Adjuvant treatment strategy after curative resection for hepatocellular carcinoma

Abstract

Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.

Keywords

hepatocellular carcinoma / adjuvant treatment / hepatic resection / recurrence

References

[1] International Agency for Research on Cancer, World Health Organization. Cancer today. accessed May 1, 2020)

[2] Global Burden of Disease Liver Cancer Collaboration; Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MS, Fischer F, Fürst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M, Nagel G, Nguyen Q, Nguyen G, Ogbo F, Patton G, Pereira DM, Pourmalek F, Qorbani M, Radfar A, Roshandel G, Salomon JA, Sanabria J, Sartorius B, Satpathy M, Sawhney M, Sepanlou S, Shackelford K, Shore H, Sun J, Mengistu DT, Topór-Mądry R, Tran B, Ukwaja KN, Vlassov V, Vollset SE, Vos T, Wakayo T, Weiderpass E, Werdecker A, Yonemoto N, Younis M, Yu C, Zaidi Z, Zhu L, Murray CJL, Naghavi M, Fitzmaurice C. 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 Oncol 2017; 3(12): 1683–1691

[3] Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115–132

[4] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017; 67(1): 7–30

[5] O’Leary C, Mahler M, Soulen MC. Curative-intent therapies in localized hepatocellular carcinoma. Curr Treat Options Oncol 2020; 21(4): 31

[6] Asham EH, Kaseb A, Ghobrial RM. Management of hepatocellular carcinoma. Surg Clin North Am 2013; 93(6): 1423–1450

[7] Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, Sugawara Y, Minagawa M, Takayama T, Kawasaki S, Makuuchi M. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003; 38(2): 200–207

[8] Ercolani G, Grazi GL, Ravaioli M, Del Gaudio M, Gardini A, Cescon M, Varotti G, Cetta F, Cavallari A. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003; 237(4): 536–543

[9] Kubo S, Hirohashi K, Tanaka H, Tsukamoto T, Shuto T, Yamamoto T, Ikebe T, Wakasa K, Nishiguchi S, Kinoshita H. Effect of viral status on recurrence after liver resection for patients with hepatitis B virus-related hepatocellular carcinoma. Cancer 2000; 88(5): 1016–1024

[10] Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, Huo TI, Sheen IJ, Lee SD, Lui WY. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009; 51(5): 890–897

[11] Huang G, Lau WY, Wang ZG, Pan ZY, Yuan SX, Shen F, Zhou WP, Wu MC. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial. Ann Surg 2015; 261(1): 56–66

[12] Huang G, Li PP, Lau WY, Pan ZY, Zhao LH, Wang ZG, Wang MC, Zhou WP. Antiviral therapy reduces hepatocellular carcinoma recurrence in patients with low HBV-DNA levels: a randomized controlled trial. Ann Surg 2018; 268(6): 943–954

[13] Huang L, Li J, Yan J, Sun J, Zhang X, Wu M, Yan Y. Antiviral therapy decreases viral reactivation in patients with hepatitis B virus-related hepatocellular carcinoma undergoing hepatectomy: a randomized controlled trial. J Viral Hepat 2013; 20(5): 336–342

[14] Yin J, Li N, Han Y, Xue J, Deng Y, Shi J, Guo W, Zhang H, Wang H, Cheng S, 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 Oncol 2013; 31(29): 3647–3655

[15] Chen LT, Jeng LB, Hsiao CF, Wu CC, Lee WC, Wang TE, Lee PH, Chen CL, Chen IS, Lee KT, Hsieh CB, Hwang WS, Yang MD, Yang YS, Lin DY, Chen MF, Chen PJ. Randomized, phase III trial of adjuvant adeforvir vs. therapeutic lamivudine in post-operative BCLC stage 0 or A HBV-related HCC: the Taiwan Cooperative Oncology Group T1206 study. J Clin Oncol 2015; 33(15_suppl): 4101

[16] Zhang G, Yu X, Liu P, Huang X, Jiang X. Efficacy of nucleoside analogs for chronic hepatitis B virus-related hepatocellular carcinoma after curative treatment: a meta-analysis. Dig Dis Sci 2018; 63(12): 3207–3219

[17] Chen XX, Cheng JW, Huang A, Zhang X, Wang J, Fan J, Zhou J, Yang XR. The effect of antiviral therapy on patients with hepatitis B virus-related hepatocellular carcinoma after curative resection: a systematic review and meta-analysis. OncoTargets Ther 2017; 10: 5363–5375

[18] Yuan P, Chen P, Qian Y. Evaluation of antiviral therapy performed after curative therapy in patients with HBV-related hepatocellular carcinoma: an updated meta-analysis. Can J Gastroenterol Hepatol 2016; 2016: 5234969

[19] Liu GM, Huang XY, Shen SL, Hu WJ, Peng BG. Adjuvant antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after curative treatment: a systematic review and meta-analysis. Hepatol Res 2016; 46(1): 100–110

