Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2021, Vol. 15 Issue (2) : 155-169    https://doi.org/10.1007/s11684-021-0848-3
REVIEW
Adjuvant treatment strategy after curative resection for hepatocellular carcinoma
Wei Zhang, Bixiang Zhang(), Xiao-ping Chen()
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
 Download: PDF(226 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
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     
Corresponding Author(s): Bixiang Zhang,Xiao-ping Chen   
Just Accepted Date: 11 March 2021   Online First Date: 22 March 2021    Issue Date: 23 April 2021
 Cite this article:   
Wei Zhang,Bixiang Zhang,Xiao-ping Chen. Adjuvant treatment strategy after curative resection for hepatocellular carcinoma[J]. Front. Med., 2021, 15(2): 155-169.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0848-3
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I2/155
Study Country/region Study design Arms and intervention Sample size Follow-up (month) Main outcomes
Yin et al. (2013) [14] China Two-stage longitudinal clinical study (RCT and non-RCT) NA (lamivudine 100 mg/day, orally within 1 week after resection until hepatitis B surface antigen seroconversion) vs. no therapy 163 in RCT (81 treatment and 82 controls) 39.93 NA treatment significantly improved liver function and decreased HCC recurrence and HCC-related death
Huang et al. (2013) [13] China RCT NA (telbivudine 600 mg/day, once daily on day 0 after surgery) vs. no therapy 84 (40 antiviral and 44 controls) NA NA treatment significantly decreased the incidence of viral reactivation during the perioperative period and could not facilitate postoperative liver function recovery
Huang et al. (2015) [11] China RCT NA (adefovir 10 mg/day, orally starting from 4 to 7 days after resection) vs. no therapy 200 (100 antiviral and 100 controls) 60 Adefovir antiviral therapy reduced late HCC recurrence and significantly improved OS. Antiviral therapy was an independent protective factor of late tumor recurrence
Chen et al. (2015) [15] Taiwan, China RCT NA (adefovir 10 mg/day for 3 years) vs. no therapy. In both groups, 18 months of lamivudine would be given when the HBV DNA titer>20 000 IU/mL and ALT>2.0× UNL 117 (58 antiviral and 59 controls) NA Three years of adjuvant adefovir did not reduce the postoperative recurrence and late recurrence of HBV-related HCC compared with observation followed by lamivudine when the HBV DNA titer > 20 000 IU/mL and ALT > 2.0× UNL
Huang et al. (2018) [12] China RCT NA (telbivudine 600 mg/day, orally starting from 4 to 7 days after surgery) vs. no therapy 200 (100 antiviral and 100 controls) 60 In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence and improved OS
Tab.1  Prospective RCTs of adjuvant antiviral therapy with NAs for patients with HBV-related HCC
Study Country/region Primary treatment Type
(IFN)
Viral hepatitis Sample size Follow-up
(months)
Main outcomes
Ikeda et al. (2000) [26] Japan Hepatic resection/PEI IFNβ HCV 20 (10 antiviral and 10 controls) 25 Intermittent administration of IFN suppressed tumor recurrence after treatment with surgery or ethanol injection in patients with HCV-related chronic liver disease
Kubo et al. (2002) [27] Japan Hepatic resection IFNα HCV 30 (15 antiviral and 15 controls) 1817 days Postoperative interferon therapy seemed to improve the outcome after resection of HCV-related HCC
Sun et al. (2006) [29] China Hepatic resection IFNα HBV 236 (118 antiviral and 118 controls) NA IFNα treatment improved the OS of patients with HBV-related HCC after curative resection, probably by postponing recurrence
Mazzaferro et al. (2006) [28] Italy Hepatic resection IFNα HBV/HCV 150 (76 antiviral and 74 controls) 45 IFN does not affect overall prevention of HCC recurrence after resection, but it may reduce late recurrence in HCV-pure patients
Lo et al. (2007) [30] Hong Kong, China Hepatic resection IFNα HBV/HCV 80 (40 antiviral and 40 controls) NA Adjuvant interferon therapy showed a trend for survival benefit, primarily in those with pTNM stage III/IVA tumors
Chen et al. (2012) [31] Taiwan, China Hepatic resection IFNα HBV/HCV 268 (133 antiviral and 135 controls) 63.8 Adjuvant IFNα-2b did not reduce the postoperative recurrence of viral hepatitis-related HCC
Tab.2  Prospective RCTs of adjuvant antiviral therapy with IFN for patients with hepatitis-related HCC
Author (year) Inclusion period Country Number of patients
(TACE/no TACE)
TACE course TACE regime Main outcomes
Izumi et al. (1994) [53] 1987–1992 Japan 50 (23/27) 1 course, 3–12 weeks postoperatively Lipiodol (2–3 mL/m2), doxorubicin (20 mg/m2), mitomycin (10 mg/m2), gelatin sponge Significantly improved DFS but not OS
Li et al. (1995) [54] 1990–1993 China 140 (70/70) 1–3 courses, 3–4 weeks postoperatively Lipiodol (4–10 mL), doxorubicin (40 mg/m2), mitomycin (6 mg/m2) Significantly reduced intrahepatic recurrence rate and improved OS
Li et al. (2006) [55] 1998–2001 China 84 (39/45) 3 courses, 4 weeks postoperatively Lipiodol (5–10 mL), doxorubicin (30 mg), mitomycin (20 mg), cisplatin (80–100 mg), or carboplatinum (400 mg) Did not significantly improve DFS
