Treatment of high-burden hepatocellular carcinoma: an oncologist perspective

Abstract

Hepatocellular carcinoma (HCC) is recognized as a major global healthcare burden. Although there have been tremendous improvements in cancer screening and treatment, HCC mortality rate remains high. Many patients with HCC present late to medical attention and thus are not candidates for curative treatment. They typically have high tumor burden at presentation showing heterogeneity in anatomical factors and biochemical profile. Despite the relatively poor prognosis for these patients, significant improvements can still be made in survival if the optimal treatment modality is chosen. Currently, there is no international consensus on how to manage this group of heterogeneous, high-burden HCC. In this article, we will address this question by reviewing the latest available evidences. Our definition of “high-burden HCC” will be based on three factors: size, number of tumors and the presence of macrovascular invasion. The different treatment modalities, namely surgery, intra-arterial therapy, radiotherapy and systemic therapy, and their respective supportive evidences, will be discussed. In the end, we will summarize with our views on the future direction of research priorities for the management of high-burden HCC.

Keywords

Cancer / hepatocellular carcinoma / liver

References

[1] McGuire S.World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015..Adv Nutr2016;7:418-9 PMCID:PMC4785485

[2] Zhong JH,Ke Y,Wang L.Hepatic resection as a safe and effective treatment for hepatocellular carcinoma involving a single large tumor, multiple tumors, or macrovascular invasion..Medicine (Baltimore)2015;94:e396 PMCID:PMC4602643

[3] Chan SL,Chan AW,Chok KS.Management of hepatocellular carcinoma with portal vein tumor thrombosis: review and update at 2016..World J Gastroenterol2016;22:7289-300 PMCID:PMC4997643

[4] Forner A,Bruix J.Treatment of intermediate-stage hepatocellular carcinoma..Nat Rev Clin Oncol2014;11:525-35

[5] Cho YB,Lee HW,Yang SH,Yi NJ.Outcomes of hepatic resection for a single large hepatocellular carcinoma..World J Surg2007;31:795-801

[6] Lee SG,Jung JP,Kim KH.Outcome of patients with huge hepatocellular carcinoma after primary resection and treatment of recurrent lesions..Br J Surg2007;94:320-6

[7] Pandey D,Wai CT,Tan KC.Long term outcome and prognostic factors for large hepatocellular carcinoma (10 cm or more) after surgical resection..Ann Surg Oncol2007;14:2817-23

[8] Shah SA,Cleary SP,McGilvray ID,Grant DR.Prognosis and results after resection of very large (> or = 10 cm) hepatocellular carcinoma..J Gastrointest Surg2007;11:589-95

[9] Young AL,Abu-Hilal M,Wyatt J,Toogood GJ.Large hepatocellular carcinoma: time to stop preoperative biopsy..J Am Coll Surg2007;205:453-62

[10] Shimada K,Esaki M.Role of a hepatectomy for the treatment of large hepatocellular carcinomas measuring 10 cm or larger in diameter..Langenbecks Arch Surg2008;393:521-6

[11] Chirica M,Massault PP,Randone B,Legmann P.Treatment of stage IVA hepatocellular carcinoma: should we reappraise the role of surgery?.Arch Surg2008;143:538-43; discussion 543

[12] Taniai N,Tajiri T.Adaptation of hepatectomy for huge hepatocellular carcinoma..J Hepatobiliary Pancreat Surg2008;15:410-6

[13] Wang BW,Liu SI,Tsai CC,Yeh MH.Is hepatectomy beneficial in the treatment of multinodular hepatocellular carcinoma?.J Formos Med Assoc2008;107:616-26

[14] Wang JH,Hu TH,Kee KM,Chen CL,Huang YJ.The efficacy of treatment schedules according to Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma - survival analysis of 3892 patients..Eur J Cancer2008;44:1000-6

[15] Ng KM,Black D,Morris DL.Prognostic determinants for survival after resection/ablation of a large hepatocellular carcinoma..HPB (Oxford)2009;11:311-20 PMCID:PMC2727084

[16] Yang LY,Ou DP,Zeng ZJ.Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection..Ann Surg2009;249:118-23

