Role of locoregional therapies in the management of patients with hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) was the sixth most common cancer and the third cause of cancer-related deaths worldwide in 2020. Liver resection and transplantation remain the cornerstone for patients with early-stage disease and represent the only option for potential cure in HCC. However, fewer than 10% of patients are considered suitable for surgery at the time of diagnosis. Locoregional therapies, defined as minimally invasive image-guided liver tumour-directed procedures, are integral to in the management of HCC. This review discusses the role of locoregional therapies in HCC management in the emergence of immune and systemic treatments.

Keywords

Locoregional therapy / hepatocellular carcinoma / ablation / transarterial embolization / radiation therapy

References

[1] Sung H,Siegel RL.Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.CA Cancer J Clin2021;71:209-49

[2] Ng KK,Poon RT,Tso WK.Thermal ablative therapy for malignant liver tumors: a critical appraisal.J Gastroenterol Hepatol2003;18:616-29

[3] Roayaie S,Tabrizian P.The role of hepatic resection in the treatment of hepatocellular cancer.Hepatology2015;62:440-51

[4] Tsilimigras DI,Guglielmi A.Recurrence beyond the Milan criteria after curative-intent resection of hepatocellular carcinoma: a novel tumor-burden based prediction model.J Surg Oncol2020;122:955-63

[5] Wei T,Xue F.Multi-institutional development and external validation of a nomogram for prediction of extrahepatic recurrence after curative-intent resection for hepatocellular carcinoma.Ann Surg Oncol2021;28:7624-33

[6] Portolani N,Ghidoni S.Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications.Ann Surg2006;243:229-35 PMCID:PMC1448919

[7] Zhou Y,Li B.Repeat hepatectomy for recurrent hepatocellular carcinoma: a local experience and a systematic review.World J Surg Oncol2010;8:55 PMCID:PMC2904292

[8] Heimbach JK,Finn RS.AASLD guidelines for the treatment of hepatocellular carcinoma.Hepatology2018;67:358-80

[9] Llovet JM,Pikarsky E.Hepatocellular carcinoma.Nat Rev Dis Primers2016;2:16018

[10] Kulik L.Epidemiology and management of hepatocellular carcinoma.Gastroenterology2019;156:477-91.e1 PMCID:PMC6340716

[11] Association for the Study of the Liver, Electronic address: [e-mail], European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol2018;69:182-236

[12] Marrero JA,Sirlin CB.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases.Hepatology2018;68:723-50

[13] Park JW,Colombo M.Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study.Liver Int2015;35:2155-66 PMCID:PMC4691343

[14] Grieco A,Caminiti G.Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: comparison of Okuda, CLIP, and BCLC staging systems in a single Italian centre.Gut2005;54:411-8 PMCID:PMC1774422

[15] Yau T,Yao TJ,Lo CM.Development of Hong Kong liver cancer staging system with treatment stratification for patients with hepatocellular carcinoma.Gastroenterology2014;146:1691-700.e3

[16] Omata M,Kokudo N.Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.Hepatol Int2017;11:317-70 PMCID:PMC5491694

[17] Voizard N,Assad A.Assessment of hepatocellular carcinoma treatment response with LI-RADS: a pictorial review.Insights Imaging2019;10:121 PMCID:PMC6920285

[18] Llovet JM,Kulik L.Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol2021;18:293-313

[19] Llovet JM,Marrero JA.AASLD Panel of Experts on Trial Design in HCCTrial design and endpoints in hepatocellular carcinoma: AASLD consensus conference.Hepatology2021;73 Suppl 1:158-91

[20] Sasaki A,Iwashita Y,Ohta M.Microsatellite distribution and indication for locoregional therapy in small hepatocellular carcinoma.Cancer2005;103:299-306

[21] Lee MJ,Dawson SL.Percutaneous ethanol injection for the treatment of hepatic tumors: indications, mechanism of action, technique, and efficacy.AJR Am J Roentgenol1995;164:215-20

[22] Joseph FB,Bernardino ME.Hepatocellular carcinoma: CT appearance after percutaneous ethanol ablation therapy. Work in progress.Radiology1993;186:553-6

[23] Lin SM,Lin CC,Chen YC.Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.Gut2005;54:1151-6 PMCID:PMC1774888

