10.1158/1078-0432.CCR-19-3259
   PubMed Web of Science ®Google Scholar
• Dai H, Tong C, Shi D, et al. Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial. Oncoimmunology. 2020;9(1):1846926. doi:10.1080/2162402X.2020.1846926
   PubMed Web of Science ®Google Scholar
• Jiang J, Wu C, Lu B. Cytokine-induced killer cells promote antitumor immunity. J Transl Med. 2013;11(83). doi:10.1186/1479-5876-11-83
   Web of Science ®Google Scholar
• Gustafsson K, Ingelsten M, Bergqvist L, Nystrom J, Andersson B, Karlsson-Parra A. Recruitment and activation of natural killer cells in vitro by a human dendritic cell vaccine. Cancer Res. 2008;68(14):5965–5971. doi:10.1158/0008-5472.CAN-07-6494
   PubMed Web of Science ®Google Scholar
• Palmer DH, Midgley RS, Mirza N, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2009;49(1):124–132. doi:10.1002/hep.22626
   PubMed Web of Science ®Google Scholar
• Tada F, Abe M, Hirooka M, et al. Phase I/II study of immunotherapy using tumor antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Int J Oncol. 2012;41(5):1601–1609. doi:10.3892/ijo.2012.1626
   PubMed Web of Science ®Google Scholar
• Nakagawa H, Mizukoshi E, Kobayashi E, et al. Association Between High-Avidity T-Cell Receptors, Induced by alpha-Fetoprotein-Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular Carcinoma. Gastroenterology. 2017;152(6):1395–1406.e10. doi:10.1053/j.gastro.2017.02.001
   PubMed Web of Science ®Google Scholar
• Sawada Y, Yoshikawa T, Ofuji K, et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology. 2016;5(5):e1129483. doi:10.1080/2162402X.2015.1129483
   PubMed Web of Science ®Google Scholar
• Mizukoshi E, Nakagawa H, Kitahara M, et al. Phase I trial of multidrug resistance-associated protein 3-derived peptide in patients with hepatocellular carcinoma. Cancer Lett. 2015;369(1):242–249. doi:10.1016/j.canlet.2015.08.020
   PubMed Web of Science ®Google Scholar
• Raja J, Ludwig JM, Gettinger SN, Schalper KA, Kim HS. Oncolytic virus immunotherapy: future prospects for oncology. J Immunother Cancer. 2018;6(1):140. doi:10.1186/s40425-018-0458-z
   PubMed Web of Science ®Google Scholar
• Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012;30(7):658–670. doi:10.1038/nbt.2287
   PubMed Web of Science ®Google Scholar
• Moehler M, Heo J, Lee HC, et al. Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE). Oncoimmunology. 2019;8(8):1615817. doi:10.1080/2162402X.2019.1615817
   PubMed Web of Science ®Google Scholar
• Genetic Engineering & Biotechnology News. Pexa-Vec/Nexavar Combination Fails Phase III Trial in Liver Cancer; 2019. Available from: https://www.genengnews.com/topics/genome-editing/pexa-vec-nexavar-combination-fails-phase-iii-trial-in-liver-cancer/. AccessedAugust 2, 2019.
   Google Scholar
• LaRocca CJ, Warner SG. Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials. Clin Transl Med. 2018;7(1):35. doi:10.1186/s40169-018-0214-5
   PubMed Web of Science ®Google Scholar
• Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018;15(5):310–324. doi:10.1038/nrclinonc.2018.9
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(Suppl 3):S267–S267. doi:10.1200/JCO.2021.39.3_suppl.267
   Web of Science ®Google Scholar
• Qin S, Ren Z, Feng Y, et al. OP02-03 Efficacy and safety of atezolizumab + bevacizumab vs sorafenib in Chinese patients with unresectable HCC in the phase III IMbrave150 study[abstract]. EASL HCC SUMMIT 2020; 2020 Feb 6-8; ORAL POSTER ABSTRACT PRESENTATIONS: 17–18.
   Google Scholar
• Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol. 2020;38(36):4317–4345. doi:10.1200/JCO.20.02672
   PubMed Web of Science ®Google Scholar
• Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: an EASL position paper. J Hepatol. 2021;75(4):960–974. doi:10.1016/j.jhep.2021.07.004
   PubMed Web of Science ®Google Scholar
• Qin S. Clinical practice of hepatocellular carcinoma: guideline of CSCO. CSCO. 2020;1:88.