[20] Xia BW, Zhang YC, Wang J, Ding FH, He XD. Efficacy of antiviral therapy with nucleotide/nucleoside analogs after curative treatment for patients with hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2015; 39(4): 458–468

[21] Zhou Y, Zhang Z, Zhao Y, Wu L, Li B. Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis. World J Surg 2014; 38(9): 2395–2402

[22] Qu LS, Liu JX, Kuai XL, Xu ZF, Jin F, Zhou GX. Significance of viral status on recurrence of hepatitis B-related hepatocellular carcinoma after curative therapy: a meta-analysis. Hepatol Res 2014; 44(7): 750–760

[23] Wong JS, Wong GL, Tsoi KK, Wong VW, Cheung SY, Chong CN, Wong J, Lee KF, Lai PB, Chan HL. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2011; 33(10): 1104–1112

[24] Mo HY, Xiang BD, Zhong JH, Li LQ, You XM. Comment on “Evaluation of Antiviral Therapy Performed after Curative Therapy in Patients with HBV-Related Hepatocellular Carcinoma: An Updated Meta-Analysis”. Can J Gastroenterol Hepatol 2016; 2016: 7625982

[25] Yu LH, Li N, Shi J, Guo WX, Wu MC, Cheng SQ. Does anti-HBV therapy benefit the prognosis of HBV-related hepatocellular carcinoma following hepatectomy? Ann Surg Oncol 2014; 21(3): 1010–1015

[26] Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, Chayama K, Murashima N, Kumada H. Interferon β prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor—a prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000; 32(2): 228–232

[27] Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita H. Randomized clinical trial of long-term outcome after resection of hepatitis C virus-related hepatocellular carcinoma by postoperative interferon therapy. Br J Surg 2002; 89(4): 418–422

[28] Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G, Tagger A, Colombo M, Bonino F, Majno P, Llovet JM;. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 2006; 44(6): 1543–1554

[29] Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, Zhou XD, Zhou J, Qiu SJ, Shen YF. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol 2006; 132(7): 458–465

[30] Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, Fan ST, Wong J. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007; 245(6): 831–842

[31] Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL, Lee WC, Chau GY, Chen YS, Lui WY, Hsiao CF, Whang-Peng J, Chen PJ; Disease Committee of Adjuvant Therapy for Postoperative Hepatocellular Carcinoma, Taiwan Cooperative Oncology Group, Health Research Institutes, Zhunan, Taiwan, China. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg 2012; 255(1): 8–17

[32] Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Mullhaupt B, Clavien PA. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009; 96(9): 975–981

[33] Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma. J Viral Hepat 2010; 17(4): 287–292

[34] Shen YC, Hsu C, Chen LT, Cheng CC, Hu FC, Cheng AL. Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol 2010; 52(6): 889–894

[35] Singal AK, Freeman DH Jr, Anand BS. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Aliment Pharmacol Ther 2010; 32(7): 851–858

[36] Miao RY, Zhao HT, Yang HY, Mao YL, Lu X, Zhao Y, Liu CN, Zhong SX, Sang XT, Huang JF. Postoperative adjuvant antiviral therapy for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis. World J Gastroenterol 2010; 16(23): 2931–2942

[37] Jiang S, Liu Y, Wang L, Duan C, Liu M. A meta-analysis and systematic review: adjuvant interferon therapy for patients with viral hepatitis-related hepatocellular carcinoma. World J Surg Oncol 2013; 11(1): 240

[38] Wang J, He XD, Yao N, Liang WJ, Zhang YC. A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can J Gastroenterol 2013; 27(6): 351–363

[39] Huang TS, Shyu YC, Chen HY, Yuan SS, Shih JN, Chen PJ. A systematic review and meta-analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis-related hepatocellular carcinoma. J Viral Hepat 2013; 20(10): 729–743

[40] Xu JB, Qi FZ, Xu G, Chen GF, Huang MD, Zhang JH. Adjuvant interferon therapy after surgical treatment for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis. Hepatol Res 2014; 44(2): 209–217

[41] Zhuang L, Zeng X, Yang Z, Meng Z. Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One 2013; 8(9): e61361

[42] Xu J, Li J, Chen J, Liu ZJ. Effect of adjuvant interferon therapy on hepatitis B/C virus-related hepatocellular carcinoma after curative therapy—meta-analysis. Adv Clin Exp Med 2015; 24(2): 331–340

[43] Wu J, Yin Z, Cao L, Xu X, Yan T, Liu C, Li D. Adjuvant pegylated interferon therapy improves the survival outcomes in patients with hepatitis-related hepatocellular carcinoma after curative treatment: a meta-analysis. Medicine (Baltimore) 2018; 97(28): e11295

[44] Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI, Su F, Berry K. Effectiveness of sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir and dasabuvir regimens for treatment of patients with hepatitis C in the Veterans Affairs National Health Care System. Gastroenterology 2016; 151(3): 457–471.e5

