International Journal of Clinical Oncology

, Volume 16, Issue 3, pp 221–229 | Cite as

Combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma

  • Kazuhiro Kasai
  • Akira Ushio
  • Yukiho Kasai
  • Kei Sawara
  • Yasuhiro Miyamoto
  • Kanta Oikawa
  • Hidekatsu Kuroda
  • Yasuhiro Takikawa
  • Kazuyuki Suzuki
Original Article



This study evaluated the efficacy of combined 5-fluorouracil (5-FU) and pegylated interferon (PEG-IFN) α-2b in patients with advanced hepatocellular carcinoma (HCC).


Fifty patients with portal vein tumor thrombosis were enrolled. Of these, 21 patients were treated using subcutaneous administration of PEG-IFNα-2b and intra-arterial infusion of 5-FU (5-FU/PEG-IFN group), 12 patients were treated using intramuscular administration of IFNα-2b and intra-arterial infusion of 5-FU (5-FU/IFN group), and 17 patients received intra-arterial infusion chemotherapy with lipiodol-cisplatin (CDDP) suspension (CDDP group).


The objective early response rate was significantly higher in the 5-FU/PEG-IFN group than in the 5-FU/IFN or CDDP groups (71.4 vs. 8.3% and 17.6%, respectively; P < 0.0001). Cumulative survival rates at 6 and 12 months were 83.8 and 77.8% in the 5-FU/PEG-IFN group, 60.8 and 16.2% in the 5-FU/IFN group, and 58.4 and 12.5% in the CDDP group, respectively. The cumulative survival rate was significantly higher in the 5-FU/PEG-IFN group than in the other 2 groups (P = 0.0272). Serious complications and treatment-related deaths were not observed in any of the 3 groups.


Although a prospective randomized controlled trial using a larger population of patients with advanced HCC is needed to evaluate combination therapy with 5-FU and PEG-IFNα-2b, this new combination therapy may be useful for patients with advanced HCC.


5-Fluorouracil Hepatocellular carcinoma PEG-IFNα-2b Portal venous invasion 



The authors wish to thank Ms. Kouko Motodate for preparing serum samples.

Conflict of interest

No author has any conflict of interest.