   Google Scholar
• Eso Y, Takeda H, Taura K, Takai A, Takahashi K, Seno H. Pretreatment Neutrophil-to-Lymphocyte Ratio as a Predictive Marker of Response to Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma. Curr Oncol. 2021;28(5):4157–4166. doi:10.3390/curroncol28050352
   PubMed Web of Science ®Google Scholar
• Wang Y, Lu LC, Guan Y, et al. Atezolizumab plus bevacizumab combination enables an unresectable hepatocellular carcinoma resectable and links immune exclusion and tumor dedifferentiation to acquired resistance. Exp Hematol Oncol. 2021;10(1):45. doi:10.1186/s40164-021-00237-y
   PubMed Web of Science ®Google Scholar
• Yamada T, Minami T, Tateishi R, Koike K. Limited efficacy of atezolizumab and bevacizumab for hepatocellular carcinoma previously treated with tyrosine kinase inhibitor. Liver Int. 2021;41(9):2233–2234. doi:10.1111/liv.15010
   PubMed Web of Science ®Google Scholar
• Zhang X, Wang J, Shi J, Jia X, Dang S, Wang W. Cost-effectiveness of Atezolizumab Plus Bevacizumab vs Sorafenib for Patients With Unresectable or Metastatic Hepatocellular Carcinoma. JAMA Netw Open. 2021;4(4):e214846. doi:10.1001/jamanetworkopen.2021.4846
   PubMed Web of Science ®Google Scholar
• Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109(12):3993–4002. doi:10.1111/cas.13806
   PubMed Web of Science ®Google Scholar
• Finn RS, Ikeda M, Zhu AX, et al. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020;38(26):2960–2970. doi:10.1200/JCO.20.00808
   PubMed Web of Science ®Google Scholar
• Rizzo A, Dadduzio V, Ricci AD, et al. Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma? Expert Opin Investig Drugs. 2021;6(6):1–8.
   Google Scholar
• Kudo M, Ikeda M, Motomura K, et al. A phase Ib study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): study 117. J Clin Oncol. 2020;38(Suppl 4):S513–S513. doi:10.1200/JCO.2020.38.4_suppl.513
   Web of Science ®Google Scholar
• Kudo M, Motomura K, Wada Y, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: results from a phase 1b trial (VEGF Liver 100). J Clin Oncol. 2019;37(Suppl 15):S4072–S4072. doi:10.1200/JCO.2019.37.15_suppl.4072
   Web of Science ®Google Scholar
• Xu J, Zhang Y, Jia R, et al. 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. doi:10.1158/1078-0432.CCR-18-2484
   PubMed Web of Science ®Google Scholar
• Xu J, Shen J, Gu S, et al. Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): a Nonrandomized, Open-label, Phase II Trial. Clin Cancer Res. 2021;27(4):1003–1011. doi:10.1158/1078-0432.CCR-20-2571
   PubMed Web of Science ®Google Scholar
• Bai L, Sun M, Xu A, et al. Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma. J Clin Oncol. 2021;39(Suppl 15):S4101–S4101. doi:10.1200/JCO.2021.39.15_suppl.4101
   Web of Science ®Google Scholar
• Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD. Combination immunotherapy: a road map. J Immunother Cancer. 2017;4(5):16. doi:10.1186/s40425-017-0218-5
   Web of Science ®Google Scholar
• Kudo M. Combination Cancer Immunotherapy in Hepatocellular Carcinoma. Liver Cancer. 2018;7(1):20–27. doi:10.1159/000486487
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1001/jamaoncol.2020.4564
   PubMed Web of Science ®Google Scholar
• El-Khoueiry AB, Yau T, Kang Y-K, et al. Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): long-term results from CheckMate 040. J Clin Oncol. 2021;39(Suppl 3):S269–S269. doi:10.1200/JCO.2021.39.3_suppl.269
   PubMed Web of Science ®Google Scholar
• Saung MT, Pelosof L, Casak S, et al. FDA Approval Summary: nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib. Oncologist. 2021;26(9):797–806. doi:10.1002/onco.13819
   PubMed Web of Science ®Google Scholar
• Parikh ND, Marshall A, Betts KA, et al. Network meta-analysis of nivolumab plus ipilimumab in the second-line setting for advanced hepatocellular carcinoma. J Comp Eff Res. 2021;10(5):343–352. doi:10.2217/cer-2020-0236
