Annals of Surgical Oncology

, Volume 19, Issue 2, pp 418–425 | Cite as

Impact of Pegylated Interferon Therapy on Outcomes of Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma After Curative Hepatic Resection

  • Yoshisato Tanimoto
  • Hirotaka Tashiro
  • Hiroshi Aikata
  • Hironobu Amano
  • Akihiko Oshita
  • Tsuyoshi Kobayashi
  • Shintaro Kuroda
  • Hirofumi Tazawa
  • Shoichi Takahashi
  • Toshiyuki Itamoto
  • Kazuaki Chayama
  • Hideki Ohdan
Hepatobiliary Tumors



Several published reports investigating the effects of interferon (IFN) therapy on survival and tumor recurrence after curative resection of hepatocellular carcinoma (HCC) have been inconclusive. The aim of this study is to investigate the efficacy of pegylated-IFN (peg-IFN) therapy after curative hepatic resection for HCC in patients infected with hepatitis C virus (HCV).


Data from 175 patients who underwent curative hepatic resection for HCC associated with HCV were retrospectively collected and analyzed; 75 patients received peg-IFN therapy after surgery, whereas 100 patients did not receive IFN therapy. To overcome biases resulting from the different distribution of covariates in the two groups, a one-to-one match was created using propensity score analysis. After matching, patient outcomes were analyzed.


After one-to-one matching, patients (n = 38) who received peg-IFN therapy after surgery and patients (n = 38) who did not receive IFN therapy had the same preoperative and operative characteristics. The 3- and 5-year overall survival rates of patients who received peg-IFN therapy after hepatic resection were significantly higher than those of patients who did not receive IFN therapy (P = 0.00135). The 3- and 5-year overall survival rates were 100 and 91.7% and 76.6 and 50.6% in the peg-IFN group and non-IFN group, respectively. There was no significant difference in disease-free survival between the two matched groups (P = 0.886).


Peg-IFN therapy may be effective as an adjuvant chemopreventive agent after hepatic resection in patients with HCV-related HCC.