[17] Choi GH,Kim DH,Kang CM,Choi JS,Park JY,Han KH,Lee WJ.Outcome after curative resection for a huge (> or = 10 cm) hepatocellular carcinoma and prognostic significance of gross tumor classification..Am J Surg2009;198:693-701

[18] Ho MC,Tsang YM,Chen DS,Chen CH.Liver resection improves the survival of patients with multiple hepatocellular carcinomas..Ann Surg Oncol2009;16:848-55

[19] Delis SG,Tassopoulos N,Kelekis D,Dervenis C.Hepatic resection for hepatocellular carcinoma exceeding Milan criteria..Surg Oncol2010;19:200-7

[20] Lin CT,Chen TW,Chan DC,Hsieh TY,Kuo SM,Hsieh CB.Comparing hepatic resection and transarterial chemoembolization for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma: change for treatment of choice?.World J Surg2010;34:2155-61

[21] Ramacciato G,Petrucciani N,Cucchetti A,Cescon M,Pinna AD.Does surgical resection have a role in the treatment of large or multinodular hepatocellular carcinoma?.Am Surg2010;76:1189-97

[22] Schiffman SC,Kooby DA,Staley CA,McMasters KM.Factors associated with recurrence and survival following hepatectomy for large hepatocellular carcinoma: a multicenter analysis..J Surg Oncol2010;101:105-10

[23] Wang J,Liu C,Chen YJ.Prognostic factors and outcome of 438 Chinese patients with hepatocellular carcinoma underwent partial hepatectomy in a single center..World J Surg2010;34:2434-41

[24] Yamashita Y,Shirabe K,Tsuijita E,Kayashima H.Outcomes of hepatic resection for huge hepatocellular carcinoma (>/= 10 cm in diameter)..J Surg Oncol2011;104:292-8

[25] Ruzzenente A,Sandri M,Valdegamberi A,Bagante F,D'Onofrio M.Surgical resection versus local ablation for HCC on cirrhosis: results from a propensity case-matched study..J Gastrointest Surg2012;16:301-11; discussion 11

[26] Luo J,Guo RP,Li JQ,Shi M.Hepatic resection versus transarterial lipiodol chemoembolization as the initial treatment for large, multiple, and resectable hepatocellular carcinomas: a prospective nonrandomized analysis..Radiology2011;259:286-95

[27] Zhou L,Wang SB,Qu Q.Prognostic factors of solitary large hepatocellular carcinoma: the importance of differentiation grade..Eur J Surg Oncol2011;37:521-5

[28] Chang WT,Chau GY,Lei HJ,Hsia CY,King KL.Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: extending the indication for resection?.Surgery2012;152:809-20

[29] Galun DA,Zuvela M,Ille T.Is there any benefit from expanding the criteria for the resection of hepatocellular carcinoma in cirrhotic liver? Experience from a developing country..World J Surg2012;36:1657-65

[30] Huang JF,Wu TH,Wu TJ,Chan KM.Liver resection for complicated hepatocellular carcinoma: challenges but opportunity for long-term survivals..J Surg Oncol2012;106:959-65

[31] Shrager B,Tabrizian P,Labow DM.Resection of large hepatocellular carcinoma (>/= 10 cm): a unique western perspective..J Surg Oncol2013;107:111-7

[32] Allemann P,Bouzourene H,Halkic N.Long-term outcome after liver resection for hepatocellular carcinoma larger than 10 cm..World J Surg2013;37:452-8

[33] Ariizumi S,Takahashi Y,Yamamoto M.Impact of hepatectomy for huge solitary hepatocellular carcinoma..J Surg Oncol2013;107:408-13

[34] Yin L,Li AJ,Pan ZY,Wu MC.Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan Criteria: a RCT..J Hepatol2014;61:82-8

[35] Chan YC,Pillai VG,Wang CC.Survival outcome between hepatic resection and transarterial embolization for hepatocellular carcinoma more than 10 cm: a propensity score model..World J Surg2015;39:1510-8

[36] Chang YJ,Chang YJ.Long-term survival of patients undergoing liver resection for very large hepatocellular carcinomas..Br J Surg2016;103:1513-20

