Euroasian Journal of Hepato-Gastroenterology

Register      Login

VOLUME 11 , ISSUE 1 ( January-June, 2021 ) > List of Articles

REVIEW ARTICLE

Updates on the Diagnosis and Management of Hepatocellular Carcinoma

Aimun Raees, Muhammad Kamran, Hasan Ozkan, Wasim Jafri

Keywords : Contrast-enhanced ultrasound, Genomics, Hepatocellular carcinoma, Immune checkpoint inhibitors, Lenvatinib, Metabolomics, Microwave ablation, Nivolumab, Transarterial radioembolization

Citation Information : Raees A, Kamran M, Ozkan H, Jafri W. Updates on the Diagnosis and Management of Hepatocellular Carcinoma. Euroasian J Hepatogastroenterol 2021; 11 (1):32-40.

DOI: 10.5005/jp-journals-10018-1335

License: CC BY-NC 4.0

Published Online: 28-06-2021

Copyright Statement:  Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.


Abstract

Introduction: Globally, the incidence, as well as mortality, related to hepatocellular carcinoma (HCC) is on the rise, owing to relatively few curative options. Underlying cirrhosis is the most common etiology leading to HCC, but risk factors of cirrhosis show great regional variability. Over the years, there has been a steady development in the diagnostic and therapeutic modalities of HCC, including the availability of a wide range of systemic chemotherapeutic agents. We aim to review the recent advancements in the diagnostic and therapeutic strategies for HCC. Methodology: The literature search was done using databases PubMed, Cochrane, and Science Direct, and the latest relevant articles were reviewed. Findings: Screening of HCC is a pivotal step in the early diagnosis of the disease. Current guidelines recommend using ultrasound and alfa fetoprotein but various new biomarkers are under active research that might aid in diagnosing very small tumors, not picked up by the current screening methods. Treatment options are decided based upon the overall performance of the patient and the extent of the disease, as per the Barcelona classification. There are very few options that offer a cure for the disease, ranging from liver resection and transplantation to tumor ablation. Downstaging has proven to have a significant role in the course of the disease. An attempt to control the disease can be made via radiological interventions, such as transarterial chemoembolization, transarterial radioembolization, or radiation therapy. For advanced disease, sorafenib used to be the only option until a couple of years ago. Recently, many other systemic agents have received approval as first-line and second-line therapies for HCC. Genomics is an area of active clinical research as understanding the mutations and genomics involved in the evolution of HCC might lead to a breakthrough therapy.


