Japanese Journal of Clinical Oncology 30:213-214 (2000)
© 2000 Foundation for Promotion of Cancer Research
Effects of Interferon Therapy on Inhibition of Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis C
Department of Gastroenterology, University of Tokyo, Tokyo, Japan
The natural history of chronic HCV infection suggests that there is a sequential but slow progression from acute HCV infection to chronic infection, leading to cirrhosis and death from either liver failure or hepatocellular carcinoma (HCC) (1–4). Although chronic hepatitis, cirrhosis and HCC are accepted sequelae, the rate of development of decompensation and/or HCC to which they contribute to mortality are not well known. Because prospective studies with long-term observation are rare, only data from selected cases or studies gathered over relatively short-follow up periods have been collected.
After the introduction of interferon (IFN) for chronic hepatitis C in the mid-1980s (5), factors contributing to sustained response to IFN have been elucidated (5). Early studies used biochemical response to assess the efficacy of IFN therapy, but biochemical response during and after IFN administration cannot predict sustained response. Instead, virological evaluation is superior to biochemical assessment in long-term follow-up studies (6). Recent long-term follow-up studies revealed that patients who tested negative for HCV RNA 6 months after treatment remained in remission with normal liver function and improved histological features, suggestive of being cured of infection (7).
Previous retrospective studies show that HCC and decompensation occur in a large proportion of advanced-stage chronic hepatitis C patients and compensated cirrhotic patients with HCV infection (8,9). The yearly incidence of HCC was 3% in a retrospective series of Caucasian patients with HCV-related compensated cirrhosis (8), in contrast to 5–7% in Japan (9). The benefit of IFN therapy is remarkable considering that cirrhosis is a major prognostic factor and IFN therapy prevents and delays these complications (10–15).
In evaluating the effect of IFN therapy on inhibition of HCC development from previously published papers, the most important points which should be taken into account are that the patients with advanced liver fibrosis are more likely to develop HCC but are resistant to IFN therapy. The risk factors for HCC include age (>60 years old), gender (male), advanced fibrosis staging (F3/4), histological activity score, high ALT level and unresponsiveness to IFN therapy.
A number of papers have demonstrated inhibition of HCC development after IFN therapy with a large number of patients with 3–5 year follow-up after the therapy (10–22). Although the annual incidence of HCC development is different according to the fibrosis stage of the liver, the differences in HCC risk in relation to fibrosis category were considered in only two papers (19,22). Our latest study (22) showed that the effect of IFN therapy on the inhibition of HCC development was demonstrated in patients with moderate fibrosis (F3 stage) in whom the risk of HCC development was high and IFN therapy may be effective. On the other hand, the effect on the inhibition of HCC development in patients with milder liver fibrosis (F0/1) did not reach statistical significance because of the low annual incidence of HCC. Among these patients, the annual incidence may increase with a longer-follow up period when progression of liver fibrosis occurs. Thus, the effect of IFN on inhibition of HCC development may reach statistical significance with a longer period of follow-up observation of 10–20 years. In addition, the difference between IFN-treated and -untreated patients with liver cirrhosis did not attain statistical significance. This may result from the low efficacy of IFN therapy among these cirrhotic patients. Further prospective studies will be necessary in order to be able to draw conclusions about the effect of IFN therapy on cirrhotic patients.
However, the reduced risk of HCC development is associated not only with the disappearance of viremia but also with histological amelioration of hepatic inflammation irrespective of fibrosis stage from these retrospective studies (10–22). Consistent with the fact that IFN treatment improves liver histological characteristics including inflammatory activity and liver fibrosis in sustained responders (unpublished observation), the decrease in histological activity after IFN therapy seems substantial in patients with normal ALT levels. Both Yoshida et al. (22) and Ikeda et al. (19) adjusted the background features using multivariate analysis, indicating that an anticarcinogenic effect of IFN was found in patients with persistent ALT normalization. The cancer-suppressive effect of IFN is found not only in patients with sustained virological response but also in those with a sustained biochemical response (patients with normal ALT but with HCV RNA positive). Hence the decreased risk of HCC development may be related to the suppression of inflammation and regeneration in the liver, indicating the inhibition of HCC development with IFN therapy among sustained virological or biochemical responders.
There is one paper (16) indicating that the risk reduction with IFN treatment was apparently greater for patients with chronic hepatitis C and no evidence of hepatitis B virus (HBV) infection, whereas the relative risk in IFN-untreated versus -treated patients was not significant among patients positive for both HCV antibody and HBc antibody. There may be a possibility that part of these HCC may be due to HBV-related mutagenesis. This point should be elucidated in the near future.
The data on inhibition of HCC development with IFN therapy discussed in this paper were obtained from recent retrospective cohort studies. Since retrospective studies contain a variety of inherited bias in the enrollment of the patients, such as differences in pretreatment parameters between treated and untreated subjects after the accumulation of knowledge about factors contributing to IFN efficacy, these points should be taken into account in the analysis of such retrospective studies and there are limitations and pitfalls in the interpretation of the data obtained. As a well-controlled, randomized study on the anticarcinogenic action of IFN therapy has not hitherto been available, a randomized controlled study using a large number of subjects with a much longer observation period will be required to elucidate the exact role of antiviral therapy for the delay of decompensation or suppression of HCC.
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