[24] Shiina S,Obi S.A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma.Gastroenterology2005;129:122-30

[25] Minami Y.Radiofrequency ablation of hepatocellular carcinoma: a literature review.Int J Hepatol2011;2011:104685 PMCID:PMC3170722

[26] Goldberg SN,Mueller PR.Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance.AJR Am J Roentgenol2000;174:323-31

[27] Lin ZY,Chen J,Chen YP.Effect of heat sink on the recurrence of small malignant hepatic tumors after radiofrequency ablation.J Cancer Res Ther2016;12:C153-8

[28] Poulou LS,Thanou I,Thanos L.Percutaneous microwave ablation vs radiofrequency ablation in the treatment of hepatocellular carcinoma.World J Hepatol2015;7:1054-63 PMCID:PMC4450182

[29] Poggi G,Montagna B.Microwave ablation of hepatocellular carcinoma.World J Hepatol2015;7:2578-89 PMCID:PMC4635143

[30] Bertot LC,Tateishi R,Koike K.Mortality and complication rates of percutaneous ablative techniques for the treatment of liver tumors: a systematic review.Eur Radiol2011;21:2584-96

[31] Nakagomi R,Shiina S.Drastically reduced neoplastic seeding related to radiofrequency ablation for hepatocellular carcinoma.Am J Gastroenterol2014;109:774-6

[32] Yu J,Yu XL,Han ZY.Needle track seeding after percutaneous microwave ablation of malignant liver tumors under ultrasound guidance: analysis of 14-year experience with 1462 patients at a single center.Eur J Radiol2012;81:2495-9

[33] Wang CC.Artificial ascites is feasible and effective for difficult-to-ablate hepatocellular carcinoma.Hepatol Int2015;9:514-9

[34] Bischof JC.Large ice crystals in the nucleus of rapidly frozen liver cells.Cryobiology1993;30:597-603

[35] Whittaker DK.Mechanisms of tissue destruction following cryosurgery.Ann R Coll Surg Engl1984;66:313-8 PMCID:PMC2493682

[36] Brown NJ,Reed MW.Effect of cryosurgery on liver blood flow.Br J Cancer1993;68:10-2 PMCID:PMC1968305

[37] Rubinsky B,Bastacky J.The process of freezing and the mechanism of damage during hepatic cryosurgery.Cryobiology1990;27:85-97

[38] Lencioni R,Narayanan G.Irreversible electroporation in the treatment of hepatocellular carcinoma.Tech Vasc Interv Radiol2015;18:135-9

[39] O'Neill CH.Cardiac synchronization and arrhythmia during irreversible electroporation.J Surg Oncol2020;122:407-11

[40] Nikfarjam M.Interstitial laser thermotherapy for liver tumours.Br J Surg2003;90:1033-47

[41] Muralidharan V,Christophi C.Effect of blood flow occlusion on laser hyperthermia for liver metastases.J Surg Res2002;103:165-74

[42] Liu DL,Wang I,Svanberg S.Laser doppler perfusion imaging: New technique for determination of perfusion and reperfusion of splanchnic organs and tumor tissue.Lasers Surg Med1997;20:473-9

[43] Diana M,Liu YY.High intensity focused ultrasound (HIFU) applied to hepato-bilio-pancreatic and the digestive system-current state of the art and future perspectives.Hepatobiliary Surg Nutr2016;5:329-44 PMCID:PMC4960411

[44] Zhou Y.Variations of bubble cavitation and temperature elevation during lesion formation by high-intensity focused ultrasound.J Acoust Soc Am2013;134:1683-94

[45] Lam VW,Chok KS.Risk factors and prognostic factors of local recurrence after radiofrequency ablation of hepatocellular carcinoma.J Am Coll Surg2008;207:20-9

[46] Lee DH,Lee JY.Radiofrequency ablation of hepatocellular carcinoma as first-line treatment: long-term results and prognostic factors in 162 patients with cirrhosis.Radiology2014;270:900-9

[47] Lencioni R,Crocetti L.Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation.Radiology2005;234:961-7

[48] N'Kontchou G,Aout M.Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis.Hepatology2009;50:1475-83

[49] Sala M,Vilana R.Barcelona Clínic Liver Cancer GroupInitial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.Hepatology2004;40:1352-60