PDF Share
  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin 2018;68(6):394–424. DOI: 10.3322/caac.21492.
  2. 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.
  3. Jafri W, Kamran M. Hepatocellular carcinoma in Asia: a challenging situation. Euroasian J Hepatogastroenterol 2019;9(1):27–33. DOI: 10.5005/jp-journals-10018-1292.
  4. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012;142(6):1264–1273.e1. DOI: 10.1053/j.gastro.2011.12.061.
  5. Dogan S, Gurakar A. Liver Transplantation update: 2014. Euroasian J Hepatogastroenterol 2015;5(2):98–106. DOI: 10.5005/jp-journals-10018-1144.
  6. Kanwal F, Kramer JR, Duan Z, et al. Trends in the burden of nonalcoholic fatty liver disease in a United States cohort of veterans. Clin Gastroenterol Hepatol 2016;14(2):301–308.e1–e2. DOI: 10.1016/j.cgh.2015.08.010.
  7. European Association For The Study Of The Liver and European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56(4):908–943. DOI: 10.1016/j.jhep.2011.12.001.
  8. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu and European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69(1):182–236. DOI: 10.1016/j.jhep.2018.03.019.
  9. 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 (Baltimore, Md.) 2018;68(2):723–750. DOI: 10.1002/hep.29913.
  10. Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11(4):317–370. DOI: 10.1007/s12072-017-9799-9.
  11. Pocha C, Dieperink E, McMaken KA, et al. Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography -- a randomised study. Aliment Pharmacol Ther 2013;38(3):303–312. DOI: 10.1111/apt.12370.
  12. Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30(1):37–47. DOI: 10.1111/j.1365-2036.2009.04014.x.
  13. Chou R, Cuevas C, Fu R, et al. Imaging techniques for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis. Ann Intern Med 2015;162(10):697–711. DOI: 10.7326/M14-2509.
  14. Lersritwimanmaen P, Nimanong S. Hepatocellular carcinoma surveillance: benefit of serum alfa-fetoprotein in real-world practice. Euroasian J Hepatogastroenterol 2018;8(1):83–87. DOI: 10.5005/jp-journals-10018-1268.
  15. Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer. J Med Screen 1999;6(2):108–110. DOI: 10.1136/jms.6.2.108.
  16. Wang M, Devarajan K, Singal AG, et al. The Doylestown algorithm: a test to improve the performance of AFP in the detection of hepatocellular carcinoma. Cancer Prev Res (Philadelphia, PA) 2016;9(2):172–179. DOI: 10.1158/1940-6207.CAPR-15-0186.
  17. Abdelaziz AO, Nabil MM, Omran DA, et al. Hepatocellular Carcinoma Multidisciplinary Clinic-Cairo University (HMC-CU) score: a new simple score for diagnosis of HCC. Arab J Gastroenterol 2020;21(2):102–105. DOI: 10.1016/j.ajg.2020.04.001.
  18. Oka H, Saito A, Ito K, et al. Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein. J Gastroenterol Hepatol 2001;16(12):1378–1383. DOI: 10.1046/j.1440-1746.2001.02643.x.
  19. Tsuchiya N, Sawada Y, Endo I, et al. Biomarkers for the early diagnosis of hepatocellular carcinoma. World J Gastroenterol 2015;21(37):10573–10583. DOI: 10.3748/wjg.v21.i37.10573.
  20. Jang ES, Jeong SH, Kim JK, et al. Diagnostic performance of alpha-fetoprotein, protein induced by vitamin K absence, osteopontin, Dickkopf-1 and its combinations for hepatocellular carcinoma. PLoS One 2016;11(3):e0151069. DOI: 10.1371/journal.pone.0151069.
  21. Ishii M, Gama H, Chida N, et al. Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District Study Group. Am J Gastroenterol 2000;95(4):1036–1040. DOI: 10.1111/j.1572-0241.2000.01978.x.
  22. Khien VV, Mao HV, Chinh TT, et al. Clinical evaluation of lentil lectin-reactive alpha-fetoprotein-L3 in histology-proven hepatocellular carcinoma. Int J Biol Markers 2001;16(2):105–111. https://doi.org/10.1177%2F172460080101600204