[45] Calleja JL, Crespo J, Rincón D, Ruiz-Antorán B, Fernandez I, Perelló C, Gea F, Lens S, García-Samaniego J, Sacristán B, García-Eliz M, Llerena S, Pascasio JM, Turnes J, Torras X, Morillas RM, Llaneras J, Serra MA, Diago M, Rodriguez CF, Ampuero J, Jorquera F, Simon MA, Arenas J, Navascues CA, Bañares R, Muñoz R, Albillos A, Mariño Z; Spanish Group for the Study of the Use of Direct-acting Drugs Hepatitis C Collaborating Group. Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real-world cohort. J Hepatol 2017; 66(6): 1138–1148

[46] Fox DS, McGinnis JJ, Tonnu-Mihara IQ, McCombs JS. Comparative treatment effectiveness of direct acting antiviral regimens for hepatitis C: data from the Veterans Administration. J Gastroenterol Hepatol 2017; 32(6): 1136–1142

[47] Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, Díaz A, Vilana R, Darnell A, Varela M, Sangro B, Calleja JL, Forns X, Bruix J. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65(4): 719–726

[48] Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65(4): 727–733

[49] Yang JD, Aqel BA, Pungpapong S, Gores GJ, Roberts LR, Leise MD. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol 2016; 65(4): 859–860

[50] ANRS Collaborative Study Group on Hepatocellular Carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J Hepatol 2016; 65(4): 734–740

[51] Singal AG, Rich NE, Mehta N, Branch AD, Pillai A, Hoteit M, Volk M, Odewole M, Scaglione S, Guy J, Said A, Feld JJ, John BV, Frenette C, Mantry P, Rangnekar AS, Oloruntoba O, Leise M, Jou JH, Bhamidimarri KR, Kulik L, Ioannou GN, Huang A, Tran T, Samant H, Dhanasekaran R, Duarte-Rojo A, Salgia R, Eswaran S, Jalal P, Flores A, Satapathy SK, Kagan S, Gopal P, Wong R, Parikh ND, Murphy CC. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 2019; 157(5): 1253–1263.e2

[52] Cabibbo G, Celsa C, Calvaruso V, Petta S, Cacciola I, Cannavò MR, Madonia S, Rossi M, Magro B, Rini F, Distefano M, Larocca L, Prestileo T, Malizia G, Bertino G, Benanti F, Licata A, Scalisi I, Mazzola G, Di Rosolini MA, Alaimo G, Averna A, Cartabellotta F, Alessi N, Guastella S, Russello M, Scifo G, Squadrito G, Raimondo G, Trevisani F, Craxì A, Di Marco V, Cammà C; Rete Sicilia Selezione Terapia – HCV (RESIST-HCV) and Italian Liver Cancer (ITA.LI.CA.) Group. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J Hepatol 2019; 71(2): 265–273

[53] Izumi R, Shimizu K, Iyobe T, Ii T, Yagi M, Matsui O, Nonomura A, Miyazaki I. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 1994; 20(2): 295–301

[54] Li JQ, Zhang YQ, Zhang WZ, Yuan YF, Li GH. Randomized study of chemoembolization as an adjuvant therapy for primary liver carcinoma after hepatectomy. J Cancer Res Clin Oncol 1995; 121(6): 364–366

[55] Li Q, Wang J, Sun Y, Cui YL, Juzi JT, Qian BY, Hao XS. Postoperative transhepatic arterial chemoembolization and portal vein chemotherapy for patients with hepatocellular carcinoma: a randomized study with 131 cases. Dig Surg 2006; 23(4): 235–240

[56] Zhong C, Guo RP, Li JQ, Shi M, Wei W, Chen MS, Zhang YQ. A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage III A hepatocellular carcinoma. J Cancer Res Clin Oncol 2009; 135(10): 1437–1445

[57] Peng BG, He Q, Li JP, Zhou F. Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Surg 2009; 198(3): 313–318

[58] Wei W, Jian PE, Li SH, Guo ZX, Zhang YF, Ling YH, Lin XJ, Xu L, Shi M, Zheng L, Chen MS, Guo RP. Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety. Cancer Commun (Lond) 2018; 38(1): 61

[59] Wang Z, Ren Z, Chen Y, Hu J, Yang G, Yu L, Yang X, Huang A, Zhang X, Zhou S, Sun H, Wang Y, Ge N, Xu X, Tang Z, Lau W, Fan J, Wang J, Zhou J. Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin Cancer Res 2018; 24(9): 2074–2081

[60] Chen W, Ma T, Zhang J, Zhang X, Chen W, Shen Y, Bai X, Liang T. A systematic review and meta-analysis of adjuvant transarterial chemoembolization after curative resection for patients with hepatocellular carcinoma. HPB (Oxford) 2020; 22(6): 795–808

[61] Liao M, Zhu Z, Wang H, Huang J. Adjuvant transarterial chemoembolization for patients after curative resection of hepatocellular carcinoma: a meta-analysis. Scand J Gastroenterol 2017; 52(6-7): 624–634