[50] Rossi S,Rosa L.Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: a long-term cohort study.Hepatology2011;53:136-47

[51] Brunello F,Carucci P.Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: a randomized controlled trial.Scand J Gastroenterol2008;43:727-35

[52] Shiina S,Arano T.Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors.Am J Gastroenterol2012;107:569-77; quiz 578 PMCID:PMC3321437

[53] Llovet JM,Villanueva A.Hepatocellular carcinoma.Nat Rev Dis Primers2021;7:6

[54] Livraghi T,Di Stasi M.Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice?.Hepatology2008;47:82-9

[55] Lencioni RA,Cioni D.Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection.Radiology2003;228:235-40

[56] Lin SM,Lin CC,Chen YC.Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm.Gastroenterology2004;127:1714-23

[57] Giorgio A,De Stefano G,Farella N,Esposito V,Giorgio V.Percutaneous radiofrequency ablation of hepatocellular carcinoma compared to percutaneous ethanol injection in treatment of cirrhotic patients: an Italian randomized controlled trial.Anticancer Res2011;31:2291-5

[58] Ng KKC,Chan ACY.Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma.Br J Surg2017;104:1775-84

[59] Xu XL,Liang M.Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: systematic review of randomized controlled trials with meta-analysis and trial sequential analysis.Radiology2018;287:461-72

[60] Izumi N,Nishioka Y.A multicenter randomized controlled trial to evaluate the efficacy of surgery vs. radiofrequency ablation for small hepatocellular carcinoma (SURF trial).Journal of Clinical Oncology2019;37.

[61] Xia Y,Liu G.Long-term effects of repeat hepatectomy vs percutaneous radiofrequency ablation among patients with recurrent hepatocellular carcinoma: a randomized clinical trial.JAMA Oncol2020;6:255-63 PMCID:PMC6902111

[62] Majumdar A,Thorburn D,Tsochatzis E.Management of people with early- or very early-stage hepatocellular carcinoma: an attempted network meta-analysis.Cochrane Database Syst Rev2017;3:CD011650 PMCID:PMC6464490

[63] Yu J,Han ZY.Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial.Gut2017;66:1172-3 PMCID:PMC5532455

[64] Vietti Violi N,Guiu B.Efficacy of microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma in patients with chronic liver disease: a randomised controlled phase 2 trial.2018;3:317-25

[65] Chong CCN,Cheung SYS.Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial).HPB (Oxford)2020;22:1121-7

[66] Tan W,Lin S,Xu G.Comparison of microwave ablation and radiofrequency ablation for hepatocellular carcinoma: a systematic review and meta-analysis.Int J Hyperthermia2019;36:264-72

[67] Glassberg MB,Clymer JW.Microwave ablation compared with radiofrequency ablation for treatment of hepatocellular carcinoma and liver metastases: a systematic review and meta-analysis.Onco Targets Ther2019;12:6407-38 PMCID:PMC6698169

[68] Facciorusso A,Muscatiello N.Microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.Int J Hyperthermia2016;32:339-44

[69] Wang C,Yang W.Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma.Hepatology2015;61:1579-90

[70] Ooka Y,Okabe S.Gadoxetic acid-enhanced MRI compared with CT during angiography in the diagnosis of hepatocellular carcinoma.Magn Reson Imaging2013;31:748-54

[71] Brown KT,Getrajdman GI.Particle embolization for hepatocellular carcinoma.J Vasc Interv Radiol1998;9:822-8

[72] Yasui D,Ueda T.Novel treatment strategy for advanced hepatocellular carcinoma: combination of conventional transcatheter arterial chemoembolization and modified method with portal vein occlusion for cases with arterioportal shunt: a preliminary study.Acta Radiol2018;59:266-74

[73] Roth GS,Abousalihac M.Idarubicin vs doxorubicin in transarterial chemoembolization of intermediate stage hepatocellular carcinoma.World J Gastroenterol2020;26:324-34 PMCID:PMC6969879

[74] Guan YS,Wang MQ.Transcatheter arterial chemoembolization: history for more than 30 years.ISRN Gastroenterol2012;2012:480650 PMCID:PMC3433134

[75] Marelli L,Triantos C.Transarterial therapy for hepatocellular carcinoma: which technique is more effective?.Cardiovasc Intervent Radiol2007;30:6-25