  23. Li Z, Mou L, Gao H, et al. Diagnostic accuracy of serum dickkopf-1 protein in diagnosis hepatocellular carcinoma: an updated meta-analysis. Medicine 2019;98(32):e16725. DOI: 10.1097/MD.0000000000016725.
  24. Yu G, Yang L, Zhou J, et al. Abnormally expressed circular RNAs are promising biomarkers for diagnosis of hepatocellular carcinoma: a meta-analysis. Clin Lab 2019;65(11):10.7754/Clin.Lab.2019.190354. DOI: 10.7754/Clin.Lab.2019.190354.
  25. Zhou J, Yu L, Gao X, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol 2011;29(36):4781–4788. DOI: 10.1200/JCO.2011.38.2697.
  26. Akkiz H. The emerging role of Micro RNAs in hepatocellular carcinoma. Euroasian J Hepatogastroenterol 2014;4(1):45–50. DOI: 10.5005/jp-journals-10018-1095.
  27. Hamdy MN, Shaheen KY, Awad MA, et al. Vascular endothelial growth factor (VEGF) as a biochemical marker for the diagnosis of hepatocellular carcinoma (HCC). Clin Pract 2020;17(1):1441–1453. DOI: https://doi.org/10.1186/s43066-020-00073-5
  28. Berhane S, Toyoda H, Tada T, et al. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol 2016;14(6):875–886.e6. DOI: 10.1016/j.cgh.2015.12.042.
  29. Khalili K, Kim TK, Jang HJ, et al. Optimization of imaging diagnosis of 1-2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J Hepatol 2011;54(4):723–728. DOI: 10.1016/j.jhep.2010.07.025.
  30. Furlan A, Marin D, Vanzulli A, et al. Hepatocellular carcinoma in cirrhotic patients at multidetector CT: hepatic venous phase versus delayed phase for the detection of tumour washout. Br J Radiol 2011;84(1001):403–412. DOI: 10.1259/bjr/18329080.
  31. Sun H, Song T. Hepatocellular carcinoma: advances in diagnostic imaging. Drug Discov Ther 2015;9(5):310–318. DOI: 10.5582/ddt.2015.01058.
  32. Vietti Violi N, Lewis S, Liao J, et al. Gadoxetate-enhanced abbreviated MRI is highly accurate for hepatocellular carcinoma screening. Eur Radiol 2020;30(11):6003–6013. DOI: 10.1007/s00330-020-07014-1.
  33. Kim DH, Choi SH, Kim SY, et al. Gadoxetic acid-enhanced MRI of hepatocellular carcinoma: value of washout in transitional and hepatobiliary phases. Radiology 2019;291(3):651–657. DOI: 10.1148/radiol.2019182587.
  34. Schellhaas B, Bernatik T, Bohle W, et al. Contrast-enhanced ultrasound algorithms (CEUS-LIRADS/ESCULAP) for the noninvasive diagnosis of hepatocellular carcinoma - a prospective multicenter DEGUM study. CEUS-Algorithmen für den kontrastverstärkten Ultraschall (CEUS-LIRADS/ESCULAP) in der nichtinvasiven Diagnostik des hepatozellulären Karzinoms – eine prospektive, multizentrische DEGUM-Studie. Ultraschall Med (Stuttgart, Germany: 1980), 2020;42(2):178–186. DOI: 10.1055/a-1198-4874.
  35. Burak KW, Sherman M. Hepatocellular carcinoma: consensus, controversies and future directions. A report from the Canadian Association for the Study of the Liver Hepatocellular Carcinoma Meeting. Can J Gastroenterol Hepatol 2015;29(4):178–184. DOI: 10.1155/2015/824263.
  36. Shin J, Lee S, Bae H, et al. Contrast-enhanced ultrasound liver imaging reporting and data system for diagnosing hepatocellular carcinoma: a meta-analysis. Liver Int 2020;40(10):2345–2352. DOI: 10.1111/liv.14617.
  37. Chernyak V, Fowler KJ, Kamaya A, et al. Liver imaging reporting and data system (LI-RADS) version 2018: imaging of hepatocellular carcinoma in at-risk patients. Radiology 2018;289(3):816–830. DOI: 10.1148/radiol.2018181494.
  38. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology (Baltimore, Md.) 2008;47(1):97–104. DOI: 10.1002/hep.21966.
  39. Tremosini S, Forner A, Boix L, et al. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut 2012;61(10):1481–1487. DOI: 10.1136/gutjnl-2011-301862.