Zhong et al. (2009) [56] 2001–2004 China 115 (57/58) 1 course, 4–6 weeks postoperatively Lipiodol (5–10 mL), carboplatin (200 mg/m2), mitomycin (6 mg/m2), epirubicin (40 mg/m2) Significantly improved OS and DFS
Peng et al. (2009) [57] 1996–2004 China 104 (51/53) 2–5 courses, 3–4 weeks postoperatively Lipiodol (10–20 mL), 5-fluorouracil (500 mg/m2), adriamycin (30 mg/m2), gelatin sponge Significantly improved OS
Wei et al. (2018) [58] 2009–2012 China 250 (125/125) 1–2 courses, 4–6 weeks postoperatively Iodized oil (4–5 mL), carboplatin (200 mg/m2), mitomycin (6 mg/m2), epirubicin (40 mg/m2) Significantly improved OS and DFS in patients with solitary tumor ≥5 cm and MVI
Wang et al. (2018) [59] 2011–2014 China 280 (140/140) 1 course, 4–6 weeks postoperatively Adriamycin (20–30 mg/m2) and lipiodol (3–5 mL) Significantly reduced tumor recurrence and improved RFS and OS
Tab.3  Prospective RCTs of adjuvant TACE for patients with HCC after curative resection
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 W Chen, R Zheng, PD Baade, S Zhang, H Zeng, F Bray, A Jemal, XQ Yu, J He. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115–132
https://doi.org/10.3322/caac.21338
4 RL Siegel, KD Miller, A Jemal. Cancer statistics, 2017. CA Cancer J Clin 2017; 67(1): 7–30
https://doi.org/10.3322/caac.21387
5 C O’Leary, M Mahler, MC Soulen. Curative-intent therapies in localized hepatocellular carcinoma. Curr Treat Options Oncol 2020; 21(4): 31
https://doi.org/10.1007/s11864-020-0725-3
6 EH Asham, A Kaseb, RM Ghobrial. Management of hepatocellular carcinoma. Surg Clin North Am 2013; 93(6): 1423–1450
https://doi.org/10.1016/j.suc.2013.08.008
7 H Imamura, Y Matsuyama, E Tanaka, T Ohkubo, K Hasegawa, S Miyagawa, Y Sugawara, M Minagawa, T Takayama, S Kawasaki, M Makuuchi. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003; 38(2): 200–207
https://doi.org/10.1016/S0168-8278(02)00360-4
8 G Ercolani, GL Grazi, M Ravaioli, M Del Gaudio, A Gardini, M Cescon, G Varotti, F Cetta, A Cavallari. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003; 237(4): 536–543
https://doi.org/10.1097/01.SLA.0000059988.22416.F2
9 S Kubo, K Hirohashi, H Tanaka, T Tsukamoto, T Shuto, T Yamamoto, T Ikebe, K Wakasa, S Nishiguchi, H Kinoshita. Effect of viral status on recurrence after liver resection for patients with hepatitis B virus-related hepatocellular carcinoma. Cancer 2000; 88(5): 1016–1024
https://doi.org/10.1002/(SICI)1097-0142(20000301)88:5<1016::AID-CNCR10>3.0.CO;2-V
10 JC Wu, YH Huang, GY Chau, CW Su, CR Lai, PC Lee, TI Huo, IJ Sheen, SD Lee, WY Lui. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009; 51(5): 890–897
https://doi.org/10.1016/j.jhep.2009.07.009
11 G Huang, WY Lau, ZG Wang, ZY Pan, SX Yuan, F Shen, WP Zhou, MC Wu. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial. Ann Surg 2015; 261(1): 56–66
https://doi.org/10.1097/SLA.0000000000000858
12 G Huang, PP Li, WY Lau, ZY Pan, LH Zhao, ZG Wang, MC Wang, WP Zhou. Antiviral therapy reduces hepatocellular carcinoma recurrence in patients with low HBV-DNA levels: a randomized controlled trial. Ann Surg 2018; 268(6): 943–954
https://doi.org/10.1097/SLA.0000000000002727
13 L Huang, J Li, J Yan, J Sun, X Zhang, M Wu, Y Yan. 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
https://doi.org/10.1111/jvh.12036
14 J Yin, N Li, Y Han, J Xue, Y Deng, J Shi, W Guo, H Zhang, H Wang, S Cheng, G Cao. 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
https://doi.org/10.1200/JCO.2012.48.5896
15 LT Chen, LB Jeng, CF Hsiao, CC Wu, WC Lee, TE Wang, PH Lee, CL Chen, IS Chen, KT Lee, CB Hsieh, WS Hwang, MD Yang, YS Yang, DY Lin, MF Chen, PJ Chen. 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 G Zhang, X Yu, P Liu, X Huang, X Jiang. 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
https://doi.org/10.1007/s10620-018-5252-8
17 XX Chen, JW Cheng, A Huang, X Zhang, J Wang, J Fan, J Zhou, XR Yang. 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
https://doi.org/10.2147/OTT.S150281
18 P Yuan, P Chen, Y Qian. 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
https://doi.org/10.1155/2016/5234969
19 GM Liu, XY Huang, SL Shen, WJ Hu, BG Peng. 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
https://doi.org/10.1111/hepr.12584
20 BW Xia, YC Zhang, J Wang, FH Ding, XD He. 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
https://doi.org/10.1016/j.clinre.2014.12.003
21 Y Zhou, Z Zhang, Y Zhao, L Wu, B Li. 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
https://doi.org/10.1007/s00268-014-2586-z
22 LS Qu, JX Liu, XL Kuai, ZF Xu, F Jin, GX Zhou. 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
https://doi.org/10.1111/hepr.12172
23 JS Wong, GL Wong, KK Tsoi, VW Wong, SY Cheung, CN Chong, J Wong, KF Lee, PB Lai, HL Chan. 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
https://doi.org/10.1111/j.1365-2036.2011.04634.x
24 HY Mo, BD Xiang, JH Zhong, LQ Li, XM You. 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
https://doi.org/10.1155/2016/7625982
25 LH Yu, N Li, J Shi, WX Guo, MC Wu, SQ Cheng. Does anti-HBV therapy benefit the prognosis of HBV-related hepatocellular carcinoma following hepatectomy? Ann Surg Oncol 2014; 21(3): 1010–1015