  1. 1.
    Poon RTP, Fan ST, Lo CM, Liu CL, Wong J. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg. 1999;229:216–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Minagawa M, Makuuchi M, Takayama T, Kokudo N. Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg. 2003;238:703–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Itamoto T, Nakahara H, Amano H, et al. Repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery. 2007;141:589–97.PubMedCrossRefGoogle Scholar
  4. 4.
    Ikeda K, Saitoh S, Arase Y, Chayama K, et al. Effects of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29:1124–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Imai Y, Kawata S, Tamura S, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group. Ann Intern Med. 1998;129:94–9.PubMedGoogle Scholar
  6. 6.
    Camma C, Giunta M, Andreone P, Craxì A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach. J Hepatol. 2001;34:593–602.PubMedCrossRefGoogle Scholar
  7. 7.
    Nishiguchi S, Shiomi S, Nakatani S, et al. Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis. Lancet. 2001;357:196–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Tomimaru Y, Nagano H, Eguchi H, et al. Effects of preceding interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma. J Surg Oncol. 2010;102:308–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Jeong SC, Aikata H, Katamura Y, et al. Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma. World J Gastroenterol. 2007;13:5188–95.PubMedGoogle Scholar
  10. 10.
    Jeong SC, Aikata H, Kayamura Y, et al. Effects of a 24-week course of interferon-α therapy after curative treatment of hepatitis C virus-associated hepatocellular carcinoma. World J Gastroenterol. 2007;13:5343–50.PubMedGoogle Scholar
  11. 11.
    Harada H, Kitagawa M, Tanaka N, et al. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science. 1993;259:971–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Liedtke C, Grogner N, Manns MP, Trautwein C. Interferon-alpha enhances TRAIL-mediated apoptosis by up-regulating caspase-8 transcription in human hepatoma cells. J Hepatol. 2006;44:342–9.PubMedCrossRefGoogle Scholar
  13. 13.
    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;89:418–22.PubMedCrossRefGoogle Scholar
  14. 14.
    Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of primary tumor-a prospective randomized study of hepatitis C virus-related liver cancer. Hepatology. 2000;32:228–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Mazzaferro V, Romito R, Schiavo M, et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 2006;44:1543–54.PubMedCrossRefGoogle Scholar
  16. 16.
    Lo CM, Liu CL, Chan SC, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg. 2007;245:831–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958–65.PubMedCrossRefGoogle Scholar
  18. 18.
    Fried MW, Shiffman ML, Rajender Reddy K, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Yoshida H, Arakawa Y, Sata M, et al. Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology. 2002;123:483–91.PubMedCrossRefGoogle Scholar
  20. 20.
    Kiyosawa K, Uemura T, Ichijo T, et al. Hepatocellular carcinoma: recent trends in Japan. Gastroenterology. 2004;127:S17–26.PubMedCrossRefGoogle Scholar
  21. 21.
    McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485–92.PubMedCrossRefGoogle Scholar
  22. 22.
    Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Eng J Med. 2004;350:2265–71.CrossRefGoogle Scholar
  23. 23.
    Shirakawa H, Matsumoto A, Joshita S, et al. Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis c patients using viral and host factors. Hepatology. 2008;48:1753–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Kogure T, Ueno Y, Fukushima K, et al. Pegylated interferon plus ribavirin for genotype 1b chronic hepatitis C in Japan. World J Gastroentrol. 2008;14:7225–30.CrossRefGoogle Scholar
  25. 25.
    Liver Cancer Study Group of Japan. General Rules for the Clinical and Pathological Study of Primary Liver Cancer. 5th ed. Tokyo: Kanehara; 2008.Google Scholar
  26. 26.
    Itamoto T, Nakahara H, Tashiro H, et al. Indications of partial hepatectomy for transplantable hepatocellular carcinoma with compensated cirrhosis. Am J Surg. 2005;189:167–72.PubMedCrossRefGoogle Scholar
  27. 27.
    Oishi K, Itamoto T, Kobayashi T, et al. Hepatectomy for hepatocellular carcinoma in elderly patients aged 75 years or more. J Gastrointest Surg. 2009;13:695–701.PubMedCrossRefGoogle Scholar
  28. 28.
    Makuuchi M, Hasegawa H, Yamazaki S. Ultrasonically guided subsegmentectomy. Surg Gynecol Obstet. 1985;161:346–50.PubMedGoogle Scholar
  29. 29.
    Yamamoto M, Takasaki K, Otsubo T, et al. Favorable surgical outcomes in patients with early hepatocellular carcinoma. Ann Surg. 2004;239:395–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Itamoto T, Katayama K, Nakahara H, Tashiro H, Asahara T. Autologous blood storage before hepatectomy for hepatocellular carcinoma with underlying liver disease. Br J Surg. 2003;90:23–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien–Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250:187–96.PubMedCrossRefGoogle Scholar
  32. 32.
    Zinsmeister AR, Connor JT. Ten common statistical errors and how to avoid them. Am J Gastroenterol. 2008;103:262–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.CrossRefGoogle Scholar
  34. 34.
    Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 1997;127:757–63.PubMedGoogle Scholar
  35. 35.
    D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to non-randomized control group. Stat Med. 1998;17:2265–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the frequency of interferon gamma-producing human CD4+T cells. J Exp Med. 1993;178:1655–63.PubMedCrossRefGoogle Scholar
  37. 37.
    Wang L, Tang ZY, Qin LX, et al. High-dose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential. Hepatology. 2000;32:43–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C. Ann Intern Med. 2003;138:299–306.PubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2011

Authors and Affiliations

  • Yoshisato Tanimoto
    • 1
  • Hirotaka Tashiro
    • 1
  • Hiroshi Aikata
    • 2
  • Hironobu Amano
    • 1
  • Akihiko Oshita
    • 1
  • Tsuyoshi Kobayashi
    • 1
  • Shintaro Kuroda
    • 1
  • Hirofumi Tazawa
    • 1
  • Shoichi Takahashi
    • 2
  • Toshiyuki Itamoto
    • 3
  • Kazuaki Chayama
    • 2
  • Hideki Ohdan
    • 1
  1. 1.Department of Gastroenterological SurgeryHiroshima University HospitalHiroshimaJapan
  2. 2.Department of GastroenterologyHiroshima University HospitalHiroshimaJapan
  3. 3.Department of SurgeryPrefectural Hiroshima HospitalHiroshimaJapan

Personalised recommendations