[37] Liu PH,Hsu CY,Lee YH,Lee RC,Huo TI.Solitary large hepatocellular carcinoma: staging and treatment strategy..PLoS One2016;11:e0155588 PMCID:PMC4866714

[38] Zhao HC,Liu FB,Wang GB,Huang F,Geng XP.A retrospective analysis of long term outcomes in patients undergoing hepatic resection for large (>5 cm) hepatocellular carcinoma..HPB (Oxford)2016;18:943-9 PMCID:PMC5094476

[39] Jin YJ.Therapeutic priorities for solitary large hepatocellular carcinoma in a hepatitis B virus endemic area; an analysis of a nationwide cancer registry database..J Surg Oncol2017;115:407-16

[40] Kumada K,Okamoto R,Yamaguchi M,Higashiyama H,Sasaki H.Hepatic resection for advanced hepatocellular carcinoma with removal of portal vein tumor thrombi..Surgery1990;108:821-7

[41] Llovet JM,Bruix J.Prognosis of hepatocellular carcinoma: the BCLC staging classification..Semin Liver Dis1999;19:329-38

[42] Ban D,Yamamoto Y,Esaki M,Kosuge T.Efficacy of a hepatectomy and a tumor thrombectomy for hepatocellular carcinoma with tumor thrombus extending to the main portal vein..J Gastrointest Surg2009;13:1921-8

[43] Peng ZW,Zhang YJ,Chen MS.Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus..Cancer2012;118:4725-36

[44] Kojima H,Taura K,Yasuchika K.Hepatic resection for hepatocellular carcinoma with tumor thrombus in the major portal vein..Dig Surg2015;32:413-20

[45] Kokudo T,Matsuyama Y,Izumi N,Kudo M,Sakamoto M,Kaneko S.Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion..J Hepatol2016;65:938-43

[46] Roayaie S,Taouli B.Resection of hepatocellular carcinoma with macroscopic vascular invasion..Ann Surg Oncol2013;20:3754-60

[47] Lee JM,Lee YJ,Choi SM,Hwang JS,Kim YH,Park SY,Kweon YO,Lee CH.Survival outcomes of hepatic resection compared with transarterial chemoembolization or sorafenib for hepatocellular carcinoma with portal vein tumor thrombosis..Clin Mol Hepatol2016;22:160-7 PMCID:PMC4825165

[48] Liu PH, Lee YH, Hsia CY, Hsu CY, Huang YH, Chiou YY, Lin HC, Huo TI. Surgical resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis. Ann Surg Oncol 2014;21:1825-33

[49] Zheng N,Zhang D,Che M,Du B.Hepatic resection or transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus..Medicine (Baltimore)2016;95:e3959 PMCID:PMC4937906

[50] Chen JS,Chen XL,Liang LJ,Huang JQ,Cheng ZX.Clinicopathologic characteristics and surgical outcomes of hepatocellular carcinoma with portal vein tumor thrombosis..J Surg Res2012;175:243-50

[51] Li N,Xue J,Shi J,Lau WY,Cheng SQ.Hepatocellular carcinoma with main portal vein tumor thrombus: a comparative study comparing hepatectomy with or without neoadjuvant radiotherapy..HPB (Oxford)2016;18:549-56 PMCID:PMC4913143

[52] Matono R,Motomura T,Kayashima H,Yoshizumi T,Shirabe K.Factors linked to longterm survival of patients with hepatocellular carcinoma accompanied by tumour thrombus in the major portal vein after surgical resection..HPB (Oxford)2012;14:247-53 PMCID:PMC3371211

[53] Shi J,Li N,Xue J,Wu MC.Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus..Ann Surg Oncol2010;17:2073-80

[54] Tang QH,Yang GM,Zhou WP,Lau WY.Surgical resection versus conformal radiotherapy combined with TACE for resectable hepatocellular carcinoma with portal vein tumor thrombus: a comparative study..World J Surg2013;37:1362-70

[55] Torzilli G,Kokudo N,Capussotti L,Vauthey JN,De Santibanes E,Morenghi E.A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations? An observational study of the HCC East-West study group..Ann Surg2013;257:929-37