   PubMed Web of Science ®Google Scholar
• Wong JSL, Kwok GGW, Tang V, et al. Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. J Immunother Cancer. 2021;9(2):e001945. doi:10.1136/jitc-2020-001945
   PubMed Web of Science ®Google Scholar
• Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol. 2017;35(Suppl 15):S4073–S4073. doi:10.1200/JCO.2017.35.15_suppl.4073
   Web of Science ®Google Scholar
• Kelley RK, Sangro B, Harris W, et al. Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: randomized Expansion of a Phase I/II Study. J Clin Oncol. 2021;39(27):2991–3001. doi:10.1200/JCO.20.03555
   PubMed Web of Science ®Google Scholar
• Kelley RK, Sangro B, Harris WP, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Oncol. 2020;38(Suppl 15):S4508–S4508. doi:10.1200/JCO.2020.38.15_suppl.4508
   Web of Science ®Google Scholar
• Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(Suppl 4):S379–S379. doi:10.1200/JCO.2022.40.4_suppl.379
   Web of Science ®Google Scholar
• Goyal L, Zheng H, Abrams TA, et al. A Phase II and Biomarker Study of Sorafenib Combined with Modified FOLFOX in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res. 2019;25(1):80–89. doi:10.1158/1078-0432.CCR-18-0847
   PubMed Web of Science ®Google Scholar
• Yau TC, Cheung FY, Lee F, et al. A multicenter phase II study of sorafenib, capecitabine, and oxaliplatin (SECOX) in patients with advanced hepatocellular carcinoma: final results of Hong Kong-Singapore Hepatocellular Carcinoma Research Collaborative Group study [abstract]. J Clin Oncol. 2013;31(Suppl 4):S4117. doi:10.1200/jco.2013.31.15_suppl.4117
   Google Scholar
• Assenat E, et al. Sorafenib (S) alone versus S combined with gemcitabine and oxaliplatin (GEMOX) in first-line treatment of advanced hepatocellular carcinoma (HCC): final analysis of the randomized phase II; GONEXT trial (a UNICANCER/FFCD PRODIGE 10 trial)[abstract]. J Clin Oncol. 2013;31(Suppl 4):S4028. doi:10.1200/jco.2013.31.15_suppl.4028
   Google Scholar
• Assenat E, Pageaux GP, Thezenas S, et al. Sorafenib alone vs. sorafenib plus GEMOX as 1(st)-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer. 2019;120(9):896–902. doi:10.1038/s41416-019-0443-4
   PubMed Web of Science ®Google Scholar
• Yau TC, Tang V, Leung RC-Y, et al. Randomized phase II trial of sorafenib, capecitabine and oxaliplatin (SECOX) versus single agent sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2019;37(Suppl 4):S365–S365. doi:10.1200/JCO.2019.37.4_suppl.365
   Web of Science ®Google Scholar
• Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304(19):2154–2160. doi:10.1001/jama.2010.1672
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Shi Q, Knox JJ, et al. Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: phase 3 CALGB 80802 Randomized Clinical Trial. JAMA Oncol. 2019;5(11):1582–1588. doi:10.1001/jamaoncol.2019.2792
   PubMed Web of Science ®Google Scholar
• Pfirschke C, Engblom C, Rickelt S, et al. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity. 2016;44(2):343–354. doi:10.1016/j.immuni.2015.11.024
   PubMed Web of Science ®Google Scholar
• Garg AD, More S, Rufo N, et al. Trial watch: immunogenic cell death induction by anticancer chemotherapeutics. Oncoimmunology. 2017;6(12):e1386829. doi:10.1080/2162402X.2017.1386829
   PubMed Web of Science ®Google Scholar
• Qin S, Chen Z, Liu Y, et al. A phase II study of anti–PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer. J Clin Oncol. 2019;37(Suppl 15):S4074–S4074. doi:10.1200/JCO.2019.37.15_suppl.4074
   Web of Science ®Google Scholar
• Garg AD, Agostinis P. Editorial: immunogenic Cell Death in Cancer: from Benchside Research to Bedside Reality. Front Immunol. 2016;1(7):110.