https://doi.org/10.1245/s10434-013-3320-z
26 K Ikeda, Y Arase, S Saitoh, M Kobayashi, Y Suzuki, F Suzuki, A Tsubota, K Chayama, N Murashima, H Kumada. 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
https://doi.org/10.1053/jhep.2000.9409
27 S Kubo, S Nishiguchi, K Hirohashi, H Tanaka, T Shuto, H Kinoshita. 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
https://doi.org/10.1046/j.0007-1323.2001.02054.x
28 V Mazzaferro, R Romito, M Schiavo, L Mariani, T Camerini, S Bhoori, L Capussotti, F Calise, R Pellicci, G Belli, A Tagger, M Colombo, F Bonino, P Majno, JM; Llovet. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 2006; 44(6): 1543–1554
https://doi.org/10.1002/hep.21415
29 HC Sun, ZY Tang, L Wang, LX Qin, ZC Ma, QH Ye, BH Zhang, YB Qian, ZQ Wu, J Fan, XD Zhou, J Zhou, SJ Qiu, YF Shen. 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
https://doi.org/10.1007/s00432-006-0091-y
30 CM Lo, CL Liu, SC Chan, CM Lam, RT Poon, IO Ng, ST Fan, J Wong. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007; 245(6): 831–842
https://doi.org/10.1097/01.sla.0000245829.00977.45
31 LT Chen, MF Chen, LA Li, PH Lee, LB Jeng, DY Lin, CC Wu, KT Mok, CL Chen, WC Lee, GY Chau, YS Chen, WY Lui, CF Hsiao, J Whang-Peng, PJ; Chen 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
https://doi.org/10.1097/SLA.0b013e3182363ff9
32 S Breitenstein, D Dimitroulis, H Petrowsky, MA Puhan, B Mullhaupt, PA Clavien. 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
https://doi.org/10.1002/bjs.6731
33 Y Miyake, A Takaki, Y Iwasaki, K Yamamoto. 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
https://doi.org/10.1111/j.1365-2893.2009.01181.x
34 YC Shen, C Hsu, LT Chen, CC Cheng, FC Hu, AL Cheng. Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol 2010; 52(6): 889–894
https://doi.org/10.1016/j.jhep.2009.12.041
35 AK Singal, DH Freeman Jr, BS Anand. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Aliment Pharmacol Ther 2010; 32(7): 851–858
https://doi.org/10.1111/j.1365-2036.2010.04414.x
36 RY Miao, HT Zhao, HY Yang, YL Mao, X Lu, Y Zhao, CN Liu, SX Zhong, XT Sang, JF Huang. Postoperative adjuvant antiviral therapy for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis. World J Gastroenterol 2010; 16(23): 2931–2942
https://doi.org/10.3748/wjg.v16.i23.2931
37 S Jiang, Y Liu, L Wang, C Duan, M Liu. 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
https://doi.org/10.1186/1477-7819-11-240
38 J Wang, XD He, N Yao, WJ Liang, YC Zhang. A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can J Gastroenterol 2013; 27(6): 351–363
https://doi.org/10.1155/2013/417894
39 TS Huang, YC Shyu, HY Chen, SS Yuan, JN Shih, PJ Chen. 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
https://doi.org/10.1111/jvh.12096
40 JB Xu, FZ Qi, G Xu, GF Chen, MD Huang, JH Zhang. Adjuvant interferon therapy after surgical treatment for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis. Hepatol Res 2014; 44(2): 209–217
https://doi.org/10.1111/hepr.12109
41 L Zhuang, X Zeng, Z Yang, Z Meng. Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One 2013; 8(9): e61361
https://doi.org/10.1371/journal.pone.0061361
42 J Xu, J Li, J Chen, ZJ Liu. 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
https://doi.org/10.17219/acem/29760
43 J Wu, Z Yin, L Cao, X Xu, T Yan, C Liu, D Li. 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
https://doi.org/10.1097/MD.0000000000011295
44 GN Ioannou, LA Beste, MF Chang, PK Green, E Lowy, JI Tsui, F Su, K Berry. 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
https://doi.org/10.1053/j.gastro.2016.05.049
45 JL Calleja, J Crespo, D Rincón, B Ruiz-Antorán, I Fernandez, C Perelló, F Gea, S Lens, J García-Samaniego, B Sacristán, M García-Eliz, S Llerena, JM Pascasio, J Turnes, X Torras, RM Morillas, J Llaneras, MA Serra, M Diago, CF Rodriguez, J Ampuero, F Jorquera, MA Simon, J Arenas, CA Navascues, R Bañares, R Muñoz, A Albillos, Z Mariño; 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
https://doi.org/10.1016/j.jhep.2017.01.028
46 DS Fox, JJ McGinnis, IQ Tonnu-Mihara, JS McCombs. Comparative treatment effectiveness of direct acting antiviral regimens for hepatitis C: data from the Veterans Administration. J Gastroenterol Hepatol 2017; 32(6): 1136–1142
https://doi.org/10.1111/jgh.13652
47 M Reig, Z Mariño, C Perelló, M Iñarrairaegui, A Ribeiro, S Lens, A Díaz, R Vilana, A Darnell, M Varela, B Sangro, JL Calleja, X Forns, J Bruix. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65(4): 719–726
https://doi.org/10.1016/j.jhep.2016.04.008
48 F Conti, F Buonfiglioli, A Scuteri, C Crespi, L Bolondi, P Caraceni, FG Foschi, M Lenzi, G Mazzella, G Verucchi, P Andreone, S Brillanti. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65(4): 727–733
https://doi.org/10.1016/j.jhep.2016.06.015
49 JD Yang, BA Aqel, S Pungpapong, GJ Gores, LR Roberts, MD Leise. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol 2016; 65(4): 859–860
https://doi.org/10.1016/j.jhep.2016.06.023
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
https://doi.org/10.1016/j.jhep.2016.05.045
