Advertisement

Postoperative interferon α treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial

  • Hui-Chuan Sun
  • Zhao-You TangEmail author
  • Lu Wang
  • Lun-Xiu Qin
  • Zeng-Chen Ma
  • Qin-Hai Ye
  • Bo-Heng Zhang
  • Yong-Bin Qian
  • Zhi-Quan Wu
  • Jia Fan
  • Xin-Da Zhou
  • Jian Zhou
  • Shuang-Jian Qiu
  • Yue-Fang Shen
Original Paper

Abstract

Background/Aims: Recurrence after resection of hepatocellular carcinoma (HCC) is a frequent event. This study evaluated the effect of postoperative interferon α (IFN α) treatment on recurrence and survival in patients with hepatitis B virus (HBV)-related HCC. Method: Two hundred and thirty six patients were randomized after resection into IFN α treatment (5 mu i.m. tiw for 18 months) and control groups. Treatment was terminated if recurrence was diagnosed, and recurrence was managed the same way in both groups. Statistical analysis was based on the method of intent-to-treat. Results: The two groups were comparable in all clinicopathological parameters. The median overall survival was 63.8 months in the treatment group and 38.8 months in the control group (P=0.0003); the median disease-free survival period was 31.2 versus 17.7 months (P=0.142). Fever, leucocytopenia, and thrombocytopenia were adverse effects in the treatment group, but were mostly manageable. Conclusions: IFN α treatment improved the overall survival of patients with HBV-related HCC after curative resection, probably by postponing recurrence.

Keywords

Hepatocellular carcinoma Resection Recurrence Interferon α 

Abbreviations

AFP

Alpha fetoprotein

ALT

Alanine aminotransferase

AST

Aspartate transaminase

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

IFN α

Interferon α

PEI

Percutaneous ethanol injection

RFA

Radiofrequency ablation

TACE

Transcatheter arterial chemoembolization

Notes

Acknowledgment

The authors thank Drs. Zhang Ke-Zhi, Qian Yong-Bing, and Lu Lu for assistance in patient follow-up and data collection. This investigation was partly supported by the Key Projects on Clinical Medicine from the Ministry of Public Health of P. R. China (2001): the novel predictive markers and preventive strategies for the recurrence of liver cancer, and Liver Cancer Center from Bureau of Public Health of Shanghai (2001).