   Google Scholar
• Kudo M, Ueshima K, Ikeda M, et al. 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(8):1492–1501. doi:10.1136/gutjnl-2019-318934
   PubMed Web of Science ®Google Scholar
• Varghese J, Kedarisetty C, Venkataraman J, et al. Combination of TACE and Sorafenib Improves Outcomes in BCLC Stages B/C of Hepatocellular Carcinoma: a Single Centre Experience. Ann Hepatol. 2017;16(2):247–254. doi:10.5604/16652681.1231585
   PubMed Web of Science ®Google Scholar
• Palmer DH, Malagari K, Kulik LM. Role of locoregional therapies in the wake of systemic therapy. J Hepatol. 2020;72(2):277–287. doi:10.1016/j.jhep.2019.09.023
   PubMed Web of Science ®Google Scholar
• Park JW, Kim YJ, Kim DY, et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J Hepatol. 2019;70(4):684–691. doi:10.1016/j.jhep.2018.11.029
   PubMed Web of Science ®Google Scholar
• Meyer T, Fox R, Ma YT, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(8):565–575. doi:10.1016/S2468-1253(17)30156-5
   PubMed Web of Science ®Google Scholar
• Li D, Pang Y, Xu L, Xu X. Efficacy and safety of sorafenib combined with TACE in the treatment of advanced hepatocellular carcinoma: a meta-analysis. J BUON. 2021;26(4):1355–1364.
   PubMedGoogle Scholar
• Xie Y, Tian H, Xiang H. Is transcatheter arterial chemoembolization plus sorafenib better than chemoembolization plus placebo in the treatment of hepatocellular carcinoma? Tumori. 2021;107(4):292–303. doi:10.1177/0300891620945029
   PubMed Web of Science ®Google Scholar
• Zhao RC, Zhou J, Wei YG, et al. Cost-effectiveness analysis of transcatheter arterial chemoembolization with or without sorafenib for the treatment of unresectable hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2017;16(5):493–498. doi:10.1016/S1499-3872(17)60009-2
   PubMed Web of Science ®Google Scholar
• He M, Li Q, Zou R, et al. Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: a Randomized Clinical Trial. JAMA Oncol. 2019;5(7):953–960. doi:10.1001/jamaoncol.2019.0250
   PubMed Web of Science ®Google Scholar
• Kondo M, Morimoto M, Kobayashi S, et al. Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial. BMC Cancer. 2019;19(1):954. doi:10.1186/s12885-019-6198-8
   PubMed Web of Science ®Google Scholar
• Kudo M, Ueshima K, Yokosuka O, et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol Hepatol. 2018;3(6):424–432. doi:10.1016/S2468-1253(18)30078-5
   PubMed Web of Science ®Google Scholar
• Wada Y, Takami Y, Matsushima H, et al. The Safety and Efficacy of Combination Therapy of Sorafenib and Radiotherapy for Advanced Hepatocellular Carcinoma: a Retrospective Study. Intern Med. 2018;57(10):1345–1353. doi:10.2169/internalmedicine.9826-17
   PubMed Web of Science ®Google Scholar
• Munoz-Schuffenegger P, Barry A, Atenafu EG, et al. Stereotactic body radiation therapy for hepatocellular carcinoma with Macrovascular invasion. Radiother Oncol. 2021;156:120–126. doi:10.1016/j.radonc.2020.11.033
   PubMed Web of Science ®Google Scholar
• Mahvash A, Murthy R, Odisio BC, et al. Yttrium-90 resin microspheres as an adjunct to sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatocell Carcinoma. 2016;4(3):1–7. doi:10.2147/JHC.S96085
   PubMed Web of Science ®Google Scholar
• Inarrairaegui M, Melero I, Sangro B. Immunotherapy of Hepatocellular Carcinoma: facts and Hopes. Clin Cancer Res. 2018;24(7):1518–1524. doi:10.1158/1078-0432.CCR-17-0289
   PubMed Web of Science ®Google Scholar
• Jung SM, Kim JM, Choi GS, et al. Characteristics of Early Recurrence After Curative Liver Resection for Solitary Hepatocellular Carcinoma. J Gastrointest Surg. 2019;23(2):304–311. doi:10.1007/s11605-018-3927-2
   PubMed Web of Science ®Google Scholar
• Portolani N, Coniglio A, Ghidoni S, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243(2):229–235. doi:10.1097/01.sla.0000197706.21803.a1
   PubMed Web of Science ®Google Scholar
• Kianmanesh R, Regimbeau JM, Belghiti J. Selective approach to major hepatic resection for hepatocellular carcinoma in chronic liver disease. Surg Oncol Clin N Am. 2003;12(1):51–63. doi:10.1016/S1055-3207(02)00090-X
   PubMedGoogle Scholar
• Su YY, Li CC, Lin YJ, et al. Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: clinical and Immunologic Perspectives. Semin Liver Dis. 2021;41(3):263–276. doi:10.1055/s-0041-1730949
   PubMed Web of Science ®Google Scholar
• European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236.
