Aim The benefit of nucleot(s)ide analogues (NA) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative treatment has been widely debated due to the relatively weak evidence. The objective of this systematic review was to evaluate the effect of NA on recurrence and survival after curative treatment of HBV-HCC. Methods A systematic electronic search was performed. All controlled trials comparing NA versus placebo or no treatment were considered for inclusion. Results were expressed as Hazard Ratio for recurrence and survival with 95% confidence intervals using RevMan 5.2. Results We included 13 trials with 6350 patients. There were significant improvements for recurrence-free survival (HR 0.66, 95% CI 0.54–0.80; p<0.0001) and overall survival (HR 0.56, 95% CI 0.43–0.73; p<0.0001) in the adjuvant NA group compared with the control group. Sensitivity analyses confirmed the robustness of the results. There were no serious adverse effects being reported. Lamivudine resistance was from 28.6% to 37.5% but could be rescued by other types of NA or combination therapy. Conclusion Our study suggested benefits of adjuvant NA therapy following curative treatment of HBV-HCC. Since the great proven efficacy of NA in improving clinical and viral parameters besides HCC, further studies should be focused on broadening the indications for NA therapy after curative treatment of HBV-HCC.
References
[1]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. (2011) Global cancer statistics. CA Cancer J Clin 61: 69–90. doi: 10.3322/caac.20107
[2]
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP (2006) The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 45: 529–538. doi: 10.1016/j.jhep.2006.05.013
[3]
Tsukuma H, Tanaka H, Ajiki W, Oshima A (2005) Liver cancer and its prevention. Asian Pac J Cancer Prev 6: 244–250.
[4]
Parkin DM (2006) The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118: 3030–3044. doi: 10.1002/ijc.21731
[5]
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, et al. (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334: 693–699. doi: 10.1056/nejm199603143341104
[6]
Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42: 1208–1236. doi: 10.1002/hep.20933
[7]
Llovet JM, Schwartz M, Mazzaferro V (2005) Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 25: 181–200. doi: 10.1055/s-2005-871198
[8]
Lai CL, Yuen MF (2013) Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 57: 399–408. doi: 10.1002/hep.25937
[9]
Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, et al. (2013) Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 58: 98–107. doi: 10.1002/hep.26180
[10]
Yin J, Li N, Han Y, Xue J, Deng Y (2013) 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 31: 3647–3655. doi: 10.1200/jco.2012.48.5896
[11]
Su CW, Chiou YW, Tsai YH, Teng RD, Chau GY, et al. (2013) The Influence of Hepatitis B Viral Load and Pre-S Deletion Mutations on Post-Operative Recurrence of Hepatocellular Carcinoma and the Tertiary Preventive Effects by Anti-Viral Therapy. PLoS One 8: e66457. doi: 10.1371/journal.pone.0066457
[12]
Ke Y, Ma L, You XM, Huang SX, Liang YR, et al. (2013) Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after radical hepatectomy. Cancer Biol Med 10: 158–164.
[13]
Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, et al. (2012) Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA 308: 1906–1914. doi: 10.1001/2012.jama.11975
[14]
Lee JW, Lee JI, Chung HJ, Kim YS, Lee DH (2012) Effect of antiviral therapy on late recurrence after curative resection of B-viral hepatocellular carcinoma (HCC). Journal of Hepatology 56: S398. doi: 10.1016/s0168-8278(12)61030-7
[15]
Hann HW, Bergin D, Coben R, Dimarino AJ (2011) Prevention of new hepatocellular carcinoma with concomitant antiviral therapy in chronic hepatitis B patients whose initial tumor was successfully ablated. International Journal of Cancer 128: 740–743. doi: 10.1002/ijc.25382
[16]
Chan ACY, Chok KSH, Yuen WK, Chan SC, Poon RTP, et al. (2011) Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. Archives of Surgery 146: 675–681. doi: 10.1001/archsurg.2011.125
[17]
Koda M, Nagahara T, Matono T, Sugihara T, Mandai M, et al. (2009) Nucleotide analogs for patients with HBV-related hepatocellular carcinoma increase the survival rate through improved liver function. Intern Med 48: 11–17. doi: 10.2169/internalmedicine.48.1534
[18]
Chuma M, Hige S, Kamiyama T, Meguro T, Nagasaka A, et al. (2009) The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma. J Gastroenterol 44: 991–999. doi: 10.1007/s00535-009-0093-z
[19]
Yoshida H, Goto E, Sato T, Ohki T, Masuzaki R, et al. (2008) Safety and efficacy of lamivudine after radiofrequency ablation in patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Int 2: 89–94. doi: 10.1007/s12072-007-9020-7
[20]
Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, et al. (2007) Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma. J Gastroenterol Hepatol 22: 1929–1935. doi: 10.1111/j.1440-1746.2006.04707.x
[21]
Kubo S, Tanaka H, Takemura S, Yamamoto S, Hai S, et al. (2007) Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus. Hepatol Res 37: 94–100. doi: 10.1111/j.1872-034x.2007.00013.x
[22]
Nishikawa H, Nishijima N, Arimoto A, Inuzuka T, Kita R, et al. (2013) Effect of nucleoside analog use in patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Res.
