Elsevier

Journal of Hepatology

Volume 34, Issue 4, April 2001, Pages 593-602
Journal of Hepatology

Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach

https://doi.org/10.1016/S0168-8278(01)00005-8Get rights and content

Abstract

Background/Aims: To evaluate by meta-analysis of available literature whether interferon (IFN) reduces the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV)-related Child A cirrhosis.

Methods: Three randomized controlled trials and 15 nonrandomized controlled trials, including 4614 patients and comparing IFN to no treatment, were selected. Data on the incidence of HCC in IFN treated and untreated patients were extracted from each study. Meta-analysis by the DerSimonian and Laird risk difference (RD) method was used to pool observations.

Results: A different incidence of HCC between treated and untreated cirrhotic patients was observed for HCV (overall RD −12.8%; 95% CI −8.3 to −17.2%, P<0.0001) and HBV (overall RD −6.4%; 95% CI−2.8 to −10%, P<0.001). In HCV-related cirrhosis, the rate of HCC development was lower in sustained responders to IFN than in untreated patients (overall RD −19.1%; 95% CI−13.1 to −25.2%, P<0.00001), with low heterogeneity among trials (P=0.053), and also in nonresponders vs. untreated patients (overall RD −11.8%; 95% CI −6.4 to −19.1%, P<0.0001), although with significant heterogeneity. Inconsistency among the studies was a major problem, both for HCV (χ2=58.16 with 13 DF; P<0.0001) and HBV (χ2=26.4 with 6 DF; P=0.0001) related cirrhosis, and also when follow-up was shorter than 60 months. Consistent results were only observed when assessing data from European reports: in this subgroup no preventive effect of HCC was shown for HBV (overall RD −4.8%; 95% CI −11.1–1.5%, P, not significant), and only a weak effect for HCV (overall RD −10%; 95% CI −5.9 to −14.2%; P<0.0001).

Conclusions: Literature data pooling suggests a slight preventive effect of IFN on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low and the observed benefit might be due to spurious associations. The preventive effect is more evident among sustained responders to IFN. IFN does not seem to affect the rate of HCC in HBV-related cirrhosis.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide. Its incidence is increasing in industrialized countries [1]. Because of the almost constant presence of underlying cirrhosis and of the high risk of recurrence, the 3 year survival rate of HCC patients undergoing surgical or percutaneous ablation (both palliative treatments) is scarce even within screening programs [2]. Benefits of orthotopic liver transplantation for patients with small HCCs are limited by the high rate of tumor progression and death due to liver disease while still on the waiting list. This applies even to countries with a high rate of available organs [3]. Therefore, HCC prevention remains a major issue in the long-term management of cirrhotic patients, especially where chronic hepatitis C virus (HCV) and/or hepatitis B virus (HBV) infection is the leading cause of chronic liver disease (up to 80% in the Mediterranean area) [4], [5]. In the current environment characterized by financial constraints in health care expenditure, intensive screening programs and, when possible, chemoprevention should be confined to patients at high risk of HCC. Since the accuracy and the reliability of recognized clinical, virological and histological risk factors for HCC are still insufficient, accurate risk prediction of developing cancer in individual patient remain an elusive goal [6], [7].

It has been argued that long-term suppression of viral replication could reduce hepatocyte turnover and lessen the risk of dysplasia and cancer [8]. In 1995, a small randomized controlled trial (RCT) showed a decrease in the incidence of HCC in patients with HCV-related cirrhosis, as compared to untreated controls [9]. On the wake of this study, several nonrandomized controlled trials (NRCTs) [10–20,23–28) and two RCTs [21], [22] were performed, mostly in patients with HCV infection. These studies, often assessed cohorts of a relatively small size retrospectively and showed a marked degree of heterogeneity, making difficult to assess the actual level of benefit obtained by α-interferon (IFN) treatment [29].

Hitherto, a number of important questions still remain unsolved by the available studies: Is the risk of HCC in viral cirrhosis reduced by IFN therapy? If a risk reduction truly exists, does the benefit apply to all patients with HCV- or HBV-related cirrhosis? Is a sustained response to IFN required to reduce the HCC incidence?

Pooling the available evidence and assessing it by meta-analysis, we made an effort to critically review the effectiveness of IFN for preventing HCC in patients with viral cirrhosis and to provide an answer to the above issues.

Section snippets

Selection of studies

The primary source of the reviewed studies was a MEDLINE search (1985–1999), with no language restriction and with the following Medical Subject Headings:hepatocellular carcinoma, interferon, cirrhosis, clinical trial, cohort study. Reference lists from all the available review articles, primary studies and proceedings of major meetings (1995–1999) were also screened, in order to identify studies not found by the MEDLINE search. In addition, a manual search of relevant articles listed as

Cirrhosis: features of the studies

The main features of the studies including cirrhotic patients evaluated by meta-analysis are shown in Table 1. Eighteen studies fulfilled the requirements and included 4614 patients, 1782 of whom received no treatment. Among the reviewed studies, three were RCTs [9], [21], [22] and 15 were NRCTs [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [23], [24], [25], [26]. Fourteen studies had been reported as full papers [9], [10], [11], [12], [13], [14], [16], [18], [20], [22], [23]

Discussion

Meta-analysis is traditionally applied and best confined to RCTs or so-called ‘true experiments’ [37]. There are clinical settings, however, in which an RCT is unfeasible as it would require a large sample size or it would be difficult to perform. In these cases, meta-analytic techniques could be applied to NRCTs [35]. NRCTs are subject to many problems that reduce their internal and external validity. Their lack of precision and reliability causes inherent biases towards false positive results

Acknowledgments

We are indebted to Doctor Joseph Lau (New England Medical Center Hospitals, Boston, MA) for providing us with the meta-analysis computer program. We would like to thank Danilo Romeres for forbearance in correcting the manuscript. An investigational grant was made available by ‘Progetto co-finanziamento MURST 1999’.

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