Prevention of Hepatocellular Carcinoma and Its Recurrence in Chronic Hepatitis C Patients by Interferon Therapy
Authors: M OMATA, H YOSHIDA, Y SHIRATORI
Journal: Clinical Gastroenterology and Hepatology (2005)

Chronic hepatitis C is a leading cause of hepatocellular carcinoma (HCC) worldwide. Prevention of chronic hepatitis C–related HCC is one of the most important issues in current hepatology. We conducted 2 cohort studies, one among patients with chronic hepatitis C mostly without cirrhosis and another among those with compensated cirrhosis, to confirm the prevention of HCC by interferon. We also conducted a randomized controlled study among patients with HCV-related HCC treated completely by ablation to examine the effect of interferon therapy on prognosis. With the chronic hepatitis C cohort, we showed that the risk of HCC development, which was strongly associated with the stage of liver fibrosis, age, and gender, was reduced by interferon therapy to one fifth among sustained virologic responders compared with untreated patients. Life expectancy was also significantly prolonged. The benefit of interferon therapy was greater among those with the higher risk of HCC. We confirmed efficacy in HCC-prevention in the second study among patients with compensated cirrhosis who received interferon therapy. The third study among HCC patients who had received complete tumor ablation showed that interferon therapy was associated with better survival, primarily as a result of the preservation of liver function and also probably prevention of recurrence. We have shown beneficial effects of interferon therapy on HCC prevention and liver function preservation. They were the strongest in sustained virologic responders. Further improvement in prognosis may be expected in the future because the current combination therapy of pegylated interferon and ribavirin shows higher efficiency than interferon alone. Chronic hepatitis C is a leading cause of hepatocellular carcinoma (HCC) worldwide. Prevention of chronic hepatitis C–related HCC is one of the most important issues in current hepatology. We conducted 2 cohort studies, one among patients with chronic hepatitis C mostly without cirrhosis and another among those with compensated cirrhosis, to confirm the prevention of HCC by interferon. We also conducted a randomized controlled study among patients with HCV-related HCC treated completely by ablation to examine the effect of interferon therapy on prognosis. With the chronic hepatitis C cohort, we showed that the risk of HCC development, which was strongly associated with the stage of liver fibrosis, age, and gender, was reduced by interferon therapy to one fifth among sustained virologic responders compared with untreated patients. Life expectancy was also significantly prolonged. The benefit of interferon therapy was greater among those with the higher risk of HCC. We confirmed efficacy in HCC-prevention in the second study among patients with compensated cirrhosis who received interferon therapy. The third study among HCC patients who had received complete tumor ablation showed that interferon therapy was associated with better survival, primarily as a result of the preservation of liver function and also probably prevention of recurrence. We have shown beneficial effects of interferon therapy on HCC prevention and liver function preservation. They were the strongest in sustained virologic responders. Further improvement in prognosis may be expected in the future because the current combination therapy of pegylated interferon and ribavirin shows higher efficiency than interferon alone. Hepatocellular carcinoma (HCC) is one of the most common malignancies in Japan and elsewhere in the world. Currently about 80%–90% of HCC patients in Japan have HCV infection. Although no vaccine is currently available to prevent HCV infection, we can prevent acute HCV infection from becoming chronic by interferon administration.1Omata M. Yokosuka O. Takano S. et al.Resolution of acute hepatitis C after therapy with natural beta interferon.Lancet. 1991; 338: 914-915Abstract PubMed Scopus (207) Google Scholar, 2Jaeckel E. Cornberg M. Wedemeyer H. et al.Treatment of acute hepatitis C with interferon alfa-2b.N Engl J Med. 2001; 345: 1452-1457Crossref PubMed Scopus (757) Google Scholar, 3Nomura H. Sou S. Tanimoto H. et al.Short-term interferon-alfa therapy for acute hepatitis C a randomized controlled trial.Hepatology. 2004; 39: 1213-1219Crossref PubMed Scopus (160) Google Scholar However, once it becomes chronic, chronic hepatitis C progresses slowly but steadily to cirrhosis and might eventually lead to HCC. The annual incidence of HCC among HCV-positive cirrhotic patients has been reported to be 1.4%–3.3% in Europe and the United States and 5%–7% in Japan.4Yoshida H. Shiratori Y. Moriyama M. et al.Interferon therapy reduces the risk for hepatocellular carcinoma national surveillance program in Japan of cirrhotic and non-cirrhotic patients with chronic hepatitis C.Ann Intern Med. 1999; 131: 174-181Crossref PubMed Scopus (1009) Google Scholar, 5Nishiguchi S. Shiomi S. Nakatani S. et al.Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis.Lancet. 2001; 357: 196-197Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 6Fattovich G. Giustina G. Degos F. et al.Morbidity and mortality in compensated cirrhosis type C a retrospective follow-up study of 384 patients.Gastroenterology. 1997; 112: 463-472Abstract Full Text Full Text PDF PubMed Scopus (1239) Google Scholar, 7Niederau C. Lange S. Heintges T. et al.Prognosis of chronic hepatitis C results of a larger, prospective cohort study.Hepatology. 