[56] Kudo M,Ichida T,Kokudo N,Takayama T,Matsui O.Report of the 19th follow-up survey of primary liver cancer in Japan..Hepatol Res2016;46:372-90

[57] Chok KS,Chan SC,Fan ST.Surgical outcomes in hepatocellular carcinoma patients with portal vein tumor thrombosis..World J Surg2014;38:490-6

[58] Zhang YF,Wei W,Wang JH,Xiao CZ,Shi M.Optimal surgical strategy for hepatocellular carcinoma with portal vein tumor thrombus: a propensity score analysis..Oncotarge2016;7:38845-56

[59] Llovet JM,Mazzaferro V.Resection and liver transplantation for hepatocellular carcinoma..Semin Liver Dis2005;25:181-200

[60] Schwartz M,Konstadoulakis M.Strategies for the management of hepatocellular carcinoma..Nat Clin Pract Oncol2007;4:424-32

[61] Matsui O,Yoshikawa J,Arai K,Miyayama S,Unoura M.Small hepatocellular carcinoma: treatment with subsegmental transcatheter arterial embolization..Radiology1993;188:79-83

[62] Hépatocellulaire Groupe d'Etude et de Traitement du Carcinome.A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma..N Engl J Med1995;332:1256-61

[63] Raoul JL,Bretagne JF,Duvauferrier R,Bekhechi D,Gosselin M.Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma..Hepatology1997;26:1156-61

[64] Bruix J,Castells A,Bru C,Vilana R.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

[65] Pelletier G,Gay F,Hagege H,Van Steenbergen W,Rougier P,Pignon JP.Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC..J Hepatol1998;29:129-34

[66] Llovet JM,Montana X,Coll S,Ayuso C,Muchart J,Rodes J.Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial..Lancet2002;359:1734-9

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

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

[69] Jianyong L,Wentao W,Bo L,Minqing X.Barcelona clinic liver cancer stage B hepatocellular carcinoma: transarterial chemoembolization or hepatic resection?.Medicine (Baltimore)2014;93:e180 PMCID:PMC4616388

[70] Lee YB,Cho Y,Lee JH,Lee HS,Yi NJ,Suh KS,Kim YJ.Comparison of transarterial chemoembolization and hepatic resection for large solitary hepatocellular carcinoma: a propensity score analysis..J Vasc Interv Radiol2015;26:651-9

[71] Nouso K,Nakamura S,Wakuta A,Ako S,Wada N,Takeuchi Y,Onishi H,Shiraha H,Okada H.Application of radiofrequency ablation for the treatment of intermediate-stage hepatocellular carcinoma..J Gastroenterol Hepatol2017;32:695-700

[72] Xue T,Chen R,Zhang L,Chen Y,Zhang B,Ren Z.Transarterial chemoembolization for huge hepatocellular carcinoma with diameter over ten centimeters: a large cohort study..Med Oncol2015;32:64

[73] Leng JJ,Dong JH.Efficacy of transarterial chemoembolization for hepatocellular carcinoma with portal vein thrombosis: a meta-analysis..ANZ J Surg2016;86:816-20

[74] Ajit Y,Saumya G,Navneet R,Anil A.Transarterial chemoembolization in unresectable hepatocellular carcinoma with portal vein thrombosis: a perspective on survival..Oman Med J2014;29:430-6 PMCID:PMC4289489

[75] Chern MC,Liang CT,Kuo TM.Transcatheter arterial chemoembolization for advanced hepatocellular carcinoma with portal vein invasion: safety, efficacy, and prognostic factors..J Vasc Interv Radiol2014;25:32-40

[76] Choi JW,Lee JH,Kim YJ,Jae HJ,Lee M.Transarterial chemoembolization of hepatocellular carcinoma with segmental portal vein tumour thrombus..Eur Radiol2017;27:1448-58

[77] Gorodetski B,Schernthaner R,Lin M,Lenis D,Nonyane BA,Tamrazi A,Schlachter T,Geschwind JF.Advanced-stage hepatocellular carcinoma with portal vein thrombosis: conventional versus drug-eluting beads transcatheter arterial chemoembolization..Eur Radiol2017;27:526-35 PMCID:PMC5470590