51 AG Singal, NE Rich, N Mehta, AD Branch, A Pillai, M Hoteit, M Volk, M Odewole, S Scaglione, J Guy, A Said, JJ Feld, BV John, C Frenette, P Mantry, AS Rangnekar, O Oloruntoba, M Leise, JH Jou, KR Bhamidimarri, L Kulik, GN Ioannou, A Huang, T Tran, H Samant, R Dhanasekaran, A Duarte-Rojo, R Salgia, S Eswaran, P Jalal, A Flores, SK Satapathy, S Kagan, P Gopal, R Wong, ND Parikh, CC Murphy. 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
https://doi.org/10.1053/j.gastro.2019.07.040
52 G Cabibbo, C Celsa, V Calvaruso, S Petta, I Cacciola, MR Cannavò, S Madonia, M Rossi, B Magro, F Rini, M Distefano, L Larocca, T Prestileo, G Malizia, G Bertino, F Benanti, A Licata, I Scalisi, G Mazzola, MA Di Rosolini, G Alaimo, A Averna, F Cartabellotta, N Alessi, S Guastella, M Russello, G Scifo, G Squadrito, G Raimondo, F Trevisani, A Craxì, V Di Marco, C Cammà; 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
https://doi.org/10.1016/j.jhep.2019.03.027
53 R Izumi, K Shimizu, T Iyobe, T Ii, M Yagi, O Matsui, A Nonomura, I Miyazaki. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 1994; 20(2): 295–301
https://doi.org/10.1002/hep.1840200205
54 JQ Li, YQ Zhang, WZ Zhang, YF Yuan, GH Li. Randomized study of chemoembolization as an adjuvant therapy for primary liver carcinoma after hepatectomy. J Cancer Res Clin Oncol 1995; 121(6): 364–366
https://doi.org/10.1007/BF01225689
55 Q Li, J Wang, Y Sun, YL Cui, JT Juzi, BY Qian, XS Hao. 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
https://doi.org/10.1159/000095396
56 C Zhong, RP Guo, JQ Li, M Shi, W Wei, MS Chen, YQ Zhang. 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
https://doi.org/10.1007/s00432-009-0588-2
57 BG Peng, Q He, JP Li, F Zhou. 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
https://doi.org/10.1016/j.amjsurg.2008.09.026
58 W Wei, PE Jian, SH Li, ZX Guo, YF Zhang, YH Ling, XJ Lin, L Xu, M Shi, L Zheng, MS Chen, RP Guo. 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
https://doi.org/10.1186/s40880-018-0331-y
59 Z Wang, Z Ren, Y Chen, J Hu, G Yang, L Yu, X Yang, A Huang, X Zhang, S Zhou, H Sun, Y Wang, N Ge, X Xu, Z Tang, W Lau, J Fan, J Wang, J Zhou. Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin Cancer Res 2018; 24(9): 2074–2081
https://doi.org/10.1158/1078-0432.CCR-17-2899
60 W Chen, T Ma, J Zhang, X Zhang, W Chen, Y Shen, X Bai, T Liang. 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
https://doi.org/10.1016/j.hpb.2019.12.013
61 M Liao, Z Zhu, H Wang, J Huang. Adjuvant transarterial chemoembolization for patients after curative resection of hepatocellular carcinoma: a meta-analysis. Scand J Gastroenterol 2017; 52(6-7): 624–634
https://doi.org/10.1080/00365521.2017.1292365
62 X Qi, L Liu, D Wang, H Li, C Su, X Guo. 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
https://doi.org/10.18632/oncotarget.5426
63 X Cheng, P Sun, QG Hu, ZF Song, J Xiong, QC Zheng. 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
https://doi.org/10.1007/s00432-014-1677-4
64 JH Zhong, LQ Li. Postoperative adjuvant transarterial chemoembolization for participants with hepatocellular carcinoma: a meta-analysis. Hepatol Res 2010; 40(10): 943–953
https://doi.org/10.1111/j.1872-034X.2010.00710.x
65 ZW Peng, RP Guo, YJ Zhang, XJ Lin, MS Chen, WY Lau. Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2012; 118(19): 4725–4736
https://doi.org/10.1002/cncr.26561
66 T Yang, C Lin, J Zhai, S Shi, M Zhu, N Zhu, JH Lu, GS Yang, MC Wu. Surgical resection for advanced hepatocellular carcinoma according to Barcelona Clinic Liver Cancer (BCLC) staging. J Cancer Res Clin Oncol 2012; 138(7): 1121–1129
https://doi.org/10.1007/s00432-012-1188-0
67 XP Chen, FZ Qiu, ZD Wu, ZW Zhang, ZY Huang, YF Chen, BX Zhang, SQ He, WG Zhang. 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
https://doi.org/10.1245/ASO.2006.08.007
68 S Liu, L Guo, H Li, B Zhang, J Sun, C Zhou, J Zhou, J Fan, Q Ye. Postoperative adjuvant trans-arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg Oncol 2018; 25(7): 2098–2104
https://doi.org/10.1245/s10434-018-6438-1
69 XP Zhang, YC Liu, ZH Chen, JX Sun, K Wang, ZT Chai, J Shi, WX Guo, MC Wu, WY Lau, SQ Cheng. 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
https://doi.org/10.1245/s10434-019-07223-z
70 A Shen, M Liu, D Zheng, Q Chen, Z Wu. 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
https://doi.org/10.1016/j.clinre.2019.06.012
71 L Li, B Li, M Zhang. 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
https://doi.org/10.1177/0284185119878357
72 ZH Chen, XP Zhang, TF Zhou, K Wang, H Wang, ZT Chai, J Shi, WX Guo, SQ Cheng. 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
https://doi.org/10.1016/j.ejso.2019.06.031
73 J Bruix, T Takayama, V Mazzaferro, GY Chau, J Yang, M Kudo, J Cai, RT Poon, KH Han, WY Tak, HC Lee, T Song, S Roayaie, L Bolondi, KS Lee, M Makuuchi, F Souza, MA Berre, G Meinhardt, JM; theSTORM investigators Llovet. 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
https://doi.org/10.1016/S1470-2045(15)00198-9