[76] Pleguezuelo M,Misseri M.TACE versus TAE as therapy for hepatocellular carcinoma.Expert Rev Anticancer Ther2008;8:1623-41

[77] Miraglia R,Maruzzelli L.Efficacy of transcatheter embolization/chemoembolization (TAE/TACE) for the treatment of single hepatocellular carcinoma.World J Gastroenterol2007;13:2952-5 PMCID:PMC4171147

[78] Bruix J,Castells A.Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution.Hepatology1998;27:1578-83

[79] Thuluvath PJ,Amjad W.Role of locoregional therapies in patients with hepatocellular cancer awaiting liver transplantation.Am J Gastroenterol2021;116:57-67

[80] Varela M,Burrel M.Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics.J Hepatol2007;46:474-81

[81] Brown KT,Gonen M.Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone.J Clin Oncol2016;34:2046-53 PMCID:PMC4966514

[82] Sangro B.Chemoembolization and radioembolization.Best Pract Res Clin Gastroenterol2014;28:909-19

[83] Wigmore SJ,Thomson BN.Postchemoembolisation syndrome--tumour necrosis or hepatocyte injury?.Br J Cancer2003;89:1423-7 PMCID:PMC2394347

[84] Paye F,Dahmane M,Flejou JF.Cytolysis following chemoembolization for hepatocellular carcinoma.Br J Surg1999;86:176-80

[85] Makary MS,Cloyd JM,Dowell JD.Locoregional therapy approaches for hepatocellular carcinoma: recent advances and management strategies.Cancers (Basel)2020;12:1914 PMCID:PMC7409274

[86] Chan AO,Hui CK,Lai CL.A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma.Cancer2002;94:1747-52

[87] Garwood ER,Hoch SE,Yao FY.Morbidity and mortality following transarterial liver chemoembolization in patients with hepatocellular carcinoma and synthetic hepatic dysfunction.Liver Transpl2013;19:164-73

[88] Wu GC,Chen CW,Peng CK.Acute respiratory distress syndrome after transcatheter arterial chemoembolization of hepatocellular carcinomas.Am J Med Sci2009;338:357-60

[89] Zivin SP,Ray CE Jr.Tumor lysis syndrome and primary hepatic malignancy: case presentation and review of the literature.Semin Intervent Radiol2015;32:3-9 PMCID:PMC4346043

[90] Brown DB,Soulen MC,Sacks D.Society of Interventional Radiology position statement on chemoembolization of hepatic malignancies.J Vasc Interv Radiol2009;20:S317-23

[91] Bhangoo MS,Hein PN.Radioembolization with Yttrium-90 microspheres for patients with unresectable hepatocellular carcinoma.J Gastrointest Oncol2015;6:469-78 PMCID:PMC4570909

[92] Kim YC,Uhm SH.Radiation safety issues in y-90 microsphere selective hepatic radioembolization therapy: possible radiation exposure from the patients.Nucl Med Mol Imaging2010;44:252-60 PMCID:PMC4042917

[93] Kennedy AS,Coldwell D,Drachenberg C.Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers.Int J Radiat Oncol Biol Phys2004;60:1552-63

[94] Sangro B,Bilbao JI.Radioembolization for hepatocellular carcinoma.J Hepatol2012;56:464-73

[95] Gil-Alzugaray B,Iñarrairaegui M.Prognostic factors and prevention of radioembolization-induced liver disease.Hepatology2013;57:1078-87

[96] Llovet JM,Montaña X.Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet2002;359:1734-9

[97] Lo CM,Tso WK.Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.Hepatology2002;35:1164-71

[98] Llovet JM.Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival.Hepatology2003;37:429-42

[99] Meyer T,Ma YT.Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.2017;2:565-75

[100] Kudo M,Finn RS.Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial.Hepatology2014;60:1697-707

[101] Okusaka T,Shioyama Y.Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.J Hepatol2009;51:1030-6

[102] Yu SC,Hui EP.Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization.Radiology2014;270:607-20

[103] Golfieri R,Renzulli M.PRECISION ITALIA STUDY GROUPRandomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma.Br J Cancer2014;111:255-64 PMCID:PMC4102934

[104] Kudo M,Park J.Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.2018;3:37-46