[78] Niu ZJ,Kang P,Meng ZB,Qi F.Transarterial chemoembolization compared with conservative treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus: using a new classification..Med Oncol2012;29:2992-7

[79] Lammer J,Vogl T,Denys A,Pitton M,Pfammatter T,Benhamou Y,Gruenberger T,Langenberger H,Dumortier J,Chevallier P.Prospective 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

[80] Sacco R,Bertini M,Romano A,Tumino E,Federici G,Metrangolo S,Bresci G,Altomare E,Bartolozzi C.Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma..J Vasc Interv Radiol2011;22:1545-52

[81] Recchia F,Filauri P,Boscarato P,Necozione S,Rea S.Chemoembolization of unresectable hepatocellular carcinoma: Decreased toxicity with slow-release doxorubicineluting beads compared with lipiodol..Oncol Rep2012;27:1377-83

[82] Gao YJ,Yang ZL,Zuo Y,Chen H,Qin FX,Wang J,Zhang L.Increased integrity of circulating cell-free DNA in plasma of patients with acute leukemia..Clin Chem Lab Med2010;48:1651-6

[83] Huang YJ,Wang CY,Chen HC,Fang FM.The treatment responses in cases of radiation therapy to portal vein thrombosis in advanced hepatocellular carcinoma..Int J Radiat Oncol Biol Phys2009;73:1155-63

[84] Gao S,Zheng Z,Deng M,Zheng S.Doxorubicin-eluting bead versus conventional TACE for unresectable hepatocellular carcinoma: a meta-analysis..Hepatogastroenterology2013;60:813-20

[85] Oliveri RS,Gluud C.Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma..Cochrane Database Syst Rev2011;(3):CD004787

[86] Hilgard P,Fouly AE,Muller S,Heusner T,Paul A,Gerken G.Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival..Hepatology2010;52:1741-9

[87] Sangro B,Cianni R,Gasparini D,Paprottka PM,Van Buskirk M,Ettorre GM,Giampalma E,Wilhelm K,Izzo F,Maini CL,Cappelli A,Ahmadzadehfar H,Lastoria S.Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation..Hepatology2011;54:868-78

[88] Salem R,Kulik L,Riaz A,Sato KT,Nikolaidis P,Yaghmai V,Senthilnathan S,Gates VL,Newman S,Chen R,Nemcek AA,Chrisman HB,Omary RA,Benson AB3rd.Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma..Gastroenterology2011;140:497-507 e2

[89] Salem R,Mulcahy MF,Ryu RK,Atassi B,Gates V,Sato KT,Gupta R,Newman SB,Abecassis M.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes..Gastroenterology2010;138:52-64

[90] Carr BI,Buch SC.Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study..Cancer2010;116:1305-14 PMCID:PMC2829376

[91] Kim DY,Kim YH,Cho SB,Uhm SH,Choi JY,Lee HC,Lee KH,Chung JW,Heo J,Joo YE.Radioembolization with yttrium-90 resin microspheres in hepatocellular carcinoma: a multicenter prospective study..Am J Clin Oncol2015;38:495-501

[92] Mazzaferro V,Bhoori S,Chiesa C,Maccauro M,Bongini M,Civelli E,Camerini T.Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study..Hepatology2013;57:1826-37

[93] Moreno-Luna LE,Sanchez W,Harnois DM,Gansen DN,Lazaridis KN,Larusso NF,Gores GJ,Slettedahl SW,Therneau TM,Andrews JC.Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma..Cardiovasc Intervent Radiol2013;36:714-23 PMCID:PMC3594060

[94] El Fouly A,El Dorry A,Dechene A,Mueller S,Lauenstein T,Gerken G.In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization?.Liver Int2015;35:627-35

[95] Cappelli A,Golfieri R.Transarterial radioembolization using yttrium-90 microspheres in the treatment of hepatocellular carcinoma: a review on clinical utility and developments..J Hepatocell Carcinoma2014;1:163-82 PMCID:PMC4918277

[96] Sacco R,Tumino E,Marceglia S,Eggenhoffner R,Cabibbo G.Transarterial radioembolization for hepatocellular carcinoma: a review..J Hepatocell Carcinoma2016;3:25-9 PMCID:PMC4994804