  40. Sangiovanni A, Manini MA, Iavarone M, et al. The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59(5):638–644. DOI: 10.1136/gut.2009.187286.
  41. Wang F, Numata K, Nakano M, et al. Diagnostic value of immunohistochemical markers in four-grade histological classification of hepatocellular carcinoma. Res Square 2020. DOI: 10.21203/rs.3.rs-99711/v1.
  42. Clish CB. Metabolomics: an emerging but powerful tool for precision medicine. Cold Spring Harb Mol Case Stud 2015;1(1):a000588. DOI: 10.1101/mcs.a000588.
  43. Beyoğlu D, Idle JR. Metabolomic and lipidomic biomarkers for premalignant liver disease diagnosis and therapy. Metabolites 2020;10(2):50. DOI: 10.3390/metabo10020050.
  44. Tellapuri S, Sutphin PD, Beg MS, et al. Staging systems of hepatocellular carcinoma: a review. Indian J Gastroenterol 2018;37(6):481–491. DOI: 10.1007/s12664-018-0915-0.
  45. Faria SC, Szklaruk J, Kaseb AO, et al. TNM/Okuda/Barcelona/UNOS/CLIP International Multidisciplinary Classification of Hepatocellular Carcinoma: concepts, perspectives, and radiologic implications. Abdom Imaging 2014;39(5):1070–1087. DOI: 10.1007/s00261-014-0130-0.
  46. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Seminars in liver disease 1999;19(3):329–338. DOI: 10.1055/s-2007-1007122.
  47. Fonseca AL, Cha CH. Hepatocellular carcinoma: a comprehensive overview of surgical therapy. J Surg Oncol 2014;110(6):712–719. DOI: 10.1002/jso.23673.
  48. Vitale A, Peck-Radosavljevic M, Giannini EG, et al. Personalized treatment of patients with very early hepatocellular carcinoma. J Hepatol 2017;66(2):412–423. DOI: 10.1016/j.jhep.2016.09.012.
  49. Lee EC, Kim SH, Park H, et al. Survival analysis after liver resection for hepatocellular carcinoma: a consecutive cohort of 1002 patients. J Gastroenterol Hepatol 2017;32(5):1055–1063. DOI: 10.1111/jgh.13632.
  50. Zhang H, Han J, Xing H, et al. Sex difference in recurrence and survival after liver resection for hepatocellular carcinoma: a multicenter study. Surgery 2019;165(3):516–524. DOI: 10.1016/j.surg.2018.08.031.
  51. Morise Z, Aldrighetti L, Belli G, et al. Laparoscopic repeat liver resection for hepatocellular carcinoma: a multicentre propensity score-based study. Br J Surg 2020;107(7):889–895. DOI: 10.1002/bjs.11436.
  52. Ruzzenente A, Bagante F, Ratti F, et al. Minimally invasive versus open liver resection for hepatocellular carcinoma in the setting of portal vein hypertension: results of an international multi-institutional analysis. Ann Surg Oncol 2020;27(9):3360–3371. DOI: 10.1245/s10434-020-08444-3.
  53. El-Gendi A, El-Shafei M, El-Gendi S, et al. Laparoscopic versus open hepatic resection for solitary hepatocellular carcinoma less than 5 cm in cirrhotic patients: a randomized controlled study. J Laparoendosc Adv Surg Tech A 2018;28(3):302–310. DOI: 10.1089/lap.2017.0518.
  54. Solaini L, Bocchino A, Cucchetti A, et al. Anatomic laparoscopic liver resection in the scenario of the hepatocellular carcinoma: a systematic review and meta-analysis. J Laparoendosc Adv Surg Tech A 2020;30(10):1076–1081. DOI: 10.1089/lap.2020.0562.
  55. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011;17(Suppl. 2):S44–S57. DOI: 10.1002/lt.22365.
  56. Fahrner R, Dondorf F, Ardelt M, et al. Liver transplantation for hepatocellular carcinoma - factors influencing outcome and disease-free survival. World J Gastroenterol 2015;21(42):12071–12082. DOI: 10.3748/wjg.v21.i42.12071.
  57. Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10(1):35–43. DOI: 10.1016/S1470-2045(08)70284-5.
  58. Facciuto ME, Rochon C, Pandey M, et al. Surgical dilemma: liver resection or liver transplantation for hepatocellular carcinoma and cirrhosis. Intention-to-treat analysis in patients within and outwith Milan criteria. HPB 2009;11(5):398–404. DOI: 10.1111/j.1477-2574.2009.00073.x.