[62] Qi X, Liu L, Wang D, Li H, Su C, Guo X. Hepatic resection alone versus in combination with pre- and post-operative transarterial chemoembolization for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 2015; 6(34): 36838–36859

[63] Cheng X, Sun P, Hu QG, Song ZF, Xiong J, Zheng QC. Transarterial (chemo)embolization for curative resection of hepatocellular carcinoma: a systematic review and meta-analyses. J Cancer Res Clin Oncol 2014; 140(7): 1159–1170

[64] Zhong JH, Li LQ. Postoperative adjuvant transarterial chemoembolization for participants with hepatocellular carcinoma: a meta-analysis. Hepatol Res 2010; 40(10): 943–953

[65] Peng ZW, Guo RP, Zhang YJ, Lin XJ, Chen MS, Lau WY. Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2012; 118(19): 4725–4736

[66] Yang T, Lin C, Zhai J, Shi S, Zhu M, Zhu N, Lu JH, Yang GS, Wu MC. Surgical resection for advanced hepatocellular carcinoma according to Barcelona Clinic Liver Cancer (BCLC) staging. J Cancer Res Clin Oncol 2012; 138(7): 1121–1129

[67] Chen XP, Qiu FZ, Wu ZD, Zhang ZW, Huang ZY, Chen YF, Zhang BX, He SQ, Zhang WG. Effects of location and extension of portal vein tumor thrombus on long-term outcomes of surgical treatment for hepatocellular carcinoma. Ann Surg Oncol 2006; 13(7): 940–946

[68] Liu S, Guo L, Li H, Zhang B, Sun J, Zhou C, Zhou J, Fan J, Ye Q. Postoperative adjuvant trans-arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg Oncol 2018; 25(7): 2098–2104

[69] Zhang XP, Liu YC, Chen ZH, Sun JX, Wang K, Chai ZT, Shi J, Guo WX, Wu MC, Lau WY, Cheng SQ. Postoperative adjuvant transarterial chemoembolization improves outcomes of hepatocellular carcinoma associated with hepatic vein invasion: a propensity score matching analysis. Ann Surg Oncol 2019; 26(5): 1465–1473

[70] Shen A, Liu M, Zheng D, Chen Q, Wu Z. Adjuvant transarterial chemoembolization after curative hepatectomy for hepatocellular carcinoma with microvascular invasion: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2020; 44(2): 142–154

[71] Li L, Li B, Zhang M. Postoperative adjuvant transarterial chemoembolization improves the prognosis of hepatocellular carcinoma patients with microvascular invasion: a systematic review and meta-analysis. Acta Radiol 2020; 61(6): 723–731

[72] Chen ZH, Zhang XP, Zhou TF, Wang K, Wang H, Chai ZT, Shi J, Guo WX, Cheng SQ. Adjuvant transarterial chemoembolization improves survival outcomes in hepatocellular carcinoma with microvascular invasion: a systematic review and meta-analysis. Eur J Surg Oncol 2019; 45(11): 2188–2196

[73] Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, Cai J, Poon RT, Han KH, Tak WY, Lee HC, Song T, Roayaie S, Bolondi L, Lee KS, Makuuchi M, Souza F, Berre MA, Meinhardt G, Llovet JM; theSTORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015; 16(13): 1344–1354

[74] Antoniou EA, Margonis GA, Amini N, Anastasiou M, Angelou A, Kim Y, Kouraklis G. Sorafenib as an adjuvant therapy for resectable hepatocellular carcinoma: a single center experience. J BUON 2016; 21(5): 1189–1194

[75] Wang SN, Chuang SC, Lee KT. Efficacy of sorafenib as adjuvant therapy to prevent early recurrence of hepatocellular carcinoma after curative surgery: a pilot study. Hepatol Res 2014; 44(5): 523–531

[76] Li J, Hou Y, Cai XB, Liu B. Sorafenib after resection improves the outcome of BCLC stage C hepatocellular carcinoma. World J Gastroenterol 2016; 22(15): 4034–4040

[77] Xia F, Wu LL, Lau WY, Huan HB, Wen XD, Ma KS, Li XW, Bie P. Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients. World J Gastroenterol 2016; 22(23): 5384–5392

[78] Liao Y, Zheng Y, He W, Li Q, Shen J, Hong J, Zou R, Qiu J, Li B, Yuan Y. Sorafenib therapy following resection prolongs disease-free survival in patients with advanced hepatocellular carcinoma at a high risk of recurrence. Oncol Lett 2017; 13(2): 984–992

[79] Zhuang L, Wen T, Xu M, Yang J, Wang W, Wu H, Zeng Y, Yan L, Wei Y, Li B. Sorafenib combined with hepatectomy in patients with intermediate-stage and advanced hepatocellular carcinoma. Arch Med Sci 2017; 13(6): 1383–1393

[80] Huang Y, Zhang Z, Zhou Y, Yang J, Hu K, Wang Z. Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy? OncoTargets Ther 2019; 12: 541–548

