Abstract
Purpose
Recurrence is a disastrous outcome in patients with hepatitis-related hepatocellular carcinoma (HCC) who have undergone curative resection, and little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk of HCC recurrence.
Patients and Methods
This retrospective study included 1,360 HBsAg-positive postoperative HCC patients with hepatitis B viral (HBV) DNA levels < 2000 IU/mL, including 298 patients in a training cohort and 1,062 patients in a validation cohort. The prognostic value of the HBsAg level was evaluated using Cox regression and Kaplan–Meier analyses.
Results
We demonstrated that 1,000 IU/mL, but not 10 or 100 IU/mL, was a meaningful cutoff level for significantly discriminating these patients into an HBsAgLow group and an HBsAgHigh group based on correlations between the HBsAg level and liver cirrhosis (p = 0.028), tumor size (p = 0.039), and hepatitis B e antigen level (p < 0.001). The postoperative 1-, 3-, and 5-year overall survival (OS) rates of HCC patients in the HBsAgLow group were significantly higher than those of HCC patients in the HBsAgHigh group. Accordingly, the 5-year recurrence-free survival (RFS) rates of patients in the HBsAgLow group were markedly higher than those of HCC patients in the HBsAgHigh group. The HBsAg level was a prognostic indicator for OS (p = 0.014) and RFS (p = 0.01).
Conclusion
HBsAg level is correlated with more aggressive tumor behavior and serves as a prognostic indicator in patients with surgically resected HCC with low HBV load.
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References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
Forner A. Hepatocellular carcinoma. Lancet. 2012;379:1245–1255.
Xu L, Xiao H, Xu M, Zhou C, Yi L, Liang H. Glioma-derived T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM4) contributes to tumor tolerance. J Biol Chemy. 2011;286(42):36694-36699.
Liu H, Xu J, Zhou L, et al. Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3 K/Akt pathway. Cancer Res. 2011;71(24):7547-7557.
Jang JW, Kwon JH, You CR, et al. Risk of HBV reactivation according to viral status and treatment intensity in patients with hepatocellular carcinoma. Antivir Ther. 2011;16(7):969-977.
Ko CJ, Chien SY, Chou CT, Chen LS, Chen ML, Chen YL. Factors affecting prognosis of small hepatocellular carcinoma in Taiwanese patients following hepatic resection. Can J Gastroenterol. 2011;25(9):485–491.
Ou DP, Yang LY, Huang GW, Tao YM, Ding X, Chang ZG. Clinical analysis of the risk factors for recurrence of HCC and its relationship with HBV. World J Gastroenterol. 2005;11(14):2061–2066.
Yin J, Li N, Han Y, et al. 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.
Li N, Lai EC, Shi J, et al. A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection. Ann Surg Oncol. 2010;17(1):179–185.
Martinot-Peignoux M, Lapalus M, Asselah T, Marcellin P. HBsAg quantification: useful for monitoring natural history and treatment outcome. Liver Int. 2014;34 Suppl 1:97–107.
Weng M, Zeng WZ, Wu XL, et al. Quantification of serum hepatitis B surface antigen in predicting the response of pegylated interferon alfa-2a in HBeAg-positive chronic hepatitis B with prior lamivudine exposure. Virol J. 2013;10(1):277.
Larsson SB, Eilard A, Malmstrom S, et al. HBsAg quantification for identification of liver disease in chronic hepatitis B virus carriers. Liver Int. 2014;34(7):e238–245.
Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology. 2012;143(3):629–636.e1.
Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology. 2013;57(2):441–450.
Tseng TC, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012;142(5):1140–1149.e3; quiz e1113–1144.
Huang G, Yang Y, Shen F, et al. Early viral suppression predicts good postoperative survivals in patients with hepatocellular carcinoma with a high baseline HBV-DNA load. Ann Surg Oncol. 2013;20(5):1482–1490.
Yeh SH, Tsai CY, Kao JH, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol. 2004;41(4):659–666.
Sun HC, Zhang W, Qin LX, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 2007;47(5):684–690.
Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25(18):2586–2593.
Moucari R, Marcellin P. Quantification of hepatitis B surface antigen: a new concept for the management of chronic hepatitis B. Liver Int. 2011;31 Suppl 1:122–128.
Arai M, Togo S, Kanda T, Fujiwara K, Imazeki F, Yokosuka O. Quantification of hepatitis B surface antigen can help predict spontaneous hepatitis B surface antigen seroclearance. Eur J Gastroenterol Hepatol. 2012;24(4):414–418.
Xun YH, Zang GQ, Guo JC, et al. Serum hepatitis B surface antigen quantification as a useful assessment for significant fibrosis in hepatitis B e antigen-positive hepatitis B virus carriers. J Gastroenterol Hepatol. 2013;28(11):1746–1755.
Chan HL, Wong VW, Wong GL, Tse CH, Chan HY, Sung JJ. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology. 2010;52(4):1232–1241.
Brunetto MR, Oliveri F, Colombatto P, et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology. 2010;139(2):483–490.
Zhu X, Gong Q, Yu D, et al. Early serum hepatitis B virus large surface protein level: a stronger predictor of virological response to peginterferon alfa-2a than that to entecavir in HBeAg-positive patients with chronic hepatitis B. J Clin Virol. 2013;57(4):318–322.
Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373(9663):582–592.
Tseng TC, Liu CJ, Chen CL, et al. Serum hepatitis B virus-DNA levels correlate with long-term adverse outcomes in spontaneous hepatitis B e antigen seroconverters. J Infect Dis. 2012;205(1):54–63.
Huang G, Lai EC, Lau WY, et al. Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels. Ann Surg. 2013;257(3):490–505.
Ke Y, Ma L, You XM, et al. Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after radical hepatectomy. Cancer Biol Med. 2013;10(3):158–164.
Sun P, Yang X, He RQ, et al. Antiviral therapy after curative treatment of hepatitis B/C virus-related hepatocellular carcinoma: a systematic review of randomized trials. Hepatol Res. 2014;44(3):259–269.
Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA. 2012;308(18):1906–1914.
Chen LT, Chen MF, Li LA, et al. 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.
Acknowledgment
This work was supported by Grants from the National Natural Science Foundation of China (No. 81272389 and 81030038), National Key Sci-Tech Project (2012ZX10002011-002), and Scholarship Award for Excellent Doctoral Student granted by the Ministry of Education (JFF152005).
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Wei-Ren Liu and Meng-Xin Tian contributed equally to this work.
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Liu, WR., Tian, MX., Jin, L. et al. High Levels of Hepatitis B Surface Antigen are Associated with Poorer Survival and Early Recurrence of Hepatocellular Carcinoma in Patients with Low Hepatitis B Viral Loads. Ann Surg Oncol 22, 843–850 (2015). https://doi.org/10.1245/s10434-014-4043-5
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DOI: https://doi.org/10.1245/s10434-014-4043-5