  59. Guy J, Kelley RK, Roberts J, et al. Multidisciplinary management of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2012;10(4):354–362. DOI: 10.1016/j.cgh.2011.11.008.
  60. Ofosu A, Gurakar A. Current concepts in hepatocellular carcinoma and liver transplantation: a review and 2014 update. Euroasian J Hepatogastroenterol 2015;5(1):19–25. DOI: 10.5005/jp-journals-10018-1123.
  61. Sapisochin G, Castells L, Dopazo C, et al. Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome according to an intention-to-treat basis. Ann Surg Oncol 2013;20(4):1194–1202. DOI: 10.1245/s10434-012-2655-1.
  62. Al-Ameri AAM, Wei X, Wen X, et al. Systematic review: risk prediction models for recurrence of hepatocellular carcinoma after liver transplantation. Transpl Int 2020;33(7):697–712. DOI: 10.1111/tri.13585.
  63. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334(11):693–699. DOI: 10.1056/NEJM199603143341104.
  64. Kasugai H, Osaki Y, Oka H, et al. Severe complications of radiofrequency ablation therapy for hepatocellular carcinoma: an analysis of 3,891 ablations in 2,614 patients. Oncology 2007;72 (Suppl. 1):72–75. DOI: 10.1159/000111710.
  65. Maeda M, Saeki I, Sakaida I, et al. Complications after radiofrequency ablation for hepatocellular carcinoma: a multicenter study involving 9,411 japanese patients. Liver Cancer 2020;9(1):50–62. DOI: 10.1159/000502744.
  66. Shiina S, Tateishi R, Arano T, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2012;107(4):569–577; quiz 578. DOI: 10.1038/ajg.2011.425.
  67. Hasegawa K, Kokudo N, Makuuchi M, et al. Comparison of resection and ablation for hepatocellular carcinoma: a cohort study based on a Japanese nationwide survey. J Hepatol 2013;58(4):724–729. DOI: 10.1016/j.jhep.2012.11.009.
  68. Lucchina N, Tsetis D, Ierardi AM, et al. Current role of microwave ablation in the treatment of small hepatocellular carcinomas. Ann Gastroenterol 2016;29(4):460–465. DOI: 10.20524/aog.2016.0066.
  69. Tan W, Deng Q, Lin S, et al. Comparison of microwave ablation and radiofrequency ablation for hepatocellular carcinoma: a systematic review and meta-analysis. Int J Hyperthermia 2019;36(1):264–272. DOI: 10.1080/02656736.2018.1562571.
  70. Glassberg MB, Ghosh S, Clymer JW, et al. Microwave ablation compared with radiofrequency ablation for treatment of hepatocellular carcinoma and liver metastases: a systematic review and meta-analysis. Onco Targets Ther 2019;12:6407–6438. DOI: 10.2147/OTT.S204340.
  71. Ricci AD, Rizzo A, Bonucci C, et al. The (eternal) debate on microwave ablation versus radiofrequency ablation in BCLC-A hepatocellular carcinoma. In Vivo (Athens, Greece) 2020;34(6):3421–3429. DOI: 10.21873/invivo.12181.
  72. Kamal A, Elmoety AAA, Rostom YAM, et al. Percutaneous radiofrequency versus microwave ablation for management of hepatocellular carcinoma: a randomized controlled trial. J Gastrointest Oncol 2019;10(3):562–571. DOI: 10.21037/jgo.2019.01.34.
  73. Forner A, Gilabert M, Bruix J, et al. Treatment of intermediate-stage hepatocellular carcinoma. Nat Rev Clin Oncol 2014;11(9):525–535. DOI: 10.1038/nrclinonc.2014.122.
  74. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology (Baltimore, Md.) 2003;37(2):429–442. DOI: 10.1053/jhep.2003.50047.
  75. Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet (London, England) 2002;359(9319):1734–1739. DOI: 10.1016/S0140-6736(02)08649-X.
  76. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology (Baltimore, Md.) 2002;35(5):1164–1171. DOI: 10.1053/jhep.2002.33156.
  77. Bruix J, Sala M, Llovet JM, et al. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl 1):S179–S188. DOI: 10.1053/j.gastro.2004.09.032.