[81] Li Z, Gao J, Zheng SM, Wang Y, Xiang X, Cheng Q, Zhu J. The efficacy of sorafenib in preventing hepatocellular carcinoma recurrence after resection: a systematic review and meta-analysis. Rev Esp Enferm Dig 2020; 112(3): 201–210

[82] Hong YP, Li ZD, Prasoon P, Zhang Q. Immunotherapy for hepatocellular carcinoma: from basic research to clinical use. World J Hepatol 2015; 7(7): 980–992

[83] Kawata A, Une Y, Hosokawa M, Wakizaka Y, Namieno T, Uchino J, Kobayashi H. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin 2, and lymphokineactivated killer cells versus adriamycin alone. Am J Clin Oncol 1995; 18(3): 257–262

[84] Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356(9232): 802–807

[85] Hui D, Qiang L, Jian W, Ti Z, Da-Lu K. A randomized, controlled trial of postoperative adjuvant cytokineinduced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 2009; 41(1): 36–41

[86] Yu X, Zhao H, Liu L, Cao S, Ren B, Zhang N, An X, Yu J, Li H, Ren X. A randomized phase II study of autologous cytokineinduced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol 2014; 34(2): 194–203

[87] Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Adjuvant immunotherapy with autologous cytokineinduced killer cells for hepatocellular carcinoma. Gastroenterology 2015; 148(7): 1383–1391.e6

[88] Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. Cancer Immunol Immunother 2019; 68(1): 23–32

[89] Xu L, Wang J, Kim Y, Shuang ZY, Zhang YJ, Lao XM, Li YQ, Chen MS, Pawlik TM, Xia JC, Li SP, Lau WY. A randomized controlled trial on patients with or without adjuvant autologous cytokineinduced killer cells after curative resection for hepatocellular carcinoma. OncoImmunology 2016; 5(3): e1083671

[90] Zhao H, Zheng M, Wang K, Wang L, He H, Wang M, Shi Y, Huang S, Ji F, Li X, Zhu H, Wang L, Zhang X, Shi X, Zhao S, Fu B, Wu T. A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Cancer Res Ther 2018; 14(4): 807–814

[91] Mo HY, Liao YY, You XM, Cucchetti A, Yuan BH, Li RH, Zhong JH, Li LQ. Timely meta-analysis on the efficacy of adoptive immunotherapy for hepatocellular carcinoma patients after curative therapy. PLoS One 2017; 12(3): e0174222

[92] Yuan BH, Li RH, Yuan WP, Yang T, Tong TJ, Peng NF, Li LQ, Zhong JH. Harms and benefits of adoptive immunotherapy for postoperative hepatocellular carcinoma: an updated review. Oncotarget 2017; 8(11): 18537–18549

[93] Kuang M, Peng BG, Lu MD, Liang LJ, Huang JF, He Q, Hua YP, Totsuka S, Liu SQ, Leong KW, Ohno T. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 2004; 10(5): 1574–1579

[94] Lee JH, Tak WY, Lee Y, Heo MK, Song JS, Kim HY, Park SY, Bae SH, Lee JH, Heo J, Kim KH, Bae YS, Kim YJ. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. OncoImmunology 2017; 6(7): e1328335

[95] Shimizu K, Kotera Y, Aruga A, Takeshita N, Katagiri S, Ariizumi S, Takahashi Y, Yoshitoshi K, Takasaki K, Yamamoto M. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma. Hum Vaccin Immunother 2014; 10(4): 970–976

[96] Harding JJ, El Dika I, Abou-Alfa GK. Immunotherapy in hepatocellular carcinoma: primed to make a difference? Cancer 2016; 122(3): 367–377

[97] Nakano S, Eso Y, Okada H, Takai A, Takahashi K, Seno H. Recent advances in immunotherapy for hepatocellular carcinoma. Cancers (Basel) 2020; 12(4): E775

[98] Yamamoto M, Arii S, Sugahara K, Tobe T. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Br J Surg 1996; 83(3): 336–340

[99] Hasegawa K, Takayama T, Ijichi M, Matsuyama Y, Imamura H, Sano K, Sugawara Y, Kokudo N, Makuuchi M. Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial. Hepatology 2006; 44(4): 891–895

[100] Xia Y, Qiu Y, Li J, Shi L, Wang K, Xi T, Shen F, Yan Z, Wu M. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 2010; 17(12): 3137–3144

[101] Ishizuka M, Kubota K, Nemoto T, Shimoda M, Kato M, Iso Y, Tago K. Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: a randomized controlled trial. Asian J Surg 2016; 39(3): 149–154

[102] Zhong J, Xiang B, Ma L, Li L. Conventional oral systemic chemotherapy for postoperative hepatocellular carcinoma: a systematic review. Mol Clin Oncol 2014; 2(6): 1091–1096