   PubMed Web of Science ®Google Scholar
• Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv238–iv255. doi:10.1093/annonc/mdy308
   PubMed Web of Science ®Google Scholar
• Miamen AG, Dong H, Roberts LR. Immunotherapeutic approaches to hepatocellular carcinoma treatment. Liver Cancer. 2012;1(3–4):226–237. doi:10.1159/000343837
   PubMed Web of Science ®Google Scholar
• Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015;148(7):1383–1391.e6. doi:10.1053/j.gastro.2015.02.055
   PubMed Web of Science ®Google Scholar
• Lee JH, Lee JH, Lim YS, et al. Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. Cancer Immunol Immunother. 2019;68(1):23–32. doi:10.1007/s00262-018-2247-4
   PubMed Web of Science ®Google Scholar
• Xu L, Wang J, Kim Y, et al. A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma. Oncoimmunology. 2016;5(3):e1083671. doi:10.1080/2162402X.2015.1083671
   PubMed Web of Science ®Google Scholar
• Yuan BH, Li RH, Yuan WP, et al. Harms and benefits of adoptive immunotherapy for postoperative hepatocellular carcinoma: an updated review. Oncotarget. 2017;8(11):18537–18549. doi:10.18632/oncotarget.14507
   PubMedGoogle Scholar
• Lee JH, Tak WY, Lee Y, et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology. 2017;6(7):e1328335. doi:10.1080/2162402X.2017.1328335
   PubMed Web of Science ®Google Scholar
• Shimizu K, Kotera Y, Aruga A, et al. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma. Hum Vaccin Immunother. 2014;10(4):970–976. doi:10.4161/hv.27678
   PubMed Web of Science ®Google Scholar
• Dawkins J, Webster RM. The hepatocellular carcinoma market. Nat Rev Drug Discov. 2019;18(1):13–14. doi:10.1038/nrd.2018.146
   PubMed Web of Science ®Google Scholar
• Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344–1354. doi:10.1016/S1470-2045(15)00198-9
   PubMed Web of Science ®Google Scholar
• Huang Y, Zhang Z, Zhou Y, Yang J, Hu K, Wang Z. Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy? Onco Targets Ther. 2019;2(12):541–548. doi:10.2147/OTT.S187357
   Web of Science ®Google Scholar
• Zhong JH, Li H, Li LQ, et al. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials. Eur J Surg Oncol. 2012;38(4):286–295. doi:10.1016/j.ejso.2012.01.006
   PubMed Web of Science ®Google Scholar
• Cheng Y, Ni S, Chen Y, et al. Erzhu Qinggan Jiedu Recipe improves the clinical outcome of hepatocellular cancer after surgical resection: a case-control retrospective study. Intern Med J. 2021;51(6):853–860. doi:10.1111/imj.14844
   PubMed Web of Science ®Google Scholar
• Chen Q, Shu C, Laurence AD, et al. Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial. Gut. 2018;67(11):2006–2016. doi:10.1136/gutjnl-2018-315983
   PubMed Web of Science ®Google Scholar
• Zhai XF, Liu XL, Shen F, et al. Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: a randomized controlled study. Cancer. 2018;124(10):2161–2168. doi:10.1002/cncr.30915
   PubMed Web of Science ®Google Scholar
• Bouattour M, Fartoux L, Rosmorduc O, et al. BIOSHARE multicenter neoadjuvant phase 2 study: results of pre-operative sorafenib in patients with resectable hepatocellular carcinoma (HCC)—From GERCOR IRC. J Clin Oncol. 2016;34(Suppl 4):S252–S252. doi:10.1200/jco.2016.34.4_suppl.252
   Web of Science ®Google Scholar
• Ye SL, Chen X, Yang J, et al. Evaluation of sorafenib in Chinese unresectable hepatocellular carcinoma patients with prior surgery and portal vein tumor thrombosis: a subset analysis of GIDEON study data. Tumour Biol. 2017;39(3):1010428317695030. doi:10.1177/1010428317695030
   Google Scholar
• Kaseb AO, Pestana RC, Vence LM, et al. Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC. J Clin Oncol. 2019;37(Suppl 4):S185–S185. doi:10.1200/JCO.2019.37.4_suppl.185
   Web of Science ®Google Scholar
• Yarchoan M, Zhu Q, Durham JN, et al. Feasibility and efficacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable or locally advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(3_suppl):335. doi:10.1200/JCO.2021.39.3_suppl.335
   Web of Science ®Google Scholar
• Chen X, Zhang Y, Zhang N, et al. Lenvatinib combined nivolumab injection followed by extended right hepatectomy is a feasible treatment for patients with massive hepatocellular carcinoma: a case report. Onco Targets Ther. 2019;3(12):7355–7359. doi:10.2147/OTT.S217123
   Web of Science ®Google Scholar
• Cheng RF, Wu ZL. Discussion of the pathogenesis theory of primary liver cancer: deficiency, depression, phlegm, blood stasis, and toxin. Shandong Zhong Yi Za Zhi. 2014;33(10):804–806.
