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Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

In Japan, sorafenib is now the first-line therapy for individuals with advanced hepatocellular carcinoma (HCC), but no other treatment is available for such patients. The aim of this study was to assess the efficacy and safety of combination therapy with systemic continuous intravenous infusion of 5-fluorouracil (5-FU) and subcutaneous peginterferon alfa-2a, which was used before sorafenib was introduced to Japan.

Methods

Two hundred and twenty-three HCC patients, who were not amenable to curative surgery, percutaneous ablation, or transarterial chemoembolization (TACE), and for whom intraarterial chemotherapy was not indicated because of the presence of extrahepatic metastasis or stenosis of the common hepatic artery, received peginterferon alfa-2a (90 μg subcutaneously on days 1, 8, 15, and 22) and 5-FU (500 mg/day intravenously given continuously on days 1–5 and 8–12). We assessed their response to treatment and survival, and treatment safety.

Results

The response rate was 9.4 % (including six patients with complete response) and the disease-control rate was 32.7 %. The median time to progression was 2.0 months. The overall median survival time was 6.5 months (Child–Pugh class A: 9.2 months vs. Child–Pugh class B: 2.8 months). In a multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status >0, Child–Pugh class B, and the presence of macroscopic vascular invasion were independent predictors of poor prognosis. The major grade 3–4 adverse events were leucopenia (13.9 %) and thrombocytopenia (5.8 %). No treatment-related deaths occurred.

Conclusions

This combination therapy was well tolerated and showed promising efficacy. Further studies are needed to establish the usefulness of this treatment.

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Abbreviations

AIC:

Akaike information criterion

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

CR:

Complete response

CT:

Computed tomography

DCP:

Des-gamma-carboxy prothrombin

ECOG:

Eastern Cooperative Oncology Group

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

MRI:

Magnetic resonance imaging

MST:

Median survival time

NA:

Not assessable

PD:

Progressive disease

PR:

Partial response

RECIST:

Response to treatment in solid tumors

SD:

Stable disease

TACE:

Transcatheter arterial chemoembolization

TTP:

Time to progression

5-FU:

5-Fluorouracil

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.

    Article  PubMed  Google Scholar 

  2. Matsuda T, Marugame T, Kamo K, Katanoda K, Ajiki W, Sobue T. Cancer incidence and incidence rates in Japan in 2003: based on data from 13 population-based cancer registries in the Monitoring of Cancer Incidence in Japan (MCIJ) Project. Jpn J Clin Oncol. 2009;39(12):850–8.

    Article  PubMed  Google Scholar 

  3. Shiratori Y, Shiina S, Imamura M, Kato N, Kanai F, Okudaira T, et al. Characteristic difference of hepatocellular carcinoma between hepatitis B- and C-viral infection in Japan. Hepatology. 1995;22(4 Pt 1):1027–33.

    Article  PubMed  CAS  Google Scholar 

  4. Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer. 1985;56(4):918–28.

    Article  PubMed  CAS  Google Scholar 

  5. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology. 2000;32(6):1224–9.

    Article  PubMed  CAS  Google Scholar 

  6. Shiina S, Tagawa K, Niwa Y, Unuma T, Komatsu Y, Yoshiura K, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. AJR Am J Roentgenol. 1993;160(5):1023–8.

    PubMed  CAS  Google Scholar 

  7. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734–9.

    Article  PubMed  Google Scholar 

  8. Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129(1):122–30.

    Article  PubMed  Google Scholar 

  9. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–9.

    Article  PubMed  CAS  Google Scholar 

  10. Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Nakagawa H, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2011 [Epub ahead of print].

  11. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  PubMed  CAS  Google Scholar 

  12. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.

    Article  PubMed  CAS  Google Scholar 

  13. Obi S, Yoshida H, Toune R, Unuma T, Kanda M, Sato S, et al. Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion. Cancer. 2006;106(9):1990–7.

    Article  PubMed  CAS  Google Scholar 

  14. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55.

    Article  PubMed  CAS  Google Scholar 

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.

    Article  PubMed  CAS  Google Scholar 

  16. Torzilli G, Minagawa M, Takayama T, Inoue K, Hui AM, Kubota K, et al. Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy. Hepatology. 1999;30(4):889–93.

    Article  PubMed  CAS  Google Scholar 

  17. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–36.

    Article  PubMed  Google Scholar 

  18. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–17.

    Article  PubMed  Google Scholar 

  19. Wadler S, Schwartz EL, Goldman M, Lyver A, Rader M, Zimmerman M, et al. Fluorouracil and recombinant alfa-2a-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol. 1989;7(12):1769–75.