  1. 1.
    EI-Serag HB, Mason A (1999) Rising incidence of hepatocellular carcinoma in United States. N Engl J Med 340:745–750CrossRefGoogle Scholar
  2. 2.
    Okuda K, Fujimoto I, Hanai A et al (1987) Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 47:4967–4972PubMedGoogle Scholar
  3. 3.
    La Vecchia C, Lucchini F, Franceschi S et al (2000) Trends in mortality from primary liver cancer in Europe. Eur J Cancer 36:909–915PubMedCrossRefGoogle Scholar
  4. 4.
    Ohtomo K, Furui S, Kokubo T et al (1985) Transcatheter arterial embolization (TAE) in treatment for hepatoma-analysis of three-year survivors. Radiat Med 3:176–180PubMedGoogle Scholar
  5. 5.
    Shiina S, Tagawa K, Unuma T et al (1990) Percutaneous ethanol injection therapy for treatment of hepatocellular carcinoma. Am J Roentgenol 154:947–951Google Scholar
  6. 6.
    Shiina S, Teratani T, Obi S et al (2002) Nonsurgical treatment of hepatocellular carcinoma: from percutaneous ethanol injection therapy and percutaneous microwave coagulation therapy to radiofrequency ablation. Oncology 62(Suppl 1):64–68 (Review)PubMedCrossRefGoogle Scholar
  7. 7.
    Stehlin JS Jr, de Ipolyi PD, Greeff PJ et al (1988) Treatment of cancer of the liver: twenty years’ experience with infusion and resection in 414 patients. Ann Surg 208:23–35PubMedCrossRefGoogle Scholar
  8. 8.
    Ono Y, Yoshimasu T, Ashikaga R et al (2000) Long-term results of lipiodol-transcatheter arterial embolization with cisplatin or doxorubicin for unresectable hepatocellular carcinoma. Am J Clin Oncol 23:564–568PubMedGoogle Scholar
  9. 9.
    Yoshikawa M, Ono N, Yodono H et al (2008) Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol Res 38:474–483PubMedCrossRefGoogle Scholar
  10. 10.
    Sakon M, Nagano H, Dono K et al (2002) Combined intraarterial 5-fluorouracil and subcutaneous interferon-alpha therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches. Cancer 94:435–442PubMedCrossRefGoogle Scholar
  11. 11.
    Obi S, Yoshida H, Toune R et al (2006) Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion. Cancer 106:1990–1997PubMedCrossRefGoogle Scholar
  12. 12.
    Glue P, Fang JW, Rouzier-Panis R et al (2000) Pegylated interferon-α2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharmacol Ther 68:556–567PubMedCrossRefGoogle Scholar
  13. 13.
    Kasai K, Kuroda H, Ushio A et al (2009) Evaluation of newly developed combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma with portal venous invasion. Hepatol Res 39:117–125PubMedCrossRefGoogle Scholar
  14. 14.
    Oken MM, Creech RH, Tormey DC et al (1982) Toxicity and response criteria of Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655PubMedCrossRefGoogle Scholar
  15. 15.
    Liver Cancer Study Group of Japan (2000) The general rules for the clinical and pathological study of primary liver cancer, 4th edn. Kanehara, Tokyo, p 19 (in Japanese)Google Scholar
  16. 16.
    Irie T (2001) Intraarterial chemotherapy of liver metastasis: implantation of microcatheter-port system with use of modified fixed catheter tip technique. J Vasc Interv Radiol 12:1215–1218PubMedCrossRefGoogle Scholar
  17. 17.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  18. 18.
    NCI Common Toxicity Criteria. Common terminology criteria for adverse events v3.0 (CTCAE). Cited 9 August 2006. Available from:
  19. 19.
    Fujii T, Takayasu K, Muramatsu Y et al (1993) Hepatocellular carcinoma with portal tumor thrombus: analysis of factors determining prognosis. Jpn J Clin Oncol 23:105–109PubMedGoogle Scholar
  20. 20.
    Chen SC, Hsieh MY, Chuang WL et al (1994) Development of portal vein invasion and its outcome in hepatocellular carcinoma treated by transcatheter arterial chemo-embolization. J Gastroenterol Hepatol 9:1–6PubMedCrossRefGoogle Scholar
  21. 21.
    Schwartz EL, Hoffman M, O’Connor CJ et al (1992) Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells. Biochem Biophys Res Commun 182:1232–1239PubMedCrossRefGoogle Scholar
  22. 22.
    Wadler S, Schwartz EL (1990) Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 50:3473–3486PubMedGoogle Scholar
  23. 23.
    Elias L, Sandoval JM (1989) Interferon effects upon fluorouracil metabolism by HL-60 cells. Biochem Biophys Res Commun 163:867–874PubMedCrossRefGoogle Scholar
  24. 24.
    Kondo M, Nagano H, Wada H et al (2005) Combination of IFN-α and 5-fluorouracil induces apoptosis through IFN-α/β receptor in human hepatocellular carcinoma cells. Clin Cancer Res 11:1277–1286PubMedCrossRefGoogle Scholar
  25. 25.
    Yano H, Iemura A, Haramaki M et al (1999) Interferon alfa receptor expression and growth inhibition by interferon alpha in human liver cell lines. Hepatology 29:1708–1717PubMedCrossRefGoogle Scholar
  26. 26.
    Silva M, Poo J, Wagner F et al (2006) A randomized trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE). J Hepatol 45:204–213PubMedCrossRefGoogle Scholar
  27. 27.
    Drewinko B, Yang L-Y (1985) Cellular basis for the inefficacy of 5-FU in human colon carcinoma. Cancer Treat Res 69:1391–1398Google Scholar
  28. 28.
    Guchelaar HJ, Vermes I, Koopmans RP et al (1998) Apoptosis-and necrosis-inducing potential of cladribine, cytarabine, cisplatin, and 5-fluorouracil in vitro: a quantitative pharmacodynamic model. Cancer Chemother Pharmacol 42:77–83PubMedCrossRefGoogle Scholar
  29. 29.
    Ueshima K, Tatsumi C, Sakaguchi Y et al (2006) Breakthrough of the hepatic arterial infusion chemotherapy of hepatocellular carcinoma. Gastroenterology (Tokyo) 43:253–259 (in Japanese)Google Scholar
  30. 30.
    Okada S, Okazaki N, Nose H et al (1992) Prognostic factors in patients with hepatocellular carcinoma receiving systemic chemotherapy. Hepatology 16:112–117PubMedCrossRefGoogle Scholar
  31. 31.
    Uka K, Aikata H, Takaki S et al (2007) Pretreatment predictor of response, time to progression, and survival to intraarterial 5-fluorouracil/interferon combination therapy in patients with advanced hepatocellular carcinoma. J Gastroenterol 42:845–853PubMedCrossRefGoogle Scholar
  32. 32.
    Kantoh T, Abo H, Tomotsu K et al (1993) Prognostic factors in patients with hepatocellular carcinoma treated by transcatheter arterial embolization (TAE)––significance of repetitive therapies and responses to them within 6 months after the first intervention. Nippon Shokakibyo Gakkai Zasshi 90:1416–1424 (in Japanese)PubMedGoogle Scholar
  33. 33.
    Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2010

Authors and Affiliations

  • Kazuhiro Kasai
    • 1
  • Akira Ushio
    • 1
  • Yukiho Kasai
    • 1
  • Kei Sawara
    • 1
  • Yasuhiro Miyamoto
    • 1
  • Kanta Oikawa
    • 1
  • Hidekatsu Kuroda
    • 1
  • Yasuhiro Takikawa
    • 1
  • Kazuyuki Suzuki
    • 1
  1. 1.Division of Gastroenterology and Hepatology, Department of Internal MedicineIwate Medical UniversityMoriokaJapan

Personalised recommendations