[23]
Higgins JPT, Green S, editors (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration.
[24]
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8: 16. doi: 10.1186/1745-6215-8-16
[25]
Wells G, Shea B, O'Connell D, Peterson J, Welch V, et al.. (2001) The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-analyses. Ottawa: Ottawa Hospital Research Institute. Available: http://www.ohri.ca/programs/clinical_epi?demiology/oxford.asp. Accessed 6 July 2014.
[26]
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151: 264–269, W264.
[27]
Huang G, Yang Y, Shen F, Pan ZY, Fu SY, et al. (2013) Early Viral Suppression Predicts Good Postoperative Survivals in Patients with Hepatocellular Carcinoma with a High Baseline HBV-DNA Load. Annals of Surgical Oncology 20: 1482–1490. doi: 10.1245/s10434-012-2803-7
[28]
Urata Y, Kubo S, Takemura S, Uenishi T, Kodai S, et al. (2012) Effects of antiviral therapy on long-term outcome after liver resection for hepatitis B virus-related hepatocellular carcinoma. J Hepatobiliary Pancreat Sci 19: 685–696. doi: 10.1007/s00534-011-0489-z
[29]
Jeong E, Lee JW, Lee JI, Kim YS, Jeong S, et al. (2011) Antiviral therapy after curative resection of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) improves the outcome in patients with high serum HBV DNA level. Hepatology 54: 1384A.
[30]
Li N, Lai ECH, Shi J, Guo WX, Xue J, et al. (2010) A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection. Annals of Surgical Oncology 17: 179–185. doi: 10.1245/s10434-009-0694-z
[31]
Chan A, Chok SH, Yuen WK, Chan SC, Ng KKC, et al. (2010) Impact of antiviral therapy on the survival outcome after hepatectomy for hepatitis B-related hepatocellular carcinoma. HPB 12: 52.
[32]
Kim JH, Park JW, Koh DW, Lee WJ, Kim CM (2009) Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus-related hepatocellular carcinoma. Liver Int 29: 203–207. doi: 10.1111/j.1478-3231.2008.01828.x
[33]
Shuqun C, Mengchao W, Han C, Feng S, Jiahe Y, et al. (2006) Antiviral therapy using lamivudine and thymosin alpha1 for hepatocellular carcinoma coexisting with chronic hepatitis B infection. Hepatogastroenterology 53: 249–252.
[34]
Piao CY, Fujioka S, Iwasaki Y, Fujio K, Kaneyoshi T, et al. (2005) Lamivudine treatment in patients with HBV-related hepatocellular carcinoma—using an untreated, matched control cohort. Acta Med Okayama 59: 217–224.
[35]
Inuzuka T (2010) Nucleotide analogues may prolong survival time without recurrence and overall survival time for HBV-related liver diseases after curative treatment of hepatocellular carcinoma. Hepatology 52: 525A.