1998; 28: 1687-1695Crossref PubMed Scopus (582) Google Scholar, 8Serfaty L. Aumaitre H. Chazouilleres O. et al.Determinants of outcome of compensated hepatitis C virus-related cirrhosis.Hepatology. 1998; 27: 1435-1440Crossref PubMed Scopus (394) Google Scholar Although the reason for the geographical difference has not been fully elucidated, certain risk factors for HCC, such as the age and gender of patients, might have played a role. Increasing incidence of HCC has been reported in European countries and the United States recently.9El-Serag H.B. Davila J.A. Petersen N.J. et al.The continuing increase in the incidence of hepatocellular carcinoma in the United States an update.Ann Intern Med. 2003; 139: 817-823Crossref PubMed Scopus (834) Google Scholar With the higher incidence of HCC, we have stood the better chance of evaluating the inhibitory effect of interferon therapy on HCC development. In this report, we will summarize our cohort studies conducted in Japan on the prevention of HCC by interferon therapy, including the inhibition of HCC recurrence. We have published several articles on HCC prevention by analyzing data obtained in 3 distinct studies. The first cohort study consisted of approximately 3000 consecutive chronic hepatitis C patients who underwent liver biopsy at 1 of the 8 institutions in Japan that participated in a national surveillance program for HCC development (University of Tokyo, Chiba University, Nihon University, Osaka City University, Kawasaki Medical College, Kumamoto University, Kurume University, and Nagasaki Medical Center). This study, conducted by the Inhibition of Hepatocarcinogenesis by Interferon Therapy Study Group, was set up in 1994 and supported by the former Ministry of Health and Welfare of Japan. About 2400 patients subsequently received interferon therapy, and a sustained virologic response was achieved in one third of them. The remaining patients were left untreated for various reasons. We have already published 4 articles based on the analyses of this cohort.4Yoshida H. Shiratori Y. Moriyama M. et al.Interferon therapy reduces the risk for hepatocellular carcinoma national surveillance program in Japan of cirrhotic and non-cirrhotic patients with chronic hepatitis C.Ann Intern Med. 1999; 131: 174-181Crossref PubMed Scopus (1009) Google Scholar, 10Shiratori Y. Imazeki F. Moriyama M. et al.Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.Ann Intern Med. 2000; 132: 517-524Crossref PubMed Scopus (662) Google Scholar, 11Yoshida H. Arakawa Y. Sata M. et al.Interferon therapy prolonged life expectancy among chronic hepatitis C patients.Gastroenterology. 2002; 123: 483-491Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 12Yoshida H. Tateishi R. Arakawa Y. et al.Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C.Gut. 2004; 53: 425-430Crossref PubMed Scopus (140) Google Scholar When interferon therapy against chronic hepatitis C was licensed in 1992 in Japan, the antiviral therapy was (and still is) contraindicated for patients with cirrhosis. However, it seems obvious, at least to us, that patients with compensated cirrhosis, with the highest risk for HCC development, are the best candidates for the therapy. Thus, we conducted the second cohort study to evaluate the efficacy and safety of interferon therapy on compensated cirrhotic hepatitis C patients. We focused on the effect of interferon therapy on HCC prevention also in this study. This study was started in 1996 as a multicenter study with 25 participating institutions, named the Tokyo-Chiba Hepatitis Research Group, enrolling 271 compensated cirrhotic patients who received interferon therapy and 74 who did not. Three articles have been published on the basis of this cohort study.13Shiratori Y. Yokosuka O. Nakata R. et al.Prospective study of interferon therapy for compensated cirrhotic patients with chronic hepatitis C by monitoring serum hepatitis C RNA.Hepatology. 1999; 29: 1573-1580Crossref PubMed Scopus (37) Google Scholar, 14Shiratori Y. Moriyama M. Imazeki F. et al.A prospective study of interferon therapy modified by pre-treatment viral load in cirrhotic patients.Liver. 2000; 20: 271-280Crossref PubMed Scopus (7) Google Scholar, 15Shiratori Y. Ito Y. Yokosuka O. et al.Antiviral therapy for cirrhotic hepatitis C association with reduced hepatocellular carcinoma development and improved survival.Ann Intern Med. 2005; 142: 105-114Crossref PubMed Scopus (247) Google Scholar The survival of HCC patients has been substantially improved recently as a result of the advances in medical and surgical treatments. Nevertheless, prognosis of HCC patients is strongly marked by frequent recurrence, even after apparently curative medical or surgical treatment. Consequently, we strongly advocate that the goal of HCC treatment should include effective prevention of recurrence. The third study was started as a randomized controlled study with HCV-positive HCC patients who received complete percutaneous ablation therapy at the Department of Gastroenterology, University of Tokyo Hospital, and subsequently underwent interferon therapy (n = 49) or did not (n = 25, control subjects). Considering the antiviral efficacy of interferon therapy at the time, only those patients with low to moderate HCV load were selectively enrolled. We have published one article on the effect of interferon therapy on prognosis studied among this cohort.16Shiratori Y. Shiina S. Teratani T. et al.Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus.Ann Intern Med. 2003; 138: 299-306Crossref PubMed Scopus (260) Google Scholar In the article we published in 1999,4Yoshida H. Shiratori Y. Moriyama M. et al.Interferon therapy reduces the risk for hepatocellular carcinoma national surveillance program in Japan of cirrhotic and non-cirrhotic patients with chronic hepatitis C.Ann Intern Med. 1999; 131: 174-181Crossref PubMed Scopus (1009) Google Scholar we demonstrated that (1) the stage of liver fibrosis (advanced > mild), age (old > young), and gender (male > female) were independent strong risk factors of HCC; (2) interferon therapy, with the observed sustained response rate of 33.5%, reduced the risk of HCC by half; and (3) the risk was further reduced, down to one fifth, when analyzed exclusively among sustained virologic responders. The risk reduction was the most prominent among patients at stage F3, followed by those at F2, at F4, and at F1, in the order of strength. Although the risk of HCC was the highest among F4 patients, they exhibited low sustained response rate and consequently low-risk reduction, showing a limitation of conventional therapy. We subsequently demonstrated that interferon therapy significantly prolonged survival by reducing the incidence of both HCC and hepatic failure.11Yoshida H. Arakawa Y. Sata M. et al.Interferon therapy prolonged life expectancy among chronic hepatitis C patients.Gastroenterology. 2002; 123: 483-491Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar We also showed evidence of histologic improvement of the liver in sustained virologic responders.10Shiratori Y. Imazeki F. Moriyama M. et al.Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.Ann Intern Med. 2000; 132: 517-524Crossref PubMed Scopus (662) Google Scholar Cirrhotic patients exhibited lower sustained response rate, 64 of 271 (23.6%), compared with the Inhibition of Hepatocarcinogenesis by Interferon Therapy cohort consisting mainly of noncirrhotic patients. Nevertheless, during the mean follow up of 6.8 years, the cumulative incidence of HCC significantly differed between the interferon-treated group as a whole and the control subjects, showing an adjusted relative risk of 0.54 (95% confidence interval, 0.33–0.89).15Shiratori Y. Ito Y. Yokosuka O. et al.Antiviral therapy for cirrhotic hepatitis C association with reduced hepatocellular carcinoma development and improved survival.Ann Intern Med. 2005; 142: 105-114Crossref PubMed Scopus (247) Google Scholar The effect was much stronger among sustained virologic responders with a relative risk of 0.05 (95% confidence interval, 0.006–0.34) against untreated patients. Survival was also significantly better in the interferon-treated group. There was no liver-related death (those caused by HCC, liver failure, or varix rupture) among 64 sustained responders, in contrast to the fact that 19 of 74 untreated patients died of liver-related causes. Among this cohort, 49 patients received interferon therapy after complete ablation of all HCC lesions, of whom 14 (28.6%) showed sustained virologic response and another 21 had sustained biochemical response, ie, persistent normalization of serum aminotransferase level.16Shiratori Y. Shiina S. Teratani T. et al.Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus.Ann Intern Med. 2003; 138: 299-306Crossref PubMed Scopus (260) Google Scholar During the observation period of 7.1 years on average, the cumulative HCC recurrence did not differ significantly between the interferon-treated and untreated groups, although there was a trend of divergence between the cumulative recurrence curves of the 2 groups after 2 years of treatment. However, cumulative survival did differ significantly between the 2 groups. In particular, sustained virologic responders showed excellent survival rates of 86% at 3 years, 78% at 5 years, and 68% at 7 years. The survival curves seemed to diverge further in the late phase. Chronic HCV infection is the major cause of HCC in Japan and various countries in the world. Horizontal transmission of HCV passed its peak decades ago in Japan17Yoshizawa H. Hepatocellular carcinoma associated with hepatitis C virus infection in Japan projection to other countries in the foreseeable future.Oncology. 2002; 62: 8-17Crossref PubMed Scopus (190) Google Scholar and seems to be doing so in most countries, but it is estimated that about 170 million people worldwide have chronic hepatitis C. We have shown that interferon therapy reduces the risk of HCC among chronic hepatitis C patients. The effect was also shown among compensated cirrhotic patients, although sustained virologic response rate was low compared with noncirrhotic patients. In addition, progression to hepatic failure was also inhibited by interferon therapy. Taken together, interferon therapy led to improved life expectancy by reducing liver-related deaths, HCC, and liver failure, whereas liver-unrelated deaths remained unchanged. Interferon therapy was also shown to improve survival when administered to HCC patients after complete ablation of primary HCC by preserving liver function and probably by also inhibiting recurrence. We used conventional interferon monotherapy in the previous studies mentioned here. Because the beneficial effect of interferon therapy was stronger by far in virologic sustained responders than in nonresponders, current antiviral therapy, namely the combination of pegylated interferon and ribavirin, can be expected to improve prognosis of patients much more. We have demonstrated that interferon therapy improves prognosis of HCV-positive patients in any of the following 3 stages, chronic hepatitis without cirrhosis, compensated cirrhosis, and complicated with HCC, through 3 successive cohort studies.