    PubMed  CAS  Google Scholar 

  20. Greco FA, Figlin R, York M, Einhorn L, Schilsky R, Marshall EM, et al. Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol. 1996;14(10):2674–81.

    PubMed  CAS  Google Scholar 

  21. Patt YZ, Yoffe B, Charnsangavej C, Pazdur R, Fischer H, Cleary K, et al. Low serum alpha-fetoprotein level in patients with hepatocellular carcinoma as a predictor of response to 5-FU and interferon-alpha-2b. Cancer. 1993;72(9):2574–82.

    Article  PubMed  CAS  Google Scholar 

  22. Sakon M, Nagano H, Dono K, Nakamori S, Umeshita K, Yamada A, et al. Combined intraarterial 5-fluorouracil and subcutaneous interferon-alpha therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches. Cancer. 2002;94(2):435–42.

    Article  PubMed  CAS  Google Scholar 

  23. Ota H, Nagano H, Sakon M, Eguchi H, Kondo M, Yamamoto T, et al. Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-alpha and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression. Br J Cancer. 2005;93(5):557–64.

    Article  PubMed  CAS  Google Scholar 

  24. Damdinsuren B, Nagano H, Sakon M, Kondo M, Yamamoto T, Umeshita K, et al. Interferon-beta is more potent than interferon-alpha in inhibition of human hepatocellular carcinoma cell growth when used alone and in combination with anticancer drugs. Ann Surg Oncol. 2003;10(10):1184–90.

    Article  PubMed  Google Scholar 

  25. Eguchi H, Nagano H, Yamamoto H, Miyamoto A, Kondo M, Dono K, et al. Augmentation of antitumor activity of 5-fluorouracil by interferon alpha is associated with up-regulation of p27Kip1 in human hepatocellular carcinoma cells. Clin Cancer Res. 2000;6(7):2881–90.

    PubMed  CAS  Google Scholar 

  26. Moriyama M, Hoshida Y, Kato N, Otsuka M, Yoshida H, Kawabe T, et al. Genes associated with human hepatocellular carcinoma cell chemosensitivity to 5-fluorouracil plus interferon-alpha combination chemotherapy. Int J Oncol. 2004;25(5):1279–87.

    PubMed  CAS  Google Scholar 

  27. Kondo M, Nagano H, Wada H, Damdinsuren B, Yamamoto H, Hiraoka N, et al. Combination of IFN-alpha and 5-fluorouracil induces apoptosis through IFN-alpha/beta receptor in human hepatocellular carcinoma cells. Clin Cancer Res. 2005;11(3):1277–86.

    PubMed  CAS  Google Scholar 

  28. Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, et al. Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence. Nature. 2003;424(6948):516–23.

    Article  PubMed  CAS  Google Scholar 

  29. Nagano H, Miyamoto A, Wada H, Ota H, Marubashi S, Takeda Y, et al. Interferon-alpha and 5-fluorouracil combination therapy after palliative hepatic resection in patients with advanced hepatocellular carcinoma, portal venous tumor thrombus in the major trunk, and multiple nodules. Cancer. 2007;110(11):2493–501.

    Article  PubMed  CAS  Google Scholar 

  30. Yamamoto T, Nagano H, Sakon M, Wada H, Eguchi H, Kondo M, et al. Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-alpha/5-fluorouracil against hepatocellular carcinoma. Clin Cancer Res. 2004;10(23):7884–95.

    Article  PubMed  CAS  Google Scholar 

  31. Nakamura M, Nagano H, Sakon M, Yamamoto T, Ota H, Wada H, et al. Role of the Fas/FasL pathway in combination therapy with interferon-alpha and fluorouracil against hepatocellular carcinoma in vitro. J Hepatol. 2007;46(1):77–88.

    Article  PubMed  CAS  Google Scholar 

  32. Patt YZ, Hassan MM, Lozano RD, Brown TD, Vauthey JN, Curley SA, et al. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol. 2003;21(3):421–7.

    Article  PubMed  CAS  Google Scholar 

  33. Burroughs A, Hochhauser D, Meyer T. Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum. Lancet Oncol. 2004;5(7):409–18.

    Article  PubMed  Google Scholar 

  34. Nowak AK, Chow PK, Findlay M. Systemic therapy for advanced hepatocellular carcinoma: a review. Eur J Cancer. 2004;40(10):1474–84.

    Article  PubMed  CAS  Google Scholar 

  35. Link JS, Bateman JR, Paroly WS, Durkin WJ, Peters RL. 5-Flourouracil in hepatocellular carcinoma: report of twenty-one cases. Cancer. 1977;39(5):1936–9.

