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
Corresponding Author
Kenji Ikeda M.D.
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Department of Gastroenterology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-0001, Japan. fax: (81) 44-860-1623.===Search for more papers by this authorYasuji Arase
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorSatoshi Saitoh
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorMasahiro Kobayashi
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorYoshiyuki Suzuki
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorFumitaka Suzuki
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorAkihito Tsubota
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorKazuaki Chayama
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorNaoya Murashima
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorHiromitsu Kumada
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Kenji Ikeda M.D.
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Department of Gastroenterology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-0001, Japan. fax: (81) 44-860-1623.===Search for more papers by this authorYasuji Arase
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorSatoshi Saitoh
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorMasahiro Kobayashi
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorYoshiyuki Suzuki
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorFumitaka Suzuki
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorAkihito Tsubota
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorKazuaki Chayama
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorNaoya Murashima
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorHiromitsu Kumada
From the Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Search for more papers by this authorAbstract
Because hepatocellular carcinoma often recurs after surgical resection or ethanol injection therapy, we conducted a prospective randomized controlled trial of interferon (IFN) in patients with chronic liver disease caused by hepatitis C virus (HCV). Twenty eligible patients with cirrhosis were randomized into two groups: 10 patients treated with 6 million units of natural IFN-β twice a week for 36 months and 10 patients without IFN therapy. One patient within the treatment group discontinued interferon therapy after 19 months of treatment because of a mild degree of retinopathy. None of the patients in either group lost HCV-RNA until the end of the observation. Although 7 (70.0%) of 10 patients in the nontreatment group showed tumor recurrence, only 1 (10.0%) of 10 patients with IFN therapy developed tumor recurrence during a median observation period of 25.0 months. Cumulative recurrence rates of the treated and untreated groups were 0% and 62.5% at the end of the first year, and 0% and 100% at the second year, respectively (log-rank test, P = .0004). In conclusion, intermittent administration of IFN suppressed tumor recurrence after treatment with surgery or ethanol injection in patients with HCV-related chronic liver disease.
REFERENCES
- 1 Bruix J, Calvet X, Costa J, Ventura M, Bruguera M, Castillo R, Barrera JM, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989; 2: 1004–1006.MEDLINE
- 2 Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA, Dioguardi N, et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989; 2: 1006–1008.MEDLINE
- 3 Hasan F, Jeffers LJ, Medina MD, Reddy KR, Parker T, Schiff ER, Houghton M, et al. Hepatitis C–associated hepatocellular carcinoma. Hepatology 1990; 12: 589–591.MEDLINE
- 4 Kew MC, Houghton M, Choo QL, Kuo G. Hepatitis C virus antibodies in southern African blacks with hepatocellular carcinoma. Lancet 1990; 335: 873–874.MEDLINE
- 5 Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, Kumada H, Kawanishi M. A multivariate analysis of risk factors for hepatocellular carcinogenesis—A prospective observation of 795 cases with viral and alcoholic cirrhosis. Hepatology 1993; 18: 47–53.MEDLINE
- 6 Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993; 328: 1797–1801.MEDLINE
- 7 Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis—A prospective observation of 2215 patients. J Hepatol 1998; 28: 930–938.MEDLINE
- 8 Franco D, Smadja C, Meakins JL, Berthoux L, Grange D. Improved early results of elective hepatic resection for liver tumors: one hundred consecutive hepatectomies in cirrhotic and noncirrhotic patients. Arch Surg 1989; 124: 1033–1037.MEDLINE
- 9 Nagao T, Inoue S, Yoshimi F, Sodeyama M, Omori Y, Mizuta T, Kawano N, et al. Postoperative recurrence of hepatocellular carcinoma. Ann Surg 1990; 211: 28–33.MEDLINE
- 10
Yamanaka N,
Okamoto E,
Toyosaka A,
Mitunobu M,
Fujiwara S,
Kato T,
Fujimoto J, et al.
Prognostic factors after hepatectomy for hepatocellular carcinomas: a univariate and multivariate analysis.
Cancer
1990;
65: 1104–1110.MEDLINE
10.1002/1097-0142(19900301)65:5<1104::AID-CNCR2820650511>3.0.CO;2-G PubMed Web of Science® Google Scholar
- 11
Arii S,
Tanaka J,
Yamazoe Y,
Minematsu S,
Morino T,
Fujita K,
Maetani S, et al.
Predictive factors for intrahepatic recurrence of hepatocellular carcinoma after partial hepatectomy.
Cancer
1992;
69: 913–919.MEDLINE
10.1002/1097-0142(19920215)69:4<913::AID-CNCR2820690413>3.0.CO;2-T CAS PubMed Web of Science® Google Scholar
- 12
Ikeda K,
Saitoh S,
Tsubota A,
Arase Y,
Chayama K,
Kumada H,
Watanabe G, et al.
Risk factors for tumor recurrence and prognosis after curative resection of hepatocellular carcinoma.
Cancer
1993;
71: 19–25.MEDLINE
10.1002/1097-0142(19930101)71:1<19::AID-CNCR2820710105>3.0.CO;2-I CAS PubMed Web of Science® Google Scholar
- 13 Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC, Perrillo RP, Carey W, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter, randomized, controlled trial. N Engl J Med 1989; 321: 1501–1506.MEDLINE
- 14 Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, et al. Recombinant interferon alfa therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1989; 321: 1506–1510.MEDLINE
- 15 Causse X, Godinot H, Chevallier M, Chossegros P, Zoulim F, Ouzan D, Heyraud JP, et al. Comparison of 1 or 3 MU of interferon alfa-2b and placebo in patients with chronic non-A, non-B hepatitis. Gastroenterology 1991; 101: 497–502.MEDLINE
- 16 Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, Shiomi S, et al. Randomized trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995; 346: 1051–1055.MEDLINE
- 17 Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, Teubota A, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C—a long-term observation study of 1643 patients using statistical bias correction with proportional hazard analysis. Hepatology 1999; 29: 1124–1130.MEDLINE
- 18 Dunk AA, Ikeda T, Pignatelli M, Thomas HC. Human lymphoblastoid interferon: in vitro and in vivo studies in hepatocellular carcinoma. J Hepatol 1986; 2: 419–429.MEDLINE
- 19 Lai CL, Lau JY, Wu PC, Ngan H, Chung HT, Mitchell SJ, Corbett TJ, et al. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology 1993; 17: 389–394.MEDLINE
- 20 Kaplan EL, Meier P. Nonparametric estimation for incomplete observation. J Am Stat Assoc 1958; 53: 457–481.
- 21 SAS Institute Inc. SAS/STAT User's Guide, Release 6.11 Edition. Cary, NC, USA, 1996.
- 22 Kasahara A, Hayashi N, Mochizuki K, Takayanagi M, Yoshioka K, Kakumu S, Iijima A, et al. Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Osaka Liver Disease Study Group. Hepatology 1998; 27: 1394–1402.MEDLINE
- 23 Moreno MG, Muriel P. Remission of liver fibrosis by interferon-alpha 2b. Biochem Pharmacol 1995; 50: 515–520.MEDLINE
- 24
Tarao K,
Takemiya S,
Tamai S,
Sugimasa Y,
Ohkawa S,
Akaike M,
Tanabe H, et al.
Relationship between the recurrence of hepatocellular carcinoma (HCC) and serum alanine aminotransferase levels in hepatectomized patients with hepatitis C virus-associated cirrhosis and HCC.
Cancer
1997;
79: 688–694.MEDLINE
10.1002/(SICI)1097-0142(19970215)79:4<688::AID-CNCR5>3.0.CO;2-A PubMed Web of Science® Google Scholar