74 EA Antoniou, GA Margonis, N Amini, M Anastasiou, A Angelou, Y Kim, G Kouraklis. Sorafenib as an adjuvant therapy for resectable hepatocellular carcinoma: a single center experience. J BUON 2016; 21(5): 1189–1194
75 SN Wang, SC Chuang, KT Lee. 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
https://doi.org/10.1111/hepr.12159
76 J Li, Y Hou, XB Cai, B Liu. Sorafenib after resection improves the outcome of BCLC stage C hepatocellular carcinoma. World J Gastroenterol 2016; 22(15): 4034–4040
https://doi.org/10.3748/wjg.v22.i15.4034
77 F Xia, LL Wu, WY Lau, HB Huan, XD Wen, KS Ma, XW Li, P Bie. Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients. World J Gastroenterol 2016; 22(23): 5384–5392
https://doi.org/10.3748/wjg.v22.i23.5384
78 Y Liao, Y Zheng, W He, Q Li, J Shen, J Hong, R Zou, J Qiu, B Li, Y Yuan. 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
https://doi.org/10.3892/ol.2016.5525
79 L Zhuang, T Wen, M Xu, J Yang, W Wang, H Wu, Y Zeng, L Yan, Y Wei, B Li. Sorafenib combined with hepatectomy in patients with intermediate-stage and advanced hepatocellular carcinoma. Arch Med Sci 2017; 13(6): 1383–1393
https://doi.org/10.5114/aoms.2017.71066
80 Y Huang, Z Zhang, Y Zhou, J Yang, K Hu, Z Wang. Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy? OncoTargets Ther 2019; 12: 541–548
https://doi.org/10.2147/OTT.S187357
81 Z Li, J Gao, SM Zheng, Y Wang, X Xiang, Q Cheng, J Zhu. 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
https://doi.org/10.17235/reed.2020.6458/2019
82 YP Hong, ZD Li, P Prasoon, Q Zhang. Immunotherapy for hepatocellular carcinoma: from basic research to clinical use. World J Hepatol 2015; 7(7): 980–992
https://doi.org/10.4254/wjh.v7.i7.980
83 A Kawata, Y Une, M Hosokawa, Y Wakizaka, T Namieno, J Uchino, H Kobayashi. 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
https://doi.org/10.1097/00000421-199506000-00014
84 T Takayama, T Sekine, M Makuuchi, S Yamasaki, T Kosuge, J Yamamoto, K Shimada, M Sakamoto, S Hirohashi, Y Ohashi, T Kakizoe. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356(9232): 802–807
https://doi.org/10.1016/S0140-6736(00)02654-4
85 D Hui, L Qiang, W Jian, Z Ti, K Da-Lu. 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
https://doi.org/10.1016/j.dld.2008.04.007
86 X Yu, H Zhao, L Liu, S Cao, B Ren, N Zhang, X An, J Yu, H Li, X Ren. A randomized phase II study of autologous cytokineinduced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol 2014; 34(2): 194–203
https://doi.org/10.1007/s10875-013-9976-0
87 JH Lee, JH Lee, YS Lim, JE Yeon, TJ Song, SJ Yu, GY Gwak, KM Kim, YJ Kim, JW Lee, JH Yoon. Adjuvant immunotherapy with autologous cytokineinduced killer cells for hepatocellular carcinoma. Gastroenterology 2015; 148(7): 1383–1391.e6
https://doi.org/10.1053/j.gastro.2015.02.055
88 JH Lee, JH Lee, YS Lim, JE Yeon, TJ Song, SJ Yu, GY Gwak, KM Kim, YJ Kim, JW Lee, JH Yoon. 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
https://doi.org/10.1007/s00262-018-2247-4
89 L Xu, J Wang, Y Kim, ZY Shuang, YJ Zhang, XM Lao, YQ Li, MS Chen, TM Pawlik, JC Xia, SP Li, WY Lau. 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
https://doi.org/10.1080/2162402X.2015.1083671
90 H Zhao, M Zheng, K Wang, L Wang, H He, M Wang, Y Shi, S Huang, F Ji, X Li, H Zhu, L Wang, X Zhang, X Shi, S Zhao, B Fu, T Wu. A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Cancer Res Ther 2018; 14(4): 807–814
https://doi.org/10.4103/jcrt.JCRT_858_17
91 HY Mo, YY Liao, XM You, A Cucchetti, BH Yuan, RH Li, JH Zhong, LQ Li. Timely meta-analysis on the efficacy of adoptive immunotherapy for hepatocellular carcinoma patients after curative therapy. PLoS One 2017; 12(3): e0174222
https://doi.org/10.1371/journal.pone.0174222
92 BH Yuan, RH Li, WP Yuan, T Yang, TJ Tong, NF Peng, LQ Li, JH Zhong. Harms and benefits of adoptive immunotherapy for postoperative hepatocellular carcinoma: an updated review. Oncotarget 2017; 8(11): 18537–18549
https://doi.org/10.18632/oncotarget.14507
93 M Kuang, BG Peng, MD Lu, LJ Liang, JF Huang, Q He, YP Hua, S Totsuka, SQ Liu, KW Leong, T Ohno. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 2004; 10(5): 1574–1579
https://doi.org/10.1158/1078-0432.CCR-03-0071
94 JH Lee, WY Tak, Y Lee, MK Heo, JS Song, HY Kim, SY Park, SH Bae, JH Lee, J Heo, KH Kim, YS Bae, YJ Kim. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. OncoImmunology 2017; 6(7): e1328335
https://doi.org/10.1080/2162402X.2017.1328335
95 K Shimizu, Y Kotera, A Aruga, N Takeshita, S Katagiri, S Ariizumi, Y Takahashi, K Yoshitoshi, K Takasaki, M Yamamoto. 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
https://doi.org/10.4161/hv.27678
96 JJ Harding, I El Dika, GK Abou-Alfa. Immunotherapy in hepatocellular carcinoma: primed to make a difference? Cancer 2016; 122(3): 367–377
https://doi.org/10.1002/cncr.29769
97 S Nakano, Y Eso, H Okada, A Takai, K Takahashi, H Seno. Recent advances in immunotherapy for hepatocellular carcinoma. Cancers (Basel) 2020; 12(4): E775
https://doi.org/10.3390/cancers12040775
98 M Yamamoto, S Arii, K Sugahara, T Tobe. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Br J Surg 1996; 83(3): 336–340
https://doi.org/10.1002/bjs.1800830313