[103] Hamada T, Yano K, Wada T, Imamura N, Hiyoshi M, Kondo K, Nanashima A. Increased survival benefit of adjuvant intra-arterial infusion chemotherapy in HCC patients with portal vein infiltration after hepatectomy. World J Surg 2020; 44(8): 2770–2776

[104] Hatano E, Uemoto S, Yamaue H, Yamamoto M; the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Significance of hepatic resection and adjuvant hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein tumor thrombus in the first branch of portal vein and the main portal trunk: a project study for hepatic surgery of the Japanese Society of Hepato–Biliary–Pancreatic Surgery. J Hepatobiliary Pancreat Sci 2018; 25(9): 395–402

[105] Hsiao JH, Tsai CC, Liang TJ, Chiang CL, Liang HL, Chen IS, Chen YC, Chang PM, Chou NH, Wang BW. Adjuvant hepatic arterial infusion chemotherapy is beneficial for selective patients with hepatocellular carcinoma undergoing surgical treatment. Int J Surg 2017; 45: 35–41

[106] Nitta H, Beppu T, Imai K, Hayashi H, Chikamoto A, Baba H. Adjuvant hepatic arterial infusion chemotherapy after hepatic resection of hepatocellular carcinoma with macroscopic vascular invasion. World J Surg 2013; 37(5): 1034–1042

[107] Nagano H, Kobayashi S, Marubashi S, Wada H, Eguchi H, Tanemura M, Tomimaru Y, Umeshita K, Doki Y, Mori M. Combined IFN-a and 5-FU treatment as a postoperative adjuvant following surgery for hepatocellular carcinoma with portal venous tumor thrombus. Exp Ther Med 2013; 5(1): 3–10

[108] Niguma T, Mimura T, Tutui N. Adjuvant arterial infusion chemotherapy after resection of hepatocellular carcinoma with portal thrombosis: a pilot study. J Hepatobiliary Pancreat Surg 2005; 12(3): 249–253

[109] Moran A, Ramos LF, Picado O, Pendola F, Sleeman D, Dudeja V, Merchant N, Yakoub D. Hepatocellular carcinoma: resection with adjuvant hepatic artery infusion therapy vs resection alone. A systematic review and meta-analysis. J Surg Oncol 2019; 119(4): 455–463

[110] Lau WY, Leung TW, Ho SK, Chan M, Machin D, Lau J, Chan AT, Yeo W, Mok TS, Yu SC, Leung NW, Johnson PJ. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999; 353(9155): 797–801

[111] Lau WY, Lai EC, Leung TW, Yu SC. Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival. Ann Surg 2008; 247(1): 43–48

[112] Partensky C, Sassolas G, Henry L, Paliard P, Maddern GJ. Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study. Arch Surg 2000; 135(11): 1298–1300

[113] Boucher E, Corbinais S, Rolland Y, Bourguet P, Guyader D, Boudjema K, Meunier B, Raoul JL. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology 2003; 38(5): 1237–1241

[114] Chua TC, Saxena A, Chu F, Butler SP, Quinn RJ, Glenn D, Morris DL. Hepatic resection with or without adjuvant iodine-131-lipiodol for hepatocellular carcinoma: a comparative analysis. Int J Clin Oncol 2011; 16(2): 125–132

[115] Tabone M, Vigano’ L, Ferrero A, Pellerito R, Carbonatto P, Capussotti L. Prevention of intrahepatic recurrence by adjuvant (131)iodine-labeled lipiodol after resection for hepatocellular carcinoma in HCV-related cirrhosis. Eur J Surg Oncol 2007; 33(1): 61–66

[116] Chung AY, Ooi LL, Machin D, Tan SB, Goh BK, Wong JS, Chen YM, Li PC, Gandhi M, Thng CH, Yu SW, Tan BS, Lo RH, Htoo AM, Tay KH, Sundram FX, Goh AS, Chew SP, Liau KH, Chow PK, Tay KH, Tan YM, Cheow PC, Ho CK, Soo KC. Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. World J Surg 2013; 37(6): 1356–1361

[117] Furtado RV, Ha L, Clarke S, Sandroussi C. Adjuvant iodine (131) lipiodol after resection of hepatocellular carcinoma. J Oncol 2015; 2015: 746917

[118] Gong L, Shi L, Sun J, Yuan WS, Chen JF, Liu P, Gong F, Dong JH. Comparative survival analysis of adjuvant therapy with iodine-131-labeled lipiodol to hepatic resection of primary hepatocellular carcinoma: a meta-analysis. Nucl Med Commun 2014; 35(5): 484–492

[119] Furtado R, Crawford M, Sandroussi C. Systematic review and meta-analysis of adjuvant I¹³¹ lipiodol after excision of hepatocellular carcinoma. Ann Surg Oncol 2014; 21(8): 2700–2707

[120] Hong Y, Wu LP, Ye F, Zhou YM. Adjuvant intrahepatic injection iodine-131-lipiodol improves prognosis of patients with hepatocellular carcinoma after resection: a meta-analysis. Indian J Surg 2015; 77(Suppl 3): 1227–1232