References

  1. Belghiti J, Panis Y, Farges O, Benhamou JP, Fekete F (1991) Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg 214:114–117PubMedCrossRefGoogle Scholar
  2. Chung YH, Song IH, Song BC, Lee GC, Koh MS, Yoon HK, Lee YS, Sung KB, Suh DJ (2000) Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis. Cancer 88:1986–1991PubMedCrossRefGoogle Scholar
  3. Dupont WD, Plummer WD Jr (1990) Power and sample size calculations. A review and computer program. Control Clin Trials 11:116–128PubMedCrossRefGoogle Scholar
  4. van der Eijk AA, Niesters HG, Hansen BE, Heijtink RA, Janssen HL, Schalm SW, de Man RA (2006) Quantitative HBV DNA levels as an early predictor of nonresponse in chronic HBe-antigen positive hepatitis B patients treated with interferon-alpha. J Viral Hepat 13:96–103PubMedCrossRefGoogle Scholar
  5. Hanazaki K, Kajikawa S, Shimozawa N, Mihara M, Shimada K, Hiraguri M, Koide N, Adachi W, Amano J (2000) Survival and recurrence after hepatic resection of 386 consecutive patients with hepatocellular carcinoma. J Am Coll Surg 191:381–388PubMedCrossRefGoogle Scholar
  6. Ikeda K, Arase Y, Kobayashi M, Someya T, Hosaka T, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Kumada H (2005) Hepatitis B virus-related hepatocellular carcinogenesis and its prevention. Intervirology 48:29–38PubMedCrossRefGoogle Scholar
  7. Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, Chayama K, Murashima N, Kumada H (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 32:228–232PubMedCrossRefGoogle Scholar
  8. Izumi R, Shimizu K, Iyobe T, Ii T, Yagi M, Matsui O, Nonomura A, Miyazaki I (1994) Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 20:295–301PubMedCrossRefGoogle Scholar
  9. Jonasch E, Haluska FG (2001) Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 6:34–55PubMedCrossRefGoogle Scholar
  10. Kohno H, Nagasue N, Hayashi T, Yamanoi A, Uchida M, Ono T, Yukaya H, Kimura N, Nakamura T (1996) Postoperative adjuvant chemotherapy after radical hepatic resection for hepatocellular carcinoma (HCC). Hepatogastroenterology 43:1405–1409PubMedGoogle Scholar
  11. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita H (2002) Randomized clinical trial of long-term outcome after resection of hepatitis C virus-related hepatocellular carcinoma by postoperative interferon therapy. Br J Surg 89:418–422PubMedCrossRefGoogle Scholar
  12. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, Shiomi S, Tamori A, Oka H, Igawa S et al (2001) Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial. Ann Intern Med 134:963–967PubMedGoogle Scholar
  13. Lai EC, Lo CM, Fan ST, Liu CL, Wong J (1998) Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg 133:183–188PubMedCrossRefGoogle Scholar
  14. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW et al (2005) Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 352:2682–2695PubMedCrossRefGoogle Scholar
  15. Lau WY, Leung TW, Ho SK, Chan M, Machin D, Lau J, Chan AT, Yeo W, Mok TS, Yu SC et al (1999) Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 353:797–801PubMedCrossRefGoogle Scholar
  16. Leung TW, Tang AM, Zee B, Yu SC, Lai PB, Lau WY, Johnson PJ (2002) Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-alpha, doxorubicin and 5-fluorouracil chemotherapy. Cancer 94:421–427PubMedCrossRefGoogle Scholar
  17. Liaw YF (2005) Prevention and surveillance of hepatitis B virus-related hepatocellular carcinoma. Semin Liver Dis 25 (suppl 1):40–47PubMedCrossRefGoogle Scholar
  18. Lin SM, Lin CJ, Hsu CW, Tai DI, Sheen IS, Lin DY, Liaw YF (2004) Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer 100:376–382PubMedCrossRefGoogle Scholar
  19. Lin ZY, Ren ZG, Xia JL, Chen Y, Wu XF, Ma ZC, Ye QH, Qin LX, Sun HC (2000) Appraisal of postoperative transcatheter arterial chemoembolization (TACE) for prevention and treatment of hepatocellular carcinoma recurrence. Zhonghua Zhongliu Zazhi 22:315–317PubMedGoogle Scholar
  20. Lok AS (2004) Prevention of hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 127:S303–S309PubMedCrossRefGoogle Scholar