   Google Scholar
• Hu B, Ping SK. Yin deficiency of liver and kidney is the basis of liver cancer. Chin J Information Traditional Chin Med. 2009;16(2):93.
   Google Scholar
• Hu Y, Wang S, Wu X, et al. Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma. J Ethnopharmacol. 2013;149(3):601–612. doi:10.1016/j.jep.2013.07.030
   PubMed Web of Science ®Google Scholar
• Xi SY, Minuk GY. Role of traditional Chinese medicine in the management of patients with hepatocellular carcinoma. World J Hepatol. 2018;10(11):799–806. doi:10.4254/wjh.v10.i11.799
   PubMed Web of Science ®Google Scholar
• Yen Y, So S, Rose M, et al. Phase I/II study of PHY906/capecitabine in advanced hepatocellular carcinoma. Anticancer Res. 2009;29(10):4083–4092.
   PubMed Web of Science ®Google Scholar
• Changou CA, Shiah HS, Chen LT, et al. A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma. Oncologist. 2021;26(3):e367–e373. doi:10.1002/onco.13582
   PubMed Web of Science ®Google Scholar
• Lam W, Jiang Z, Guan F, et al. PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment. Sci Rep. 2015;3(5):9384. doi:10.1038/srep09384
   Web of Science ®Google Scholar
• Yang X, Lam W, Jiang Z, et al. YIV-906 potentiated anti-PD1 action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment. Sci Rep. 2021;11(1):13482. doi:10.1038/s41598-021-91623-3
   PubMed Web of Science ®Google Scholar
• Chen C, Ai QD, Wei YH. Kanglaite enhances the efficacy of cisplatin in suppression of hepatocellular carcinoma via inhibiting CKLF1 mediated NF-kappaB pathway and regulating transporter mediated drug efflux. J Ethnopharmacol. 2021;2(264):113388. doi:10.1016/j.jep.2020.113388
   Web of Science ®Google Scholar
• Fan Y, Li S, Ding X, et al. First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers. BMC Cancer. 2019;19(1):279. doi:10.1186/s12885-019-5471-1
   PubMed Web of Science ®Google Scholar
• Qin SK, Li Q, Ming xu J, et al. Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma: immunodynamic biomarkers and overall survival. Cancer Sci. 2020;111(11):4218–4231. doi:10.1111/cas.14641
   PubMed Web of Science ®Google Scholar
• Li JJ, Liang Q, Sun GC. Traditional Chinese medicine for prevention and treatment of hepatocellular carcinoma: a focus on epithelial-mesenchymal transition. J Integr Med. 2021;19(6):469–477. doi:10.1016/j.joim.2021.08.004
   PubMed Web of Science ®Google Scholar
• Wang X, Wang N, Cheung F, et al. Chinese medicines for prevention and treatment of human hepatocellular carcinoma: current progress on pharmacological actions and mechanisms. J Integr Med. 2015;13(3):142–164. doi:10.1016/S2095-4964(15)60171-6
   PubMedGoogle Scholar
• Yau T, Zagonel V, Santoro A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol. 2020;38(Suppl 4):S478–S478. doi:10.1200/JCO.2020.38.4_suppl.478
   Web of Science ®Google Scholar
• Liu F, Qin L, Liao Z, et al. Microenvironment characterization and multi-omics signatures related to prognosis and immunotherapy response of hepatocellular carcinoma. Exp Hematol Oncol. 2020;1(9):10. doi:10.1186/s40164-020-00165-3
   Web of Science ®Google Scholar
• Angelbello AJ, Chen JL, Childs-Disney JL, et al. Using Genome Sequence to Enable the Design of Medicines and Chemical Probes. Chem Rev. 2018;118(4):1599–1663. doi:10.1021/acs.chemrev.7b00504
   PubMed Web of Science ®Google Scholar