  78. Boyvat F. Interventional radiologic treatment of hepatocellular carcinoma. Exp Clin Transplant 2017;15(Suppl. 2):25–30. DOI: 10.6002/ect.TOND16.L8.
  79. Gao ZH, Bai DS, Jiang GQ, et al. Review of preoperative transarterial chemoembolization for resectable hepatocellular carcinoma. World J Hepatol 2015;7(1):40–43. DOI: 10.4254/wjh.v7.i1.40.
  80. Puppala S. Management of post-embolization syndrome. In: Kessel D, Ray C, editors. Transcatheter embolization and therapy. Techniques in interventional radiology. London: Springer; 2010. DOI: 10.1007/978-1-84800-897-7_13.
  81. Lammer J, Malagari K, Vogl T, et al. 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(1):41–52. DOI: 10.1007/s00270-009-9711-7.
  82. V arela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007;46(3):474–481. DOI: 10.1016/j.jhep.2006.10.020.
  83. Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovasc Intervent Radiol 2012;35(5):1119–1128. DOI: 10.1007/s00270-012-0394-0.
  84. Raoul JL, Forner A, Bolondi L, et al. Updated use of TACE for hepatocellular carcinoma treatment: how and when to use it based on clinical evidence. Cancer Treat Rev 2019;72:28–36. DOI: 10.1016/j.ctrv.2018.11.002.
  85. Haubold J, Reinboldt MP, Wetter A, et al. DSM-TACE of HCC: evaluation of tumor response in patients ineligible for other systemic or loco-regional therapies. DSM-TACE des HCC: Bewertung des Tumoransprechens von Patienten mit Kontraindikationen gegen andere systemische oder lokoregionale Therapien. Rofo 2020;192(9):862–869. DOI: 10.1055/a-1111-9955.
  86. Gross A, Albrecht T. Transarterial chemoembolisation (TACE) with degradable starch microspheres (dsm) and anthracycline in patients with locally extensive hepatocellular carcinoma (hcc): safety and efficacy. Cardiovasc Intervent Radiol 2020;43(3):402–410. DOI: 10.1007/s00270-019-02364-w.
  87. Iezzi R, Pompili M, Rinninella E, et al. TACE with degradable starch microspheres (DSM-TACE) as second-line treatment in HCC patients dismissing or ineligible for sorafenib. Eur Radiol 2019;29(3):1285–1292. DOI: 10.1007/s00330-018-5692-8.
  88. Levi Sandri GB, Ettorre GM, Giannelli V, et al. Trans-arterial radio-embolization: a new chance for patients with hepatocellular cancer to access liver transplantation, a world review. Transl Gastroenterol Hepatol 2017;2:98. DOI: 10.21037/tgh.2017.11.11.
  89. Cappelli A, Pettinato C, Golfieri R. Transarterial radioembolization using yttrium-90 microspheres in the treatment of hepatocellular carcinoma: a review on clinical utility and developments. J Hepatocell Carcinoma 2014;1:163–182. DOI: 10.2147/JHC.S50472.
  90. Sundram FX, Buscombe JR. Selective internal radiation therapy for liver tumours. Clin Med (London, England) 2017;17(5):449–453. DOI: 10.7861/clinmedicine.17-5-449.
  91. Abdel-Rahman O, Elsayed Z. Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2020;1(1):CD011313. DOI: 10.1002/14651858.CD011313.pub3.
  92. Salem R, Lewandowski RJ, Kulik L, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2011;140(2):497–507.e2. DOI: 10.1053/j.gastro.2010.10.049.
  93. Benson AB, D'Angelica MI, Abbott DE, et al. NCCN guidelines insights: hepatobiliary cancers, version 1.2017. J Natl Compr Canc Netw 2017;15(5):563–573. DOI: 10.6004/jnccn.2017.0059.
  94. Chopra S, George K, Engineer R, et al. Stereotactic body radio therapy for inoperable large hepatocellular cancers: results from a clinical audit. Br J Radiol 2019;92(1101):20181053. DOI: 10.1259/bjr.20181053.
  95. Yeung CSY, Chiang CI, Wong NSM, et al. Palliative liver radiotherapy (RT) for symptomatic hepatocellular carcinoma (HCC). Sci Rep 2020;10(1):1254. DOI: 10.1038/s41598-020-58108-1.