[105] Ikeda M,Aikata H.; Miriplatin TACE Study Group. Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial.J Gastroenterol2018;53:281-90 PMCID:PMC5846877

[106] Lammer J,Vogl T.PRECISION V InvestigatorsProspective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.Cardiovasc Intervent Radiol2010;33:41-52 PMCID:PMC2816794

[107] Lobo L,Picado O.Unresectable hepatocellular carcinoma: radioembolization versus chemoembolization: a systematic review and meta-analysis.Cardiovasc Intervent Radiol2016;39:1580-8

[108] Salem R,Mouli S.Y90 Radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma.Gastroenterology2016;151:1155-63.e2 PMCID:PMC5124387

[109] Salem R,Riaz A.Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience.Hepatology2018;68:1429-40

[110] Hilgard P,Fouly AE.Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.Hepatology2010;52:1741-9

[111] Mazzaferro V,Bhoori S.Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.Hepatology2013;57:1826-37

[112] Salem R,Mulcahy MF.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology2010;138:52-64

[113] Sangro B,Cianni R.; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation.Hepatology2011;54:868-78

[114] Vilgrain V,Assenat E.Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.Lancet Oncology2017;18:1624-36

[115] Chow PKH,Tan SB.Asia-Pacific Hepatocellular Carcinoma Trials GroupSIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma.J Clin Oncol2018;36:1913-21

[116] Ricke J,Amthauer H.Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.J Hepatol2019;71:1164-74

[117] Garin E,Guiu B.Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial.2021;6:17-29

[118] Lewandowski RJ,Riaz A.A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization.Am J Transplant2009;9:1920-8

[119] Zori AG,Limaye AR.Locoregional therapy protocols with and without radioembolization for hepatocellular carcinoma as bridge to liver Transplantation.Am J Clin Oncol2020;43:325-33

[120] Salem R,Kim E.Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: the LEGACY study.Hepatology2021;74:2342-52 PMCID:PMC8596669

[121] Schaub SK,Lock MI.Stereotactic body radiation therapy for hepatocellular carcinoma: current trends and controversies.Technol Cancer Res Treat2018;17:1533033818790217 PMCID:PMC6071169

[122] Liang SX,Xu ZY.Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: the risk factors and hepatic radiation tolerance.Int J Radiat Oncol Biol Phys2006;65:426-34

[123] Benson R,Kilambi R.Radiation induced liver disease: a clinical update.J Egypt Natl Canc Inst2016;28:7-11

[124] Kimura T,Takahashi I.The time course of dynamic computed tomographic appearance of radiation injury to the cirrhotic liver following stereotactic body radiation therapy for hepatocellular carcinoma.PLoS One2015;10:e0125231 PMCID:PMC4466204

[125] Lee J,Yoon WS,Rim CH.Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: meta-analyses and a systematic review.Radiother Oncol2020;145:63-70

[126] Bang A.Radiotherapy for HCC: ready for prime time?.JHEP Rep2019;1:131-7 PMCID:PMC7001576

[127] Shen PC,Lo CH.Comparison of stereotactic body radiation therapy and transarterial chemoembolization for unresectable medium-sized hepatocellular carcinoma.Int J Radiat Oncol Biol Phys2019;105:307-18

[128] Sapir E,Schipper MJ.Stereotactic body radiation therapy as an alternative to transarterial chemoembolization for hepatocellular carcinoma.Int J Radiat Oncol Biol Phys2018;100:122-30 PMCID:PMC5818982

[129] Yoon SM,Lee SJ.Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial.JAMA Oncol2018;4:661-9 PMCID:PMC5885246

[130] Sapisochin G,Doherty M.Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis.J Hepatol2017;67:92-9

[131] Iezzi R,Posa A,Gasbarrini A.Combined locoregional treatment of patients with hepatocellular carcinoma: state of the art.World J Gastroenterol2016;22:1935-42 PMCID:PMC4726669

[132] Lu Z,Guo Q,Mao X.Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: a meta-analysis of randomized-controlled trials.Eur J Gastroenterol Hepatol2013;25:187-94

[133] Kim JW,Won HJ.Hepatocellular carcinomas 2-3 cm in diameter: transarterial chemoembolization plus radiofrequency ablation vs. radiofrequency ablation alone.Eur J Radiol2012;81:e189-93

