Treatment options for recurrence of hepatocellular carcinoma after surgical resection: review of the literature and current recommendations for management

Abstract

The recurrence rate after primary resection for hepatocellular carcinoma (HCC) has been reported to be up to 80%. There is no consensus or guideline about the best treatment option for such recurrent HCC (rHCC). It is therefore of paramount importance to select patients for suitable treatment due to the high risk of associated morbidity and mortality. In this paper, we review the literature on treatment for rHCC and propose a strategy based on the best evidence available. Even in rHCC, it is still possible to achieve cure and good survival rates through careful patient selection. Repeat hepatectomy is recognized as a feasible and safe procedure even in cirrhotic patients and should be considered as the best option with curative intent when the patient is fit enough. Greater adoption of minimally-invasive liver surgery could have the potential to increase the number of candidate patients with rHCC for repeat resection in the next few years. Liver transplantation offers longer disease-free survival compared to repeat resection, curing the underlying cirrhosis, but is not widely available due to organ shortage. When surgery is not feasible, locoregional treatments such as radiofrequency ablation and transarterial chemoembolization have an important role for patients who cannot tolerate repeat hepatectomy and are not suitable for transplantation. For advanced cases, systemic therapy could be considered.

Keywords

Recurrence / hepatocellular carcinoma / hepatic resection / second resection

References

[1] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries..CA Cancer J Clin2018;68:394-424

[2] Akinyemiju T,Ahmed M,Alemayohu MA.The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level results from the global burden of disease study 2015..JAMA Oncol2017;3:1683-91 PMCID:PMC5824275

[3] Kokudo N,Hasegawa K,Kubo S.Clinical practice guidelines for hepatocellular carcinoma: the Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update..Hepatol Res2019;49:1109-13

[4] European Association for the Study of the LiverEASL Clinical Practice Guidelines: Management of hepatocellular carcinoma..J Hepatol2018;69:182-236

[5] Bruix J.Management of hepatocellular carcinoma: an update..Hepatology2011;53:1020-2 PMCID:PMC3084991

[6] Bralet MP,Pineau P,Loas G.Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases..Hepatology2000;32:200-4

[7] El-Serag HB.Hepatocellular carcinoma..N Engl J Med2011;365:1118-27

[8] Llovet JM,Bruix J.Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation..Hepatology1999;30:1434-40

[9] Cucchetti A,Vivarelli M,Ravaioli M.Impact of model for end-stage liver disease (MELD) score on prognosis after hepatectomy for hepatocellular carcinoma on cirrhosis..Liver Transpl2006;12:966-71

[10] Miyagawa S,Kawasaki S.Criteria for safe hepatic resection..Am J Surg1995;169:589-94

[11] Seyama Y.Assessment of liver function for safe hepatic resection..Hepatol Res2009;39:107-16

[12] Serenari M,Alvarez FA,Giunta D.Interstage assessment of remnant liver function in alpps using hepatobiliary scintigraphy: prediction of posthepatectomy liver failure and introduction of the HIBA index..Ann Surg2018;267:1141-7

[13] Serenari M,Bonatti C,Odaldi F.Hepatobiliary scintigraphy in the preoperative evaluation of potential living liver donors..Transplant Proc2019;51:167-70

[14] Cucchetti A,Golfieri R,Renzulli M.Hepatic venous pressure gradient in the preoperative assessment of patients with resectable hepatocellular carcinoma..J Hepatol2016;64:79-86

[15] Qi X,Li Z,Xiang Y.HVPG signature: A prognostic and predictive tool in hepatocellular carcinoma..Oncotarget2016;7:62789-96 PMCID:PMC5308766

[16] Cescon M,Cucchetti A,Montrone L.Value of transient elastography measured with FibroScan in predicting the outcome of hepatic resection for hepatocellular carcinoma..Ann Surg2012;256:706-12

[17] Torzilli G,Kokudo N,Capussotti L.Reply to Letter: “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”: when the study setting “ignores” the patients..Ann Surg2015;262:e30-1

[18] Imamura H,Tanaka E,Hasegawa K.Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy..J Hepatol2003;38:200-7

[19] Meniconi RL,Perdigao F,Soubrane O.Recurrent hepatocellular carcinoma: a Western strategy that emphasizes the impact of pathologic profile of the first resection..Surgery2015;157:454-62

[20] Ercolani G,Ravaioli M,Gardini A.Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence..Ann Surg2003;237:536-43 PMCID:PMC1514472