  96. Culleton S, Jiang H, Haddad CR, et al. Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma. Radiother Oncol 2014;111(3):412–417. DOI: 10.1016/j.radonc.2014.05.002.
  97. Song JH, Jeong BK, Choi HS, et al. Defining radiation-induced hepatic toxicity in hepatocellular carcinoma patients treated with stereotactic body radiotherapy. J Cancer 2017;8(19):41551. DOI: 10.7150/jca.21561.
  98. Yoon SM, Kim SY, Lim YS, et al. Stereotactic body radiation therapy for small (≤5 cm) hepatocellular carcinoma not amenable to curative treatment: results of a single-arm, phase II clinical trial. Clin Mol Hepatol 2020;26(4):506–515. DOI: 10.3350/cmh.2020.0038.
  99. Lee J, Shin IS, Yoon WS, et al. Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: meta-analyses and a systematic review. Radiother Oncol 2020;145:63–70. DOI: 10.1016/j.radonc.2019.12.004.
  100. El Alfy E, Bondiau PY, Rostom YA, et al. Results of stereotactic body radiotherapy (SBRT) for management of primary and secondary hepatic tumors: analysis of early outcomes. J Clin Oncol 2015;33(15 Suppl.). DOI: 10.1200/jco.2015.33.15_suppl.e15160.
  101. 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. DOI: 10.1200/JCO.2012.44.1659.
  102. 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.
  103. Raoul JL, Bruix J, Greten TF, et al. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol 2012;56(5):1080–1088. DOI: 10.1016/j.jhep.2011.12.009.
  104. Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012;57(4):821–829. DOI: 10.1016/j.jhep.2012.06.014.
  105. 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. DOI: 10.1016/j.jhep.2014.03.030.
  106. 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 (London, England) 2018;391(10126):1163–1173. DOI: 10.1016/S0140-6736(18)30207-1.
  107. Bi F, Qin S, Gu S, et al. Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: an open-label, randomized, multicenter phase II/III trial. J Clin Oncol 2020;38(15_suppl):4506–4506. DOI: 10.1200/JCO.2020.38.15_suppl.4506.
  108. 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 (London, England) 2017;389(10064):56–66. DOI: 10.1016/S0140-6736(16)32453-9.
  109. 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.
  110. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20(2):282–296. DOI: 10.1016/S1470-2045(18)30937-9.
  111. 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 (London, England) 2017;389(10088):2492–2502. DOI: 10.1016/S0140-6736(17)31046-2.
  112. 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.
  113. 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 Check Mate 040 randomized clinical trial. JAMA Oncol 2020;6(11):e204564. DOI: 10.1001/jamaoncol.2020.4564.
  114. Llovet JM, Kudo M, Cheng AL, et al. Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): phase 3 LEAP-002 study. J Clin Oncol 2019;37(15_suppl.):TPS4152. DOI: 10.1200/JCO.2019.37.15_suppl.TPS4152.
  115. 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(15_suppl):4073–4073. DOI: 10.1200/JCO.2017.35.15_suppl.4073.
  116. 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(15_suppl):4074–4074. DOI: 10.1200/JCO.2019.37.15_suppl.4074.
  117. Adeniji N, Dhanasekaran R. Genomic Landscape of HCC. Curr Hepatol Rep 2020:1–4. DOI: 10.1007/s11901-020-00553-7
  118. Mei Q, Chen M, Lu X, et al. An open-label, single-arm, phase I/II study of lower-dose decitabine based therapy in patients with advanced hepatocellular carcinoma. Oncotarget 2015;6(18):16698–16711. DOI: 10.18632/oncotarget.3677.
  119. Liu A, Wu Q, Peng D, et al. A novel strategy for the diagnosis, prognosis, treatment, and chemoresistance of hepatocellular carcinoma: DNA methylation. Med Res Rev 2020;40(5):1973–2018. DOI: 10.1002/med.21696.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.