99 K Hasegawa, T Takayama, M Ijichi, Y Matsuyama, H Imamura, K Sano, Y Sugawara, N Kokudo, M Makuuchi. Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial. Hepatology 2006; 44(4): 891–895
https://doi.org/10.1002/hep.21341
100 Y Xia, Y Qiu, J Li, L Shi, K Wang, T Xi, F Shen, Z Yan, M Wu. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 2010; 17(12): 3137–3144
https://doi.org/10.1245/s10434-010-1148-3
101 M Ishizuka, K Kubota, T Nemoto, M Shimoda, M Kato, Y Iso, K Tago. Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: a randomized controlled trial. Asian J Surg 2016; 39(3): 149–154
https://doi.org/10.1016/j.asjsur.2015.04.008
102 J Zhong, B Xiang, L Ma, L Li. Conventional oral systemic chemotherapy for postoperative hepatocellular carcinoma: a systematic review. Mol Clin Oncol 2014; 2(6): 1091–1096
https://doi.org/10.3892/mco.2014.337
103 T Hamada, K Yano, T Wada, N Imamura, M Hiyoshi, K Kondo, A Nanashima. 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
https://doi.org/10.1007/s00268-020-05527-w
104 E Hatano, S Uemoto, H Yamaue, M; the Japanese Society of Hepato-Biliary-Pancreatic Surgery Yamamoto. 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
https://doi.org/10.1002/jhbp.574
105 JH Hsiao, CC Tsai, TJ Liang, CL Chiang, HL Liang, IS Chen, YC Chen, PM Chang, NH Chou, BW Wang. Adjuvant hepatic arterial infusion chemotherapy is beneficial for selective patients with hepatocellular carcinoma undergoing surgical treatment. Int J Surg 2017; 45: 35–41
https://doi.org/10.1016/j.ijsu.2017.07.071
106 H Nitta, T Beppu, K Imai, H Hayashi, A Chikamoto, H Baba. Adjuvant hepatic arterial infusion chemotherapy after hepatic resection of hepatocellular carcinoma with macroscopic vascular invasion. World J Surg 2013; 37(5): 1034–1042
https://doi.org/10.1007/s00268-013-1957-1
107 H Nagano, S Kobayashi, S Marubashi, H Wada, H Eguchi, M Tanemura, Y Tomimaru, K Umeshita, Y Doki, M Mori. 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
https://doi.org/10.3892/etm.2012.736
108 T Niguma, T Mimura, N Tutui. Adjuvant arterial infusion chemotherapy after resection of hepatocellular carcinoma with portal thrombosis: a pilot study. J Hepatobiliary Pancreat Surg 2005; 12(3): 249–253
https://doi.org/10.1007/s00534-004-0969-5
109 A Moran, LF Ramos, O Picado, F Pendola, D Sleeman, V Dudeja, N Merchant, D Yakoub. 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
https://doi.org/10.1002/jso.25338
110 WY Lau, TW Leung, SK Ho, M Chan, D Machin, J Lau, AT Chan, W Yeo, TS Mok, SC Yu, NW Leung, PJ Johnson. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999; 353(9155): 797–801
https://doi.org/10.1016/S0140-6736(98)06475-7
111 WY Lau, EC Lai, TW Leung, SC Yu. 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
https://doi.org/10.1097/SLA.0b013e3181571047
112 C Partensky, G Sassolas, L Henry, P Paliard, GJ Maddern. 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
https://doi.org/10.1001/archsurg.135.11.1298
113 E Boucher, S Corbinais, Y Rolland, P Bourguet, D Guyader, K Boudjema, B Meunier, JL Raoul. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology 2003; 38(5): 1237–1241
https://doi.org/10.1053/jhep.2003.50473
114 TC Chua, A Saxena, F Chu, SP Butler, RJ Quinn, D Glenn, DL Morris. Hepatic resection with or without adjuvant iodine-131-lipiodol for hepatocellular carcinoma: a comparative analysis. Int J Clin Oncol 2011; 16(2): 125–132
https://doi.org/10.1007/s10147-010-0143-9
115 M Tabone, L Vigano’, A Ferrero, R Pellerito, P Carbonatto, L Capussotti. 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
https://doi.org/10.1016/j.ejso.2006.10.039
116 AY Chung, LL Ooi, D Machin, SB Tan, BK Goh, JS Wong, YM Chen, PC Li, M Gandhi, CH Thng, SW Yu, BS Tan, RH Lo, AM Htoo, KH Tay, FX Sundram, AS Goh, SP Chew, KH Liau, PK Chow, KH Tay, YM Tan, PC Cheow, CK Ho, KC Soo. 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
https://doi.org/10.1007/s00268-013-1970-4
117 RV Furtado, L Ha, S Clarke, C Sandroussi. Adjuvant iodine (131) lipiodol after resection of hepatocellular carcinoma. J Oncol 2015; 2015: 746917
https://doi.org/10.1155/2015/746917
118 L Gong, L Shi, J Sun, WS Yuan, JF Chen, P Liu, F Gong, JH Dong. 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
https://doi.org/10.1097/MNM.0000000000000081
119 R Furtado, M Crawford, C Sandroussi. Systematic review and meta-analysis of adjuvant I131 lipiodol after excision of hepatocellular carcinoma. Ann Surg Oncol 2014; 21(8): 2700–2707
https://doi.org/10.1245/s10434-014-3511-2
120 Y Hong, LP Wu, F Ye, YM Zhou. 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
https://doi.org/10.1007/s12262-015-1261-4
121 K Chen, Y Xia, H Wang, F Xiao, G Xiang, F Shen. Adjuvant iodine-125 brachytherapy for hepatocellular carcinoma after complete hepatectomy: a randomized controlled trial. PLoS One 2013; 8(2): e57397
https://doi.org/10.1371/journal.pone.0057397
122 D Oh, DH Lim, HC Park, SW Paik, KC Koh, JH Lee, MS Choi, BC Yoo, HK Lim, WJ Lee, H Rhim, SW Shin, KB Park. 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
https://doi.org/10.1097/COC.0b013e3181b0c298