[21] Xing H,Cescon M,Li C.Defining and predicting early recurrence after liver resection of hepatocellular carcinoma: a multi-institutional study..HPB (Oxford)2019;

[22] Joliat GR,Labgaa I,Halkic N.Treatment and outcomes of recurrent hepatocellular carcinomas..Langenbecks Arch Surg2017;402:737-44

[23] Erridge S,Markar SR,Athanasiou T.Meta-analysis of determinants of survival following treatment of recurrent hepatocellular carcinoma..Br J Surg2017;104:1433-42

[24] Wu CC,Yeh DC,P’eng FK.Second and third hepatectomies for recurrent hepatocellular carcinoma are justified..Br J Surg2009;96:1049-57

[25] Imamura H,Tanaka E,Hasegawa K.Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy..J Hepatol2003;38:200-7

[26] Tabrizian P,Shrager B,Roayaie S.Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis..Ann Surg2015;261:947-55

[27] Nagasue N,Ogawa Y,Chang YC.Second hepatic resection for recurrent hepatocellular carcinoma..Br J Surg1986;73:434-8

[28] Hu RH,Yu SC,Sheu JC.Surgical resection for recurrent hepatocellular carcinoma: prognosis and analysis of risk factors..Surgery1996;120:23-9

[29] Lee PH,Tsang YM,Sheu JC.Clinical management of recurrent hepatocellular carcinoma..Ann Surg1995;222:670-6 PMCID:PMC1234995

[30] Shimada M,Taguchi K,Gion T.Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma..Ann Surg1998;227:80-5 PMCID:PMC1191176

[31] Sun HC,Ma ZC,Wang L.The prognostic factor for outcome following second resection for intrahepatic recurrence of hepatocellular carcinoma with a hepatitis B virus infection background..J Cancer Res Clin Oncol2005;131:284-8

[32] Huang ZY,Xiong M,Wei S.Long-term outcomes of repeat hepatic resection in patients with recurrent hepatocellular carcinoma and analysis of recurrent types and their prognosis: a single-center experience in China..Ann Surg Oncol2012;19:2515-25

[33] Minagawa M,Takayama T.Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma..Ann Surg2003;238:703-10 PMCID:PMC1356149

[34] Roayaie S,Tarchi P,Schwartz M.Second hepatic resection for recurrent hepatocellular cancer: a Western experience..J Hepatol2011;55:346-50

[35] Zou Q,Wu D,Wan X.Nomograms for pre-operative and post-operative prediction of long-term survival of patients who underwent repeat hepatectomy for recurrent hepatocellular carcinoma..Ann Surg Oncol2016;23:2618-26

[36] Chan DL,Chua TC.Clinical efficacy and predictors of outcomes of repeat hepatectomy for recurrent hepatocellular carcinoma - a systematic review..Surg Oncol2013;22:e23-30

[37] Huang ZY,Xiong M,Wei S.Long-term outcomes of repeat hepatic resection in patients with recurrent hepatocellular carcinoma and analysis of recurrent types and their prognosis: a single-center experience in China..Ann Surg Oncol2012;19:2515-25

[38] Faber W,Neuhaus P,Denecke T.Repeated liver resection for recurrent hepatocellular carcinoma..J Gastroenterol Hepatol2011;26:1189-94

[39] Kubo S,Uenishi T,Ohba K.Second hepatic resection for recurrent hepatocellular carcinoma in patients with chronic hepatitis C..World J Surg2008;32:632-8

[40] Itamoto T,Amano H,Ohdan H.Repeat hepatectomy for recurrent hepatocellular carcinoma..Surgery2007;141:589-97

[41] Tralhão JG,Lino T,Franco D.Treatment of tumour recurrence after resection of hepatocellular carcinoma. Analysis of 97 consecutive patients..Eur J Surg Oncol2007;33:746-51

[42] Kobayashi A,Miyagawa S,Noike T.Results of 404 hepatic resections including 80 repeat hepatectomies for hepatocellular carcinoma..Hepatogastroenterology2006;53:736-41

[43] Sugimachi K,Tanaka S,Sugimachi K.Repeat hepatectomy is the most useful treatment for recurrent hepatocellular carcinoma..J Hepatobiliary Pancreat Surg2001;8:410-6

[44] Hu RH,Yu SC,Sheu JC.Surgical resection for recurrent hepatocellular carcinoma: prognosis and analysis of risk factors..Surgery1996;120:23-9