[134] Peng ZW,Chen MS.Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial.J Clin Oncol2013;31:426-32

[135] Chen K,Wang H.Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial.J Hepatol2014;61:1304-11

[136] Fuchs K,Dormond O.Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model.J Vasc Interv Radiol2014;25:379-87,387.e1

[137] Bize P,Fuchs K.Antitumoral effect of sunitinib-eluting beads in the rabbit VX2 tumor model.Radiology2016;280:425-35

[138] Hagan A,Macfarlane WM,Czuczman P.Preparation and characterisation of vandetanib-eluting radiopaque beads for locoregional treatment of hepatic malignancies.Eur J Pharm Sci2017;101:22-30

[139] Sakr OS,Carpentier G,Jordan O.Arming embolic beads with anti-VEGF antibodies and controlling their release using LbL technology.J Control Release2016;224:199-207

[140] Slovak R,Gettinger SN,Kim HS.Immuno-thermal ablations-boosting the anticancer immune response.J Immunother Cancer2017;5:78 PMCID:PMC5644150

[141] Tak WY,Wang Y.Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions.Clin Cancer Res2018;24:73-83

[142] Bruix J,Llovet JM.Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference.Journal of Hepatology2001;35:421-30

[143] Lencioni R,Han G.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial.J Hepatol2016;64:1090-8

[144] Kudo M,Ikeda M.TACTICS study groupRandomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.Gut2020;69:1492-501 PMCID:PMC7398460

[145] Mathias-Machado M.C. dFLG. Neoadjuvant and adjuvant systemic treatment for hepatocellular carcinoma.Hepatoma Res2021;7:67 PMCID:PMC6676544

[146] Brown ZJ.Adjuvant treatment of hepatocellular carcinoma after resection.Hepatoma Res2021;7:68

[147] Gregory J,Corrias G,Ronot M.Evaluation of liver tumour response by imaging.JHEP Rep2020;2:100100 PMCID:PMC7267412

[148] Therasse P,Eisenhauer EA.New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.J Natl Cancer Inst2000;92:205-16

[149] Lencioni R.Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.Semin Liver Dis2010;30:52-60

[150] Kielar A,Lewis S.Locoregional therapies for hepatocellular carcinoma and the new LI-RADS treatment response algorithm.Abdom Radiol (NY)2018;43:218-30 PMCID:PMC5771991

[151] Sato Y,Sone M.Japan Interventional Radiology in Oncology Study Group-JIVROSGTumor response evaluation criteria for HCC (hepatocellular carcinoma) treated using TACE (transcatheter arterial chemoembolization): RECIST (response evaluation criteria in solid tumors) version 1.1 and mRECIST (modified RECIST): JIVROSG-0602.Ups J Med Sci2013;118:16-22 PMCID:PMC3572665

[152] Tovoli F,Granito A,Bolondi L.Radiologic criteria of response to systemic treatments for hepatocellular carcinoma.Hepat Oncol2017;4:129-37 PMCID:PMC6096444

[153] Huh YJ,Kim B,Rha SE.Per-feature accuracy of liver imaging reporting and data system locoregional treatment response algorithm: a systematic review and meta-analysis.Cancers (Basel)2021;13:4432 PMCID:PMC8430492

[154] Kierans AS,Dutruel SP.Evaluation of the LI-RADS treatment response algorithm in hepatocellular carcinoma after trans-arterial chemoembolization.Clin Imaging2021;80:117-22

[155] Seo N,Park MS.Evaluation of treatment response in hepatocellular carcinoma in the explanted liver with liver imaging reporting and data system version 2017.Eur Radiol2020;30:261-71 PMCID:PMC7485122

[156] Kellock T,Harris A.Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma: imaging evaluation post treatment.Br J Radiol2018;91:20170118 PMCID:PMC6190776

[157] Ma Y,Dong Q,Zhang J.How to differentiate pseudoprogression from true progression in cancer patients treated with immunotherapy.Am J Cancer Res2019;9:1546-53 PMCID:PMC6726978

[158] Llovet JM.mRECIST for HCC: Performance and novel refinements.J Hepatol2020;72:288-306

[159] Park JW,Kim DY.Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial.J Hepatol2019;70:684-91