• Rizzo A, Ricci AD, Brandi G. Immune-based combinations for advanced hepatocellular carcinoma: shaping the direction of first-line therapy. Future Oncol. 2021;17(7):755–757. doi:10.2217/fon-2020-0986
   PubMed Web of Science ®Google Scholar
• Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151–172. doi:10.1038/s41571-021-00573-2
   PubMed Web of Science ®Google Scholar
• Rimola J, Da Fonseca LG, Sapena V, et al. Radiological response to nivolumab in patients with hepatocellular carcinoma: a multicenter analysis of real-life practice. Eur J Radiol. 2021;3(135):109484. doi:10.1016/j.ejrad.2020.109484
   Web of Science ®Google Scholar
• Reig M, Rimola J, Torres F, et al. Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design. Hepatology. 2013;58(6):2023–2031. doi:10.1002/hep.26586
   PubMed Web of Science ®Google Scholar
• Gu Y, Li X, Bi Y, et al. CCL14 is a prognostic biomarker and correlates with immune infiltrates in hepatocellular carcinoma. Aging. 2020;12(1):784–807. doi:10.18632/aging.102656
   PubMedGoogle Scholar
• Huang B, Tian ZF, Li LF, et al. LHX3 is an advanced-stage prognostic biomarker and metastatic oncogene in hepatocellular carcinoma. Cancer Biomark. 2019;26(1):31–39. doi:10.3233/CBM-182257
   PubMed Web of Science ®Google Scholar
• Yang Y, Li G, Lu Z, et al. Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma. Front Oncol. 2021;1(11):726213. doi:10.3389/fonc.2021.726213
   Web of Science ®Google Scholar
• Lu LC, Hsu CH, Hsu C, Cheng AL. Tumor Heterogeneity in Hepatocellular Carcinoma: facing the Challenges. Liver Cancer. 2016;5(2):128–138. doi:10.1159/000367754
   PubMed Web of Science ®Google Scholar
• von Felden J, Craig AJ, Villanueva A. Role of circulating tumor DNA to help decision-making in hepatocellular carcinoma. Oncoscience. 2018;5(7–8):209–211. doi:10.18632/oncoscience.446
   PubMedGoogle Scholar
• Qu C, Wang Y, Wang P, et al. Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy. Proc Natl Acad Sci U S A. 2019;116(13):6308–6312. doi:10.1073/pnas.1819799116
   PubMed Web of Science ®Google Scholar
• Rizzo A, Brandi G. Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma. Cancer Treat Res Commun. 2021;1(27):100328. doi:10.1016/j.ctarc.2021.100328
   Google Scholar
• Piratvisuth T, Tanwandee T, Thongsawat S, et al. Multimarker Panels for Detection of Early Stage Hepatocellular Carcinoma: a Prospective, Multicenter, Case-Control Study. Hepatol Commun. 2021;1(4):1847.
   Google Scholar
• Fuca G, Galli G, Poggi M, et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open. 2019;4(1):e000457.
   PubMed Web of Science ®Google Scholar
• 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(2):318–324.
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Meyer T, Cheng A-L, et al. Association of adverse events (AEs) with efficacy outcomes for cabozantinib (C) in patients (pts) with advanced hepatocellular carcinoma (aHCC) in the phase III CELESTIAL trial. J Clin Oncol. 2019;37(Suppl 15):S4088–S4088.
   Web of Science ®Google Scholar
• Sung MW, Finn RS, Qin S, et al. Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT). J Clin Oncol. 2019;37(Suppl 4):S317–S317.
   Web of Science ®Google Scholar
• Pinato DJ, Marron TU, Mishra-Kalyani PS, et al. Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice. Eur J Cancer. 2021;1(157):140–152.
   Web of Science ®Google Scholar