[45] Cai W,Xiao Y,Tang D.Comparison of clinical outcomes of laparoscopic versus open surgery for recurrent hepatocellular carcinoma: a meta-analysis..Surg Endosc2019;33:3550-7

[46] Halls MC,Cipriani F,Lainas P.Development and validation of a difficulty score to predict intraoperative complications during laparoscopic liver resection..Br J Surg2018;105:1182-91

[47] Majno PE,Mentha G.Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis..Hepatology2000;31:899-906

[48] Kostakis ID,Prodromidou A,Garoufalia Z.Comparison between salvage liver transplantation and repeat liver resection for recurrent hepatocellular carcinoma: a systematic review and meta-analysis..Transplant Proc2019;51:433-6

[49] Lim C,Hasegawa K,Salloum C.Salvage liver transplantation or repeat hepatectomy for recurrent hepatocellular carcinoma: An intent-to-treat analysis..Liver Transpl2017;23:1553-63

[50] Adam R,Castaing D,Pascal G.Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy?.Ann Surg2003;238:508-18 PMCID:PMC1360109

[51] Wang HL,Zhong JH,Wu FX.Systematic review of treatment strategy for recurrent hepatocellular carcinoma: Salvage liver transplantation or curative locoregional therapy..Medicine (Baltimore)2019;98:e14498 PMCID:PMC6408068

[52] Lucidi V,Moreno C.Liver transplantation in the context of organ shortage: toward extension and restriction of indications considering recent clinical data and ethical framework..Curr Opin Crit Care2015;21:163-70

[53] Taura K,Hatano E,Uyama N.Implication of frequent local ablation therapy for intrahepatic recurrence in prolonged survival of patients with hepatocellular carcinoma undergoing hepatic resection: an analysis of 610 patients over 16 years old..Ann Surg2006;244:265-73 PMCID:PMC1602154

[54] Lü MD,Liang LJ,Peng BG.Surgical resection versus percutaneous thermal ablation for early-stage hepatocellular carcinoma: a randomized clinical trial..Zhonghua Yi Xue Za Zhi2006;86:801-5(in Chinese)

[55] Chen MS,Zheng Y,Liang HH.A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma..Ann Surg2006;243:321-8 PMCID:PMC1448947

[56] Chan AC,Cheung TT,Chan SC.Survival analysis of re-resection versus radiofrequency ablation for intrahepatic recurrence after hepatectomy for hepatocellular carcinoma..World J Surg2012;36:151-6 PMCID:PMC3243850

[57] Gavriilidis P,Azoulay D.Survival following redo hepatectomy vs radiofrequency ablation for recurrent hepatocellular carcinoma: a systematic review and meta-analysis..HPB (Oxford)2017;19:3-9

[58] Thomasset SC,Garcea G.Ablation for recurrent hepatocellular carcinoma: a systematic review of clinical efficacy and prognostic factors..World J Surg2015;39:1150-60

[59] Wang K,Li J,Xia Y.Early intrahepatic recurrence of hepatocellular carcinoma after hepatectomy treated with re-hepatectomy, ablation or chemoembolization: a prospective cohort study..Eur J Surg Oncol2015;41:236-42

[60] Malagari K,Chatzimichail K,Koskinas J.Transcatheter chemoembolization in the treatment of HCC in patients not eligible for curative treatments: midterm results of doxorubicin-loaded DC bead..Abdom Imaging2008;33:512-9

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

[62] Jin YJ,Lee OH,Kim YS.Transarterial chemoembolization versus surgery/radiofrequency ablation for recurrent hepatocellular carcinoma with or without microvascular invasion..J Gastroenterol Hepatol2014;29:1056-64

[63] Takayasu K,Ikai I,Matsuyama Y.Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis..AJR Am J Roentgenol2010;194:830-7

[64] Erridge S,Markar SR,Athanasiou T.Meta-analysis of determinants of survival following treatment of recurrent hepatocellular carcinoma..Br J Surg2017;104:1433-42

[65] Llovet JM,Mazzaferro V,Gane E.Sorafenib in advanced hepatocellular carcinoma..N Engl J Med2008;359:378-90

[66] Bruix J,Merle P,Huang YH.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

[67] Kudo M,Qin S,Ikeda K.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial..Lancet2018;391:1163-73

[68] Kumar M.Role of supportive care for terminal stage hepatocellular carcinoma..J Clin Exp Hepatol2014;4:S130-9 PMCID:PMC4284220