[97] Russell AH,Wasserman TH,Rotman M.Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol..Int J Radiat Oncol Biol Phys1993;27:117-23

[98] Matsuo Y,Nishimura H,Miyawaki D,Ishihara T,Fukumoto T,Yamaguchi M,Sasaki R.Efficacy of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis/inferior vena cava tumor thrombosis: evaluation by comparison with conventional three-dimensional conformal radiotherapy..J Radiat Res2016;57:512-23 PMCID:PMC5045071

[99] Bae SH,Cho CK,Lee DH,Park SC.Feasibility and efficacy of stereotactic ablative radiotherapy for Barcelona Clinic Liver Cancer-C stage hepatocellular carcinoma..J Korean Med Sci2013;28:213-9 PMCID:PMC3565132

[100] Culleton S,Haddad CR,Brierley J,Ringash J.Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma..Radiother Oncol2014;111:412-7

[101] Bujold A,Kim JJ,Cho C,Dinniwell RE,Ringash J,Sykes J,Knox JJ.Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma..J Clin Oncol2013;31:1631-9

[102] Lo CH,Liu MY,Lin CS,Huang WY.Survival and prognostic factors for patients with advanced hepatocellular carcinoma after stereotactic ablative radiotherapy..PLoS One2017;12:e0177793 PMCID:PMC5435316

[103] Toya R,Baba Y,Morishita S,Kawanaka K,Sugiyama S,Yamashita Y.Conformal radiation therapy for portal vein tumor thrombosis of hepatocellular carcinoma..Radiother Oncol2007;84:266-71

[104] Oh D,Park HC,Koh KC,Choi MS,Lim HK,Rhim H,Park KB.Early three-dimensional conformal radiotherapy for patients with unresectable hepatocellular carcinoma after incomplete transcatheter arterial chemoembolization: a prospective evaluation of efficacy and toxicity..Am J Clin Oncol2010;33:370-5

[105] Cho JY,Park HC,Sohn W,Choi MS,Koh KC,Yoo BC.The feasibility of combined transcatheter arterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma..Liver Int2014;34:795-801

[106] Leon SA,Sklaroff DM.Free DNA in the serum of cancer patients and the effect of therapy..Cancer Res1977;37:646-50

[107] Chan KC,Yeung SW,Lo YM.Persistent aberrations in circulating DNA integrity after radiotherapy are associated with poor prognosis in nasopharyngeal carcinoma patients..Clin Cancer Res2008;14:4141-5

[108] Yoon SM,Won HJ,Kim KM,Chung YH,Lee SG,Suh DJ.Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes..Int J Radiat Oncol Biol Phys2012;82:2004-11

[109] Okazaki E,Nishida N,Ogino R,Shimatani Y,Hamamoto S,Jogo A.Three-dimensional conformal radiotherapy for locally advanced hepatocellular carcinoma with portal vein tumour thrombosis: evaluating effectiveness of the model for end-stage liver disease (MELD) score compared with the Child-Pugh classification..Br J Radiol2016;89:20150945 PMCID:PMC5257306

[110] Llovet JM,Mazzaferro V,Gane E,de Oliveira AC,Raoul JL,Schwartz M,Zeuzem S,Greten TF,Seitz JF,Haussinger D,Shan M,Voliotis D.Sorafenib in advanced hepatocellular carcinoma..N Engl J Med2008;359:378-90

[111] Cheng AL,Chen Z,Qin S,Luo R,Ye S,Xu J,Liang H,Wang J,Pan H,Zou J,Guan Z.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 Oncol2009;10:25-34

[112] Zhu AX,Evans TR,Santoro A,Bruix J,Thuluvath PJ,Leberre MA,Meinhardt G.SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma..J Clin Oncol2015;33:559-66

[113] Cheng AL,Lin DY,Kudo M,Chung HC,Xu J,Omata M,Lanzalone S,Lechuga MJ.Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial..J Clin Oncol2013;31:4067-75

[114] Kudo M,Finn RS,Blanc JF,Yang J,Tak WY,Lee JH,Wu C,Shao G,Dela Cruz C,Wang JH.Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial..Hepatology2014;60:1697-707