[121] Chen K, Xia Y, Wang H, Xiao F, Xiang G, Shen F. Adjuvant iodine-125 brachytherapy for hepatocellular carcinoma after complete hepatectomy: a randomized controlled trial. PLoS One 2013; 8(2): e57397

[122] Oh D, Lim DH, Park HC, Paik SW, Koh KC, Lee JH, Choi MS, Yoo BC, Lim HK, Lee WJ, Rhim H, Shin SW, 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 Oncol 2010; 33(4): 370–375

[123] Yoon SM, Lim YS, Won HJ, Kim JH, Kim KM, Lee HC, Chung YH, Lee YS, Lee SG, Park JH, Suh DJ. Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes. Int J Radiat Oncol Biol Phys 2012; 82(5): 2004–2011

[124] Yu W, Wang W, Rong W, Wang L, Xu Q, Wu F, Liu L, Wu J. Adjuvant radiotherapy in centrally located hepatocellular carcinomas after hepatectomy with narrow margin (<1 cm): a prospective randomized study. J Am Coll Surg 2014; 218(3): 381–392

[125] Wang L, Wang W, Rong W, Li Z, Wu F, Liu Y, Zheng Y, Zhang K, Siqin T, Liu M, Chen B, Wu J. Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study. BMC Cancer 2020; 20(1): 614

[126] Wang L, Wang W, Yao X, Rong W, Wu F, Chen B, Liu M, Lin S, Liu Y, Wu J. Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion. Oncotarget 2017; 8(45): 79971–79981

[127] Wang L, Chen B, Li Z, Yao X, Liu M, Rong W, Wu F, Lin S, Liu Y, Zheng Y, Li Y, Wang W, Wu J. Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis. OncoTargets Ther 2019; 12: 1237–1247

[128] Sun J, Yang L, Shi J, Liu C, Zhang X, Chai Z, Lau WY, Meng Y, Cheng SQ. Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial. Radiother Oncol 2019; 140: 20–25

[129] Nakamura M, Nagano H, Noda T, Wada H, Ota H, Damdinsuren B, Marubashi S, Miyamoto A, Takeda Y, Doki Y, Umeshita K, Dono K, Sakon M, Monden M. Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-α and fluorouracil in vitro. Hepatol Res 2006; 35(4): 289–295

[130] Jinghe X, Mizuta T, Ozaki I. Vitamin K and hepatocellular carcinoma: the basic and clinic. World J Clin Cases 2015; 3(9): 757–764

[131] Mizuta T, Ozaki I, Eguchi Y, Yasutake T, Kawazoe S, Fujimoto K, Yamamoto K. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Cancer 2006; 106(4): 867–872

[132] Hotta N, Ayada M, Sato K, Ishikawa T, Okumura A, Matsumoto E, Ohashi T, Kakumu S. Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Hepatogastroenterology 2007; 54(79): 2073–2077

[133] Kakizaki S, Sohara N, Sato K, Suzuki H, Yanagisawa M, Nakajima H, Takagi H, Naganuma A, Otsuka T, Takahashi H, Hamada T, Mori M. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. J Gastroenterol Hepatol 2007; 22(4): 518–522

[134] Yoshiji H, Noguchi R, Toyohara M, Ikenaka Y, Kitade M, Kaji K, Yamazaki M, Yamao J, Mitoro A, Sawai M, Yoshida M, Fujimoto M, Tsujimoto T, Kawaratani H, Uemura M, Fukui H. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol 2009; 51(2): 315–321

[135] Yoshida H, Shiratori Y, Kudo M, Shiina S, Mizuta T, Kojiro M, Yamamoto K, Koike Y, Saito K, Koyanagi N, Kawabe T, Kawazoe S, Kobashi H, Kasugai H, Osaki Y, Araki Y, Izumi N, Oka H, Tsuji K, Toyota J, Seki T, Osawa T, Masaki N, Ichinose M, Seike M, Ishikawa A, Ueno Y, Tagawa K, Kuromatsu R, Sakisaka S, Ikeda H, Kuroda H, Kokuryu H, Yamashita T, Sakaida I, Katamoto T, Kikuchi K, Nomoto M, Omata M. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011; 54(2): 532–540

[136] Ishizuka M, Kubota K, Shimoda M, Kita J, Kato M, Park KH, Shiraki T. Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial. Anticancer Res 2012; 32(12): 5415–5420

[137] Hosho K, Okano J, Koda M, Murawaki Y. Vitamin K2 has no preventive effect on recurrence of hepatocellular carcinoma after effective treatment. Yonago Acta Med 2008; 51: 95–99

[138] Zhong JH, Mo XS, Xiang BD, Yuan WP, Jiang JF, Xie GS, Li LQ. Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. PLoS One 2013; 8(3): e58082

[139] Moriwaki H, Muto Y, Ninomiya M, Kawai K, Suzuki Y, Seto T. Inhibitory effects of synthetic acidic retinoid and polyprenoic acid on the development of hepatoma in rats induced by 3-methyl-N,N-dimethyl-4-aminoazobenzene. Gastroenterol Jpn 1988; 23(5): 546–552