  21. Mathurin P, Raynard B, Dharancy S, Kirzin S, Fallik D, Pruvot FR, Roumilhac D, Canva V, Paris JC, Chaput JC, Naveau S (2003) Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther 17:1247–1261PubMedCrossRefGoogle Scholar
  22. Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E et al (1996) Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 334:1561–1567PubMedCrossRefGoogle Scholar
  23. Muto Y, Moriwaki H, Saito A (1999) Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 340:1046–1047PubMedCrossRefGoogle Scholar
  24. Ono T, Nagasue N, Kohno H, Hayashi T, Uchida M, Yukaya H, Yamanoi A (1997) Adjuvant chemotherapy with epirubicin and carmofur after radical resection of hepatocellular carcinoma: a prospective randomized study. Semin Oncol 24:S6-18–S16-25Google Scholar
  25. Patt YZ, Hassan MM, Lozano RD, Brown TD, Vauthey JN, Curley SA, Ellis LM (2003) Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 21:421–427PubMedCrossRefGoogle Scholar
  26. Poon RT, Fan ST, Lo CM, Ng IO, Liu CL, Lam CM, Wong J (2001) Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg 234:63–70PubMedCrossRefGoogle Scholar
  27. Regimbeau JM, Abdalla EK, Vauthey JN, Lauwers GY, Durand F, Nagorney DM, Ikai I, Yamaoka Y, Belghiti J (2004) Risk factors for early death due to recurrence after liver resection for hepatocellular carcinoma: results of a multicenter study. J Surg Oncol 85:36–41PubMedCrossRefGoogle Scholar
  28. Schwartz JD, Schwartz M, Mandeli J, Sung M (2002) Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol 3:593–603PubMedCrossRefGoogle Scholar
  29. Shigeno M, Nakao K, Ichikawa T, Suzuki K, Kawakami A, Abiru S, Miyazoe S, Nakagawa Y, Ishikawa H, Hamasaki K et al (2003) Interferon-alpha sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-kappa B inactivation. Oncogene 22:1653–1662PubMedCrossRefGoogle Scholar
  30. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T (2000) Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356:802–807PubMedCrossRefGoogle Scholar
  31. Tang ZY, Yu YQ, Zhou XD, Ma ZC, Wu ZQ (1998) Progress and prospects in hepatocellular carcinoma surgery. Ann Chir 52:558–563PubMedGoogle Scholar
  32. Truong BX, Seo Y, Kato M, Hamano K, Ninomiya T, Katayama M, Kato H, Yano Y, Hayashi Y, Kasuga M (2005) Long-term follow-up of Japanese patients with chronic hepatitis B treated with interferon-alpha. Int J Mol Med 16:279–284PubMedGoogle Scholar
  33. Wang L, Tang ZY, Qin LX, Wu XF, Sun HC, Xue Q, Ye SL (2000) 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 32:43–48PubMedCrossRefGoogle Scholar
  34. Wang L, Wu WZ, Sun HC, Wu XF, Qin LX, Liu YK, Liu KD, Tang ZY (2003) Mechanism of interferon alpha on inhibition of metastasis and angiogenesis of hepatocellular carcinoma after curative resection in nude mice. J Gastrointest Surg 7:587–594PubMedCrossRefGoogle Scholar
  35. Xiao YS, Tang ZY, Fan J, Zhou J, Wu ZQ, Sun QM, Xue Q, Zhao Y, Liu YK, Ye SL (2004) Interferon-alpha 2a up-regulated thymidine phosphorylase and enhanced antitumor effect of capecitabine on hepatocellular carcinoma in nude mice. J Cancer Res Clin Oncol 130:546–550PubMedCrossRefGoogle Scholar
  36. Yano H, Iemura A, Haramaki M, Ogasawara S, Takayama A, Akiba J, Kojiro M (1999) Interferon alfa receptor expression and growth inhibition by interferon alfa in human liver cancer cell lines. Hepatology 29:1708–1717PubMedCrossRefGoogle Scholar
  37. Yu SZ (1995) Primary prevention of hepatocellular carcinoma. J Gastroenterol Hepatol 10:674–682PubMedCrossRefGoogle Scholar
  38. Yuen MF, Hui CK, Cheng CC, Wu CH, Lai YP, Lai CL (2001) Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology 34:139–145PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Hui-Chuan Sun
    • 1
  • Zhao-You Tang
    • 1
    Email author
  • Lu Wang
    • 1
  • Lun-Xiu Qin
    • 1
  • Zeng-Chen Ma
    • 1
  • Qin-Hai Ye
    • 1
  • Bo-Heng Zhang
    • 1
  • Yong-Bin Qian
    • 1
  • Zhi-Quan Wu
    • 1
  • Jia Fan
    • 1
  • Xin-Da Zhou
    • 1
  • Jian Zhou
    • 1
  • Shuang-Jian Qiu
    • 1
  • Yue-Fang Shen
    • 1
  1. 1.Liver Cancer Institute and Zhong Shan HospitalFudan UniversityShanghaiPeople’s Republic of China

Personalised recommendations