123 SM Yoon, YS Lim, HJ Won, JH Kim, KM Kim, HC Lee, YH Chung, YS Lee, SG Lee, JH Park, DJ Suh. 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
https://doi.org/10.1016/j.ijrobp.2011.03.019
124 W Yu, W Wang, W Rong, L Wang, Q Xu, F Wu, L Liu, J Wu. 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
https://doi.org/10.1016/j.jamcollsurg.2013.11.030
125 L Wang, W Wang, W Rong, Z Li, F Wu, Y Liu, Y Zheng, K Zhang, T Siqin, M Liu, B Chen, J Wu. Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study. BMC Cancer 2020; 20(1): 614
https://doi.org/10.1186/s12885-020-07087-7
126 L Wang, W Wang, X Yao, W Rong, F Wu, B Chen, M Liu, S Lin, Y Liu, J Wu. Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion. Oncotarget 2017; 8(45): 79971–79981
https://doi.org/10.18632/oncotarget.20402
127 L Wang, B Chen, Z Li, X Yao, M Liu, W Rong, F Wu, S Lin, Y Liu, Y Zheng, Y Li, W Wang, J Wu. Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis. OncoTargets Ther 2019; 12: 1237–1247
https://doi.org/10.2147/OTT.S179247
128 J Sun, L Yang, J Shi, C Liu, X Zhang, Z Chai, WY Lau, Y Meng, SQ Cheng. Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial. Radiother Oncol 2019; 140: 20–25
https://doi.org/10.1016/j.radonc.2019.05.006
129 M Nakamura, H Nagano, T Noda, H Wada, H Ota, B Damdinsuren, S Marubashi, A Miyamoto, Y Takeda, Y Doki, K Umeshita, K Dono, M Sakon, M Monden. 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
https://doi.org/10.1016/j.hepres.2006.04.014
130 X Jinghe, T Mizuta, I Ozaki. Vitamin K and hepatocellular carcinoma: the basic and clinic. World J Clin Cases 2015; 3(9): 757–764
https://doi.org/10.12998/wjcc.v3.i9.757
131 T Mizuta, I Ozaki, Y Eguchi, T Yasutake, S Kawazoe, K Fujimoto, K Yamamoto. 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
https://doi.org/10.1002/cncr.21667
132 N Hotta, M Ayada, K Sato, T Ishikawa, A Okumura, E Matsumoto, T Ohashi, S Kakumu. Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Hepatogastroenterology 2007; 54(79): 2073–2077
133 S Kakizaki, N Sohara, K Sato, H Suzuki, M Yanagisawa, H Nakajima, H Takagi, A Naganuma, T Otsuka, H Takahashi, T Hamada, M Mori. 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
https://doi.org/10.1111/j.1440-1746.2007.04844.x
134 H Yoshiji, R Noguchi, M Toyohara, Y Ikenaka, M Kitade, K Kaji, M Yamazaki, J Yamao, A Mitoro, M Sawai, M Yoshida, M Fujimoto, T Tsujimoto, H Kawaratani, M Uemura, H Fukui. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol 2009; 51(2): 315–321
https://doi.org/10.1016/j.jhep.2009.04.011
135 H Yoshida, Y Shiratori, M Kudo, S Shiina, T Mizuta, M Kojiro, K Yamamoto, Y Koike, K Saito, N Koyanagi, T Kawabe, S Kawazoe, H Kobashi, H Kasugai, Y Osaki, Y Araki, N Izumi, H Oka, K Tsuji, J Toyota, T Seki, T Osawa, N Masaki, M Ichinose, M Seike, A Ishikawa, Y Ueno, K Tagawa, R Kuromatsu, S Sakisaka, H Ikeda, H Kuroda, H Kokuryu, T Yamashita, I Sakaida, T Katamoto, K Kikuchi, M Nomoto, M Omata. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011; 54(2): 532–540
https://doi.org/10.1002/hep.24430
136 M Ishizuka, K Kubota, M Shimoda, J Kita, M Kato, KH Park, T Shiraki. 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 K Hosho, J Okano, M Koda, Y Murawaki. Vitamin K2 has no preventive effect on recurrence of hepatocellular carcinoma after effective treatment. Yonago Acta Med 2008; 51: 95–99
138 JH Zhong, XS Mo, BD Xiang, WP Yuan, JF Jiang, GS Xie, LQ Li. Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. PLoS One 2013; 8(3): e58082
https://doi.org/10.1371/journal.pone.0058082
139 H Moriwaki, Y Muto, M Ninomiya, K Kawai, Y Suzuki, T Seto. 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
https://doi.org/10.1007/BF02779487
140 Y Muto, H Moriwaki, M Ninomiya, S Adachi, A Saito, KT Takasaki, T Tanaka, K Tsurumi, M Okuno, E Tomita, T Nakamura, T Kojima; 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
https://doi.org/10.1056/NEJM199606133342402
141 K Takai, M Okuno, I Yasuda, R Matsushima-Nishiwaki, T Uematsu, H Tsurumi, Y Shiratori, Y Muto, H Moriwaki. 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
https://doi.org/10.1159/000082093
142 J Liu, S Wang, Y Zhang, HT Fan, HS Lin. Traditional chinese medicine and cancer: history, present situation, and development. Thorac Cancer 2015; 6(5): 561–569
https://doi.org/10.1111/1759-7714.12270
143 L Li, S Ye, Y Wang, Z Tang. Progress on experimental research and clinical application of Trametes robiniophila. China Cancer (Zhongguo Zhong Liu) 2007; 16(2): 110–113 (in Chinese)
144 H Bao, P Liu, K Jiang, X Zhang, L Xie, Z Wang, P Gong. Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MaPK. Oncol Lett 2016; 12(2): 1058–1066
https://doi.org/10.3892/ol.2016.4686
145 L Shan, Y Li, H Jiang, Y Tao, Z Qian, L Li, F Cai, L Ma, Y Yu. Huaier restrains proliferative and migratory potential of hepatocellular carcinoma cells partially through decreased yes-associated protein 1. J Cancer 2017; 8(19): 4087–4097
https://doi.org/10.7150/jca.21018
146 C Li, X Wu, H Zhang, G Yang, M Hao, S Sheng, Y Sun, J Long, C Hu, X Sun, L Li, J Zheng. A Huaier polysaccharide restrains hepatocellular carcinoma growth and metastasis by suppression angiogenesis. Int J Biol Macromol 2015; 75: 115–120