[140] Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T, Kojima T; Hepatoma Prevention Study Group. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. N Engl J Med 1996; 334(24): 1561–1568

[141] Takai K, Okuno M, Yasuda I, Matsushima-Nishiwaki R, Uematsu T, Tsurumi H, Shiratori Y, Muto Y, Moriwaki H. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology 2005; 48(1): 39–45

[142] Liu J, Wang S, Zhang Y, Fan HT, Lin HS. Traditional chinese medicine and cancer: history, present situation, and development. Thorac Cancer 2015; 6(5): 561–569

[143] Li L, Ye S, Wang Y, Tang Z. Progress on experimental research and clinical application of Trametes robiniophila. China Cancer (Zhongguo Zhong Liu) 2007; 16(2): 110–113 (in Chinese)

[144] Bao H, Liu P, Jiang K, Zhang X, Xie L, Wang Z, Gong P. Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MaPK. Oncol Lett 2016; 12(2): 1058–1066

[145] Shan L, Li Y, Jiang H, Tao Y, Qian Z, Li L, Cai F, Ma L, Yu Y. Huaier restrains proliferative and migratory potential of hepatocellular carcinoma cells partially through decreased yes-associated protein 1. J Cancer 2017; 8(19): 4087–4097

[146] Li C, Wu X, Zhang H, Yang G, Hao M, Sheng S, Sun Y, Long J, Hu C, Sun X, Li L, Zheng J. A Huaier polysaccharide restrains hepatocellular carcinoma growth and metastasis by suppression angiogenesis. Int J Biol Macromol 2015; 75: 115–120

[147] Chen Q, Shu C, Laurence AD, Chen Y, Peng BG, Zhen ZJ, Cai JQ, Ding YT, Li LQ, Zhang YB, Zheng QC, Xu GL, Li B, Zhou WP, Cai SW, Wang XY, Wen H, Peng XY, Zhang XW, Dai CL, Bie P, Xing BC, Fu ZR, Liu LX, Mu Y, Zhang L, Zhang QS, Jiang B, Qian HX, Wang YJ, Liu JF, Qin XH, Li Q, Yin P, Zhang ZW, Chen XP. Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial. Gut 2018; 67(11): 2006–2016

[148] Zhai XF, Liu XL, Shen F, Fan J, Ling CQ. Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: a randomized controlled study. Cancer 2018; 124(10): 2161–2168

[149] Cabre E, Gonzalez-Huix F, Abad-Lacruz A, Esteve M, Acero D, Fernandez-Bañares F, Xiol X, Gassull MA. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial. Gastroenterology 1990; 98(3): 715–720

[150] No authors listed. Long-term oral administration of branched chain amino acids after curative resection of hepatocellular carcinoma: a prospective randomized trial. The San-in Group of Liver Surgery. Br J Surg 1997; 84(11): 1525–1531

[151] Meng WC, Leung KL, Ho RL, Leung TW, Lau WY. Prospective randomized control study on the effect of branched-chain amino acids in patients with liver resection for hepatocellular carcinoma. Aust N Z J Surg 1999; 69(11): 811–815

[152] Okabayashi T, Iyoki M, Sugimoto T, Kobayashi M, Hanazaki K. Oral supplementation with carbohydrate- and branched-chain amino acid-enriched nutrients improves postoperative quality of life in patients undergoing hepatic resection. Amino Acids 2011; 40(4): 1213–1220

[153] Ichikawa K, Okabayashi T, Maeda H, Namikawa T, Iiyama T, Sugimoto T, Kobayashi M, Mimura T, Hanazaki K. Oral supplementation of branched-chain amino acids reduces early recurrence after hepatic resection in patients with hepatocellular carcinoma: a prospective study. Surg Today 2013; 43(7): 720–726

[154] Joyce JA, Freeman C, Meyer-Morse N, Parish CR, Hahahan D. A functional heparan sulphate mimetic implicates both heparanase and heparan sulphate in tumor angiogenesis in a mouse model of multistage cancer. Oncogene 2005; 24(25): 4037–4051

[155] Liu CJ, Lee PH, Lin DY, Wu CC, Jeng LB, Lin PW, Mok KT, Lee WC, Yeh HZ, Ho MC, Yang SS, Lee CC, Yu MC, Hu RH, Peng CY, Lai KL, Chang SS, Chen PJ. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol 2009; 50(5): 958–968

[156] Liu CJ, Chang J, Lee PH, Lin DY, Wu CC, Jeng LB, Lin YJ, Mok KT, Lee WC, Yeh HZ, Ho MC, Yang SS, Yang MD, Yu MC, Hu RH, Peng CY, Lai KL, Chang SS, Chen PJ. Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World J Gastroenterol 2014; 20(32): 11384–11393

RIGHTS & PERMISSIONS

Higher Education Press