    Article  PubMed  CAS  Google Scholar 

  36. Zaniboni A, Simoncini E, Marpicati P, Marini G. Phase II study of 5-fluorouracil (5-FU) and high dose folinic acid (HDFA) in hepatocellular carcinoma. Br J Cancer. 1988;57(3):319.

    Article  PubMed  CAS  Google Scholar 

  37. Tetef M, Doroshow J, Akman S, Coluzzi P, Leong L, Margolin K, et al. 5-Fluorouracil and high-dose calcium leucovorin for hepatocellular carcinoma: a phase II trial. Cancer Invest. 1995;13(5):460–3.

    Article  PubMed  CAS  Google Scholar 

  38. Llovet JM, Ruff P, Tassopoulos N, Castells L, Bruix J, El-Hariry I, et al. A phase II trial of oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma. Eur J Cancer. 2001;37(11):1352–8.

    Article  PubMed  CAS  Google Scholar 

  39. Benson AB 3rd, Mitchell E, Abramson N, Klencke B, Ritch P, Burnhan JP, et al. Oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma. Ann Oncol. 2002;13(4):576–81.

    Article  PubMed  Google Scholar 

  40. Mani S, Schiano T, Garcia JC, Ansari RH, Samuels B, Sciortino DF, et al. Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced hepatocellular carcinoma. Invest New Drugs. 1998;16(3):279–83.

    Article  PubMed  CAS  Google Scholar 

  41. Ishikawa T, Ichida T, Sugitani S, Tsuboi Y, Genda T, Sugahara S, et al. Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IV-A hepatocellular carcinoma. J Gastroenterol Hepatol. 2001;16(4):452–9.

    Article  PubMed  CAS  Google Scholar 

  42. Leung TW, Patt YZ, Lau WY, Ho SK, Yu SC, Chan AT, et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res. 1999;5(7):1676–81.

    PubMed  CAS  Google Scholar 

  43. Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97(20):1532–8.

    Article  PubMed  CAS  Google Scholar 

  44. Ensminger WD, Rosowsky A, Raso V, Levin DC, Glode M, Come S, et al. A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil. Cancer Res. 1978;38(11 Pt 1):3784–92.

    PubMed  CAS  Google Scholar 

  45. Goldberg JA, Kerr DJ, Watson DG, Willmott N, Bates CD, McKillop JH, et al. The pharmacokinetics of 5-fluorouracil administered by arterial infusion in advanced colorectal hepatic metastases. Br J Cancer. 1990;61(6):913–5.

    Article  PubMed  CAS  Google Scholar 

  46. Ueno H, Okada S, Okusaka T, Ikeda M, Kuriyama H. Phase I and pharmacokinetic study of 5-fluorouracil administered by 5-day continuous infusion in patients with hepatocellular carcinoma. Cancer Chemother Pharmacol. 2002;49(2):155–60.

    Article  PubMed  CAS  Google Scholar 

  47. Uchino K, Tateishi R, Shiina S, Kanda M, Masuzaki R, Kondo Y, et al. Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors. Cancer. 2011;117(19):4475–83.

    Article  PubMed  Google Scholar 

  48. Worns MA, Weinmann A, Pfingst K, Schulte-Sasse C, Messow CM, Schulze-Bergkamen H, et al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol. 2009;43(5):489–95.

    Article  PubMed  Google Scholar 

  49. Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Konigsberg R, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist. 2009;14(1):70–6.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by Health Sciences Research Grants of The Ministry of Health, Labour and Welfare of Japan (Research on Hepatitis).

Conflict of interest

Kazuhiko Koike received lecture fees and grant support from Chugai Pharmaceutical Co., Ltd.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Koji Uchino, Ryosuke Tateishi, Toru Arano, Kenichiro Enooku, Eriko Goto, Ryota Masuzaki, Hayato Nakagawa, Yoshinari Asaoka, Yuji Kondo, Noriyo Yamashiki, Tadashi Goto, Shuichiro Shiina, Haruhiko Yoshida & Kazuhiko Koike

  2. Department of Gastroenterology and Hepatology, Kyoundo Hospital, Tokyo, Japan

    Shuntaro Obi, Shinpei Sato, Miho Kanda & Takahisa Sato

  3. Yamanashi Prefectural Hospital Organization, Yamanashi, Japan

    Masao Omata

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  1. Koji Uchino
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  2. Shuntaro Obi
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Corresponding author

Correspondence to Ryosuke Tateishi.

Additional information

K. Uchino and S. Obi contributed equally to this work.

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Uchino, K., Obi, S., Tateishi, R. et al. Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma. J Gastroenterol 47, 1152–1159 (2012). https://doi.org/10.1007/s00535-012-0574-3

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