[36]
Shim JH, Lee HC, Choi JG, Lee D, Kim KM, et al. (2011) Clinical implication of hepatitis B viral load in hepatitis B E antigen-negative chronic hepatitis B patients with hepatocellular carcinoma treated with curative resection. Journal of Hepatology 54: S301. doi: 10.1016/s0168-8278(11)60751-4
[37]
An HJ, Jang JW, Kwon JH, You CR, Kim JD, et al. (2010) Effect of hepatitis B viral status on cancer recurrence and long-term prognosis after surgical resection in patients with hepatocellular carcinoma. Hepatology International 4: 310.
[38]
Goto T, Yoshida H, Tateishi R, Enooku K, Goto E, et al. (2011) Influence of serum HBV DNA load on recurrence of hepatocellular carcinoma after treatment with percutaneous radiofrequency ablation. Hepatology International 5: 767–773. doi: 10.1007/s12072-011-9255-1
[39]
Wong JSW, Wong GLH, Tsoi KKF, Wong VWS, Cheung SYS, et al. (2011) Meta-analysis: The efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Alimentary Pharmacology and Therapeutics 33: 1104–1112. doi: 10.1111/j.1365-2036.2011.04634.x
[40]
Hung IF, Poon RT, Lai CL, Fung J, Fan ST, et al. (2008) Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection. Am J Gastroenterol 103: 1663–1673. doi: 10.1111/j.1572-0241.2008.01872.x
[41]
Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A (2010) Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 53: 348–356. doi: 10.1016/j.jhep.2010.02.035
[42]
Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, et al. (2004) Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 351: 1521–1531. doi: 10.1056/nejmoa033364
[43]
Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, et al. (2009) Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med 150: 111–124. doi: 10.7326/0003-4819-150-2-200901200-00101
[44]
Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, et al. (2012) Long-term results of a randomized, observation-controlled, phase III Trial of Adjuvant Interferon alfa-2b in hepatocellular carcinoma after curative resection. Annals of Surgery 255: 8–17. doi: 10.1097/sla.0b013e3182363ff9
[45]
Lo CM, Liu CL, Chan SC, Lam CM, Poon RTP, et al. (2007) A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Annals of Surgery 245: 831–842. doi: 10.1097/01.sla.0000245829.00977.45
[46]
Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, et al. (2006) 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 132: 458–465. doi: 10.1007/s00432-006-0091-y
[47]
Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, et al. (2006) Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 44: 1543–1554. doi: 10.1002/hep.21415
[48]
Nishiguchi S, Tamori A, Kubo S (2005) Effect of long-term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus-related hepatocellular carcinoma. Intervirology 48: 71–75. doi: 10.1159/000082098
[49]
Lin SM, Lin CJ, Hsu CW, Tai DI, Sheen IS, et al. (2004) Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer 100: 376–382. doi: 10.1002/cncr.20004
[50]
Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, et al. (2003) Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 138: 299–306. doi: 10.7326/0003-4819-138-4-200302180-00008
[51]
Miyaguchi S, Watanabe T, Takahashi H, Nakamura M, Saito H, et al. (2002) Interferon therapy for hepatocellular carcinoma patients with low HCV-RNA levels. Hepatogastroenterology 49: 724–729.
[52]
Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, et al. (2000) Interferon beta 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 32: 228–232. doi: 10.1053/jhep.2000.9409
[53]
Sun P, Yang X, He RQ, Hu QG, Song ZF, et al.. (2013) Antiviral therapy after curative treatment of hepatitis B/C virus-related hepatocellular carcinoma: A systematic review of randomized trials. Hepatol Res.
[54]
EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 57: 167–185. doi: 10.1016/j.jhep.2012.09.013
[55]
Huang G, Lai ECH, Lau WY, Zhou WP, Shen F, et al. (2013) Posthepatectomy HBV reactivation in hepatitis B-Related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels. Annals of Surgery 257: 490–505. doi: 10.1097/sla.0b013e318262b218
[56]
Huang L, Li J, Yan J, Sun J, Zhang X, et al. (2013) Antiviral therapy decreases viral reactivation in patients with hepatitis B virusrelated hepatocellular carcinoma undergoing hepatectomy: a randomized controlled trial. Journal of Viral Hepatitis 20: 336–342. doi: 10.1111/jvh.12036