[115] Cainap C,Huang WT,Pan H,Kudo M,Chen PJ,Gorbunova V,Qian J,Ricker JL,El-Nowiem S.Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial..J Clin Oncol2015;33:172-9 PMCID:PMC4279237

[116] Cheng AL,Lim HY,Yang TS,Chao Y,Kudo M,Kang YK,Numata K,Balsara B,Rodriguez AM,Wang Y.Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma..Hepatology2016;64:774-84

[117] Bruix J,Merle P,Huang YH,Pracht M,Rosmorduc O,Gerolami R,Ross PJ,Bronowicki JP,Kudo M,Llovet JM,LeBerre MA,Meinhardt G.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet2017;389:56-66

[118] Kudo M.Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials..Oncology2017;92 Suppl 1:50-62

[119] Whiteside TL,Rodriguez-Ruiz ME,Melero I.Emerging opportunities and challenges in cancer immunotherapy..Clin Cancer Res2016;22:1845-55 PMCID:PMC4943317

[120] Tomita Y,Shinohara N,Oya M,Tanabe K,Yonese J,Motzer RJ,McHenry MB,Ozono S.Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study..Jpn J Clin Oncol2017;47:639-46

[121] Weber JS,Minor D,Gutzmer R,Hoeller C,Miller WH., Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial..Lancet Oncol2015;16:375-84

[122] Sangro B,de la Mata M,Garralda E,Riezu-Boj JI,Alfaro C,Lasarte JJ,Melero I.A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C..J Hepatol2013;59:81-8

[123] El-Khoueiry AB,Yau T,Kudo M,Kim TY,Trojan J,Meyer T,Yeo W,Anderson J,Lang L,Tang H,Melero I.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial..Lancet2017;389:2492-502

[124] El-Serag HB.Epidemiology of viral hepatitis and hepatocellular carcinoma..Gastroenterology2012;142:1264-73e1.

[125] Zhang YQ.Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma..World J Gastroenterol2015;21:3860-6 PMCID:PMC4385532

[126] Sparchez Z.Hepatocellular carcinoma occurrence and recurrence after antiviral treatment in HCV-related cirrhosis. Are outcomes different after direct antiviral agents? A review..J Gastrointestin Liver Dis2017;26:403-10

[127] Yin J,Han Y,Deng Y,Guo W,Wang H,Cao G.Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study..J Clin Oncol2013;31:3647-55

[128] Lao XM,Ye LT,Shi M,Guo R,Li S,Yuan Y.Effects of antiviral therapy on hepatitis B virus reactivation and liver function after resection or chemoembolization for hepatocellular carcinoma..Liver Int2013;33:595-604

[129] Kim JH,Kim TH,Lee WJ.Hepatitis B virus reactivation after three-dimensional conformal radiotherapy in patients with hepatitis B virus-related hepatocellular carcinoma..Int J Radiat Oncol Biol Phys2007;69:813-9

[130] Kubo S,Hirohashi K,Shuto T,Shiomi S,Oka H,Kuroki T.Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial..Ann Intern Med2001;134:963-7

[131] Mazzaferro V,Schiavo M,Camerini T,Capussotti L,Pellicci R,Tagger A,Bonino F,Llovet JM.Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis..Hepatology2006;44:1543-54

[132] Conti F,Scuteri A,Bolondi L,Foschi FG,Mazzella G,Andreone P.Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals..J Hepatol2016;65:727-33

[133] Reig M,Perello C,Ribeiro A,Diaz A,Darnell A,Sangro B,Forns X.Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy..J Hepatol2016;65:719-26

[134] Verslype C,Kelley RK,Su WC,Lee Y,Cutsem EV.Activity of cabozantinib (XL184) in hepatocellular carcinoma: results from a phase II randomized discontinuation trial (RDT)..J Clin Oncol2012;30 Suppl 15:4007

[135] Kobayashi S,Moriguchi M,Izumi N,Hino K,Chiba T,Kato J,Ido A,Sato T,Okusaka T,Tamura K.JET-HCC: a phase 3 randomized, double-blind, placebo-controlled study of tivantinib as a second-line therapy in patients with c-Met high hepatocellular carcinoma..Ann Oncol2017;28:mdx369