https://doi.org/10.1016/j.ijbiomac.2015.01.016
147 Q Chen, C Shu, AD Laurence, Y Chen, BG Peng, ZJ Zhen, JQ Cai, YT Ding, LQ Li, YB Zhang, QC Zheng, GL Xu, B Li, WP Zhou, SW Cai, XY Wang, H Wen, XY Peng, XW Zhang, CL Dai, P Bie, BC Xing, ZR Fu, LX Liu, Y Mu, L Zhang, QS Zhang, B Jiang, HX Qian, YJ Wang, JF Liu, XH Qin, Q Li, P Yin, ZW Zhang, XP Chen. Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial. Gut 2018; 67(11): 2006–2016
https://doi.org/10.1136/gutjnl-2018-315983
148 XF Zhai, XL Liu, F Shen, J Fan, CQ Ling. Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: a randomized controlled study. Cancer 2018; 124(10): 2161–2168
https://doi.org/10.1002/cncr.30915
149 E Cabre, F Gonzalez-Huix, A Abad-Lacruz, M Esteve, D Acero, F Fernandez-Bañares, X Xiol, MA Gassull. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial. Gastroenterology 1990; 98(3): 715–720
https://doi.org/10.1016/0016-5085(90)90293-A
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
https://doi.org/10.1002/bjs.1800841109 pmid: 9393270
151 WC Meng, KL Leung, RL Ho, TW Leung, WY Lau. 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
https://doi.org/10.1046/j.1440-1622.1999.01701.x
152 T Okabayashi, M Iyoki, T Sugimoto, M Kobayashi, K Hanazaki. 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
https://doi.org/10.1007/s00726-010-0748-3
153 K Ichikawa, T Okabayashi, H Maeda, T Namikawa, T Iiyama, T Sugimoto, M Kobayashi, T Mimura, K Hanazaki. 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
https://doi.org/10.1007/s00595-012-0288-4
154 JA Joyce, C Freeman, N Meyer-Morse, CR Parish, D Hahahan. 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
https://doi.org/10.1038/sj.onc.1208602
155 CJ Liu, PH Lee, DY Lin, CC Wu, LB Jeng, PW Lin, KT Mok, WC Lee, HZ Yeh, MC Ho, SS Yang, CC Lee, MC Yu, RH Hu, CY Peng, KL Lai, SS Chang, PJ Chen. 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
https://doi.org/10.1016/j.jhep.2008.12.023
156 CJ Liu, J Chang, PH Lee, DY Lin, CC Wu, LB Jeng, YJ Lin, KT Mok, WC Lee, HZ Yeh, MC Ho, SS Yang, MD Yang, MC Yu, RH Hu, CY Peng, KL Lai, SS Chang, PJ Chen. Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World J Gastroenterol 2014; 20(32): 11384–11393
https://doi.org/10.3748/wjg.v20.i32.11384
[1] Chao Gao, Shenghao Wang, Weiqing Shao, Yu Zhang, Lu Lu, Huliang Jia, Kejin Zhu, Jinhong Chen, Qiongzhu Dong, Ming Lu, Wenwei Zhu, Lunxiu Qin. Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma[J]. Front. Med., 2022, 16(3): 467-482.
[2] Jiayi Wu, Weiqi Gao, Xiaosong Chen, Chunxiao Fei, Lin Lin, Weiguo Chen, Ou Huang, Siji Zhu, Jianrong He, Yafen Li, Li Zhu, Kunwei Shen. Prognostic value of the 21-gene recurrence score in ER-positive, HER2-negative, node-positive breast cancer was similar in node-negative diseases: a single-center study of 800 patients[J]. Front. Med., 2021, 15(4): 621-628.
[3] Jianpeng Liu, Xinhua Chen, Shusen Zheng. Immune response triggered by the ablation of hepatocellular carcinoma with nanosecond pulsed electric field[J]. Front. Med., 2021, 15(2): 170-177.
[4] Amy Lee, Fa-Chyi Lee. Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check[J]. Front. Med., 2020, 14(3): 273-283.
[5] Renyu Zhang, Zhao Zhang, Zekun Liu, Ding Wei, Xiaodong Wu, Huijie Bian, Zhinan Chen. Adoptive cell transfer therapy for hepatocellular carcinoma[J]. Front. Med., 2019, 13(1): 3-11.
[6] Shasha Zhu, Huimin Zhang, Li Bai. NKT cells in liver diseases[J]. Front. Med., 2018, 12(3): 249-261.
[7] Guangbiao Zhou, Xinchun Zhao. Carcinogens that induce the A:T>T:A nucleotide substitutions in the genome[J]. Front. Med., 2018, 12(2): 236-238.
[8] Min Yu, Zonghai Li. Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches[J]. Front. Med., 2017, 11(4): 509-521.
[9] Zhen He,Cheng Hu,Weiping Jia. miRNAs in non-alcoholic fatty liver disease[J]. Front. Med., 2016, 10(4): 389-396.
[10] Xinsen Xu,Yanyan Zhou,Runchen Miao,Wei Chen,Kai Qu,Qing Pang,Chang Liu. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis[J]. Front. Med., 2016, 10(2): 183-190.
[11] Zhi Xu,Chunxiang Cao,Haiyan Xia,Shujing Shi,Lingzhi Hong,Xiaowei Wei,Dongying Gu,Jianmin Bian,Zijun Liu,Wenbin Huang,Yixin Zhang,Song He,Nikki Pui-Yue Lee,Jinfei Chen. Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma[J]. Front. Med., 2016, 10(1): 52-60.
[12] Felice Ho-Ching Tsang,Sandy Leung-Kuen Au,Lai Wei,Dorothy Ngo-Yin Fan,Joyce Man-Fong Lee,Carmen Chak-Lui Wong,Irene Oi-Lin Ng,Chun-Ming Wong. MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility[J]. Front. Med., 2015, 9(3): 331-343.
[13] Farhad Sahebjam,John M. Vierling. Autoimmune hepatitis[J]. Front. Med., 2015, 9(2): 187-219.
[14] Guanghua Rong,Wenlin Bai,Zheng Dong,Chunping Wang,Yinying Lu,Zhen Zeng,Jianhui Qu,Min Lou,Hong Wang,Xudong Gao,Xiujuan Chang,Linjing An,Yan Chen,Yongping Yang. Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases[J]. Front. Med., 2015, 9(1): 63-71.
[15] Du Yan, Han Xue, Pu Rui, Xie Jiaxin, Zhang Yuwei, Cao Guangwen. Association of miRNA-122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk[J]. Front. Med., 2014, 8(2): 217-226.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed