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Keywords:

  • interferon;
  • hepatitis C virus;
  • hepatitis B virus;
  • hepatocellular carcinoma;
  • survival

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Available literature on the effects of interferon (IFN) treatment on development and progression of hepatocellular carcinoma (HCC) in patients with chronic virus infection reports controversial results. The primary objective of this meta-analysis was to evaluate the effect of IFN on HCC risk in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; IFN's efficacy on local tumor progression and survival of advanced HCC patients was also assessed. All randomized controlled trials (RCTs) comparing IFN with no antiviral treatment were selected. Finally, we identified 11 RCTs including 1,772 patients, who met our inclusion criteria to perform this meta-analysis. Our analysis results showed that IFN significantly decreased the overall HCC incidence in HCV-infected patients [relative risk (RR) = 0.39; 95% confidence interval (CI) = 0.26–0.59; p = 0.000], subgroup analysis indicated that IFN decreased HCC incidence in HCV-related cirrhotic patients evidently (RR = 0.44; 95% CI = 0.28–0.68; p = 0.000); but HCC incidence in nonresponders to initial antiviral therapy did not reduce by maintenance IFN therapy (RR = 0.96; 95% CI = 0.59–1.56; p = 0.864). Analysis results also demonstrated that IFN did not significantly affect the overall rate of HCC in HBV-infected patients although there was a trend favoring IFN therapy (RR = 0.23; 95% CI = 0.05–1.04; p = 0.056). Besides, IFN did not improve one-year overall survival of advanced HCC patients significantly (RR = 1.61; 95% CI = 0.96–2.69; p = 0.072); however, a quantitative analysis on local tumor progression could not be performed owing to lack of unified definitions among trials included in our study. By this meta-analysis, we conclude that IFN therapy is effective in reducing overall HCC risk in chronic HCV-infected patients; using it in this subpopulation seems promising, but its administration in other subpopulations still requires further exploration.

Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors and is the third most common cause of death from cancer in the world.1 Despite extensive efforts to improve its prognosis, the overall survival rate of HCC patients remains very low to date. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are the most common etiologies of HCC, and they are estimated to be causally associated with 53 and 25% of HCC worldwide, respectively.2 Thus, HCC prevention and treatment have become an important issue in patients with chronic HCV or HBV infection.

Studies show that interferon (IFN) can not only suppress the replication of HCV and HBV, but also has a tumoricidal effect on a number of tumors including HCC.3 In the past few years, several clinical studies have reported the preventive effect of IFN treatment on HCC occurrence in patients with HCV or HBV infection, especially in sustained virologic responders.4–7 However, in those with advanced hepatitis C who did not achieve a sustained virologic response (SVR) to initial IFN-based antiviral therapy, maintenance peginterferon (PEG-IFN) treatment could not reduce overall HCC risk, as reported by the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) and Colchicine Versus Pegintron Long-term Therapy (CO-PILOT) trials recently.8, 9 Based on previous reports, several meta-analyses have been performed to evaluate the preventive effect of IFN on development of HCC in HCV- or HBV-infected patients.10–12 However, in these meta-analyses, the authors pooled data mostly from the retrospective or nonrandomized studies, and they also included studies of different publication types (including full papers, abstracts, etc.) for analysis; therefore, the combined information might have been open to heterogeneity and bias, and the overall results were also not very convincing.10–12 Moreover, previous analysis results now should also be outdated as some randomized controlled trials (RCTs) have emerged in recent years. As to the effect of IFN on HCC progression, relevant clinical trials are few, and systematic review on this issue is still lacking currently.

In view of the conflicting data of available clinical trials and the limitations of previously published meta-analyses, to reach a general conclusion, we conducted this systematic review and meta-analysis only on the basis of RCTs (which were considered as the best design to evaluate health-care interventions), tried to make an objective evaluation of the effect of IFN on HCC risk in patients with chronic HCV or HBV infection. Furthermore, an assessment of IFN's therapeutic effect on advanced HCC patients was also performed.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Identification and selection of trials

Study objectives

The primary endpoint was to evaluate the effect of IFN on HCC development in patients with chronic HCV or HBV infection. The secondary endpoint was to assess the therapeutic effect of IFN on advanced HCC patients, regarding tumor response, local tumor progression and overall survival.

Search strategy

Studies were identified by searching PubMed, EMBASE, Cochrane Library and Web of Science databases (last search updated to July 2010). The search strategy was based on combinations of the following terms: (interferon [MESH] or interferon [TEXT WORD]) AND (carcinoma, hepatocellular [MESH] or hepatocellular carcinoma [TEXT WORD]) AND (randomized controlled trial [MESH] or randomized trial [TEXT WORD]). Reports as full papers in English were eligible for inclusion. A manual search and review of reference lists were also performed. Investigators were contacted and asked to supply additional data when key information relevant to the meta-analysis was missing.

Selection criteria of trials

All RCTs comparing IFN treated with no antiviral treated (placebo, systematic or no treatment) patients were identified. Selection criteria for studies evaluating the effect of nonmaintenance IFN therapy on HCC risk in patients with HCV or HBV infection were as follows: (i) less than two years of initial treatment with IFN without regard to type, dose and the way of injection; (ii) minimum of two-year mean/median follow-up period; (iii) both patients who achieved SVR (defined as serum clearance of HCV-RNA by six months after the end of therapy) in HCV-infected patients, virologic response (VR, defined as HBV-DNA and hepatitis B e antigen seroclearance during therapy or within 12 months after the end of therapy) in HBV-infected patients and those who did not achieve SVR and VR were included; and (iv) assessing HCC as an outcome measure of the treatment's effect. Selection criteria for studies evaluating the effect of maintenance IFN on HCC risk in patients with HCV infection were as follows: (i) inclusion of patients with failure to achieve SVR in initial IFN-based antiviral therapy (IFN monotherapy or combination therapy with IFN and ribavirin); (ii) minimum of two years of retreatment with IFN; (iii) minimum of two-year mean/median follow-up period; and (iv) assessing HCC as an outcome measure of the treatment's effect. Inclusion criteria for studies assessing the therapeutic effect of IFN on HCC patients were as follows: (i) patients with advanced primary HCC who were not suitable for potentially curative treatments were included; (ii) IFN was initially used as basic therapy after HCC was confirmed; (iii) assessing patient survival as one of the main outcome measures; and (iv) comparing IFN treatment with no antitumor treatment.

Qualitative analysis

The methodological quality of trials was evaluated using the Jadad scale [a 5-point scale assessing randomization (0–2 points), double-blinding (0–2 points), and follow-up (0-1 points)].13 The scale consists of items relating to randomization, blinding, and description of withdrawals and dropouts during follow-up; scores range from 0 to 5 with trials scoring 3 or greater considered high-quality trials, while scoring 0–2 regarded low-quality studies. Two reviewers independently assessed trial quality, and disagreements were resolved by consensus.

Quantitative analysis (meta-analysis)

Statistical methods

This meta-analysis was performed in accordance with recommendations from the Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines.14 Statistical analysis for dichotomous variables was carried out using relative risk (RR) as the summary statistic. The treatment effect was reported as RR with 95% confidence interval (CI). A RR of <1 favored the treatment group in analysis of IFN's effect on HCC development, a RR of >1 favored the treatment group in analysis of IFN's effect on survival of HCC patients; and the point estimate of the RR was considered statistically significant at the p < 0.05 level if the 95% CI did not include the value 1. When analyzing the efficacy of IFN on overall survival of HCC patients, if the absolute number of survival was not reported, it will be estimated from the survival curves according to the method proposed by Parmar et al.15 In the course of data pooling, we used the I-squared (I2) statistic to measure the extent of inconsistency among the results and tested the heterogeneity using chi-square (χ2) test; because this test has poor power in the case of few studies, we considered both the presence of significant heterogeneity at the 10% level of significance and values of I2 exceeding 56% as an indicator of significant heterogeneity.16 We apply a random effect model to analyze if significant heterogeneity exists; otherwise, a fixed effect model will be used; furthermore, metaregression analysis will be conducted by using comprehensive meta-analysis software (Bio-stat, Englewood, NJ) to identify variables that result in heterogeneity (if it exists). To evaluate the potential risk bias in the overall results of pooled analysis of the included studies, sensitivity analysis and publication bias estimate were performed. Analyses on main results were performed by using STATA 10.0 software (Stata Corporation, College Station, Texas.).

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Selection and characteristics of trials

By the primary literature search, 221 records were identified pertaining to the effect of IFN therapy on HCC development and progression in patients with HCV or HBV infection; 165 studies were excluded after screening the titles or abstracts, because they were either review articles, meta-analyses, case reports, commentaries and letters, reports in language other than English or irrelevant to the current analysis. Fifty-six relevant studies were selected for detailed evaluation, 44 were excluded after full assessment (33 were nonrandomized trials, four were reported only in abstract form, five reported combination therapy with IFN and other antiviral agents, two reported effect comparison between IFN and other chemotherapy drugs). After careful evaluation by applying the inclusion criteria, a total of 12 eligible RCTs were identified.8, 17–27 Of the 12 studies, two were reported by the same study center, and the patients selected were also same in the two studies17, 18; but they reported data on IFN treatment versus no antiviral treatment in one report18 and the data of HCC based on SVR in the other report17; so both of the two studies were included in our analysis. Another two studies were also from the same research group8, 23; however, only the most recent one was included.23 Thus, 11 RCTs with 1,772 patients, which met our inclusion criteria, were selected for our meta-analysis finally.17–27 Among the selected studies, four assessed the incidence of HCC in HCV-infected patients initially treated with nonmaintenance IFN compared with no antiviral treated patients18–21; two reported data on nonmaintenance IFN and HCC risk in HCV-infected patients based on SVR and nonresponse (NR, defined as detectable serum HCV RNA levels and no decrease of serum alanine aminotransferase levels into the normal range throughout the treatment period)17, 21; two assessed the retreatment effect of maintenance IFN in HCV-infected patients who were nonresponding to initial IFN-based antiviral therapy22, 23; two evaluated HCC incidence between nonmaintenance IFN treated and untreated patients with HBV infection24, 25; and the other two analyzed the therapeutic effect of IFN on advanced HCC patients.26, 27 Six studies were published from Western countries,19, 20, 22–24, 27 and five were published from Asia.17, 18, 21, 25, 26 Sample size in each study varied from 28 to 495 in the IFN-treated group and 23 to 510 in the control group, with mean age varying from 32 to 61 years in the IFN-treated group and 32 to 63 years in the control group. The male population varied from 45 to 100% in the IFN-treated group and 43 to 100% in the control group. In patients included for analysis of IFN's effect and HCC risk,17–25 the mean/median duration of follow-up ranged from 2 to 9.2 years in the IFN-treated group and 2 to 8.2 years in the control group. Overall, eight studies were rated as good quality (scoring three for each study) based on Jadad scale evaluation.17–20, 22, 23, 26, 27 Tables 1 and 2 show the feature description of the 11 RCTs: sample size, percentage of males, mean age, mean/median follow-up, basal cirrhosis, IFN regimen, rate of HCC, HCV or HBV infection, SVR or VR, Child-Pugh classification, Okuda stage, median survival and study quality, etc.

Table 1. Baseline characteristics of randomized trials assessing effect of IFN on HCC risk in HCV or HBV-infected patients
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Table 2. Baseline characteristics of randomized trials assessing therapeutic effect of IFN on HCC patients
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Nonmaintenance IFN and HCC risk in patients with HCV infection: Treatment versus no antiviral treatment

Four studies reported data on the effect of nonmaintenance IFN treatment on HCC risk in patients with HCV infection18–21; among the four studies, three reported data on IFN treatment for patients with HCV-related cirrhosis.18–20 IFN seemingly reduced HCC incidence in one study,19 and a statistically significant reduction was observed in two studies.18, 21 On the other hand, IFN seemingly slightly increased HCC incidence in one study.20 Pooled data from the four studies showed significant overall risk reduction in occurrence of HCC (RR = 0.39; 95% CI = 0.26–0.59; p = 0.000; Fig. 1), without any heterogeneity in the data (χ2 = 3.0, I2 = 0.2%, p = 0.391). Subgroup analysis indicated that IFN treatment could also decrease HCC occurrence in patients with HCV-related cirrhosis evidently (RR = 0.44; 95% CI = 0.28–0.68; p = 0.000), without heterogeneity in the data (χ2 = 1.61, I2 = 0.0%, p = 0.448).

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Figure 1. Meta-analysis of RCTs evaluating nonmaintenance IFN and overall HCC risk in HCV-infected patients. The fixed effect model was applied. RR and 95% CI for each study are plotted on the graph. The blocks indicate the estimate of RR, and their size relates to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Nonmaintenance IFN and HCC risk in patients with HCV infection: SVR versus NR

Two studies reported data on the effect of nonmaintenance IFN treatment on HCC risk in patients with HCV infection based on SVR and NR (the percentage of SVR was shown in Table 1).17, 21 IFN seemingly reduced HCC incidence in the two studies. Pooled data from the two studies showed HCC risk reduction in patients with SVR was lower than that in nonresponders although the difference did not reach statistical level (RR = 0.30; 95% CI = 0.04–2.15; p = 0.229; Fig. 2), without heterogeneity in the data (χ2 = 0.53, I2 = 0.0%, p = 0.468).

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Figure 2. Meta-analysis of RCTs evaluating nonmaintenance IFN and HCC risk in HCV-infected patients based on SVR and NR. The fixed effect model was applied. RR and 95% CI for each study are plotted on the graph. The blocks indicate the estimate of RR, and their size relates to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Download figure to PowerPoint

Maintenance IFN and HCC risk in patients with HCV infection: Treatment versus no antiviral treatment

Two studies reported data on the effect of maintenance IFN treatment on HCC risk in patients with HCV infection nonresponding to initial IFN-based antiviral therapy.22, 23 IFN seemingly did not reduce HCC incidence in the two studies. Pooled estimate from the two studies suggested no significant effect or evident trend for risk reduction in HCC occurrence (RR = 0.96; 95% CI = 0.59–1.56; p = 0.864; Fig. 3) although there was no heterogeneity among these studies (χ2 = 0.01, I2 = 0.0%, p = 0.930).

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Figure 3. Meta-analysis of RCTs evaluating maintenance IFN and HCC risk in HCV-infected patients nonresponding to initial antiviral therapy. The fixed effect model was applied. RR and 95% CI for each study are plotted on the graph. The blocks indicate the estimate of RR, and their size relates to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Download figure to PowerPoint

Nonmaintenance IFN and HCC risk in patients with HBV infection: Treatment versus no antiviral treatment

Two studies reported data on this issue.24, 25 IFN seemingly reduced HCC incidence in both two studies. Analysis results indicated that the overall HCC incidence in IFN treated patients was less frequent than that in no antiviral treated ones, although not significantly so (RR = 0.23; 95% CI = 0.05–1.04; p = 0.056; Fig. 4), the heterogeneity in the data was not evident (χ2 = 0.75, I2 = 0.0%, p = 0.386). However, of the two studies, only one provided data on HCC incidence among virologic responders and nonresponders; so the pooled analysis based on VR and NR could not be performed.

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Figure 4. Meta-analysis of RCTs evaluating nonmaintenance IFN and overall HCC risk in HBV-infected patients. The fixed effect model was applied. RR and 95% CI for each study are plotted on the graph. The blocks indicate the estimate of RR, and their size relates to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Download figure to PowerPoint

Effect of IFN on advanced HCC patients: Treatment versus no antitumor treatment

Two studies reported data on the effect of initial IFN treatment on advanced HCC patients who were unsuitable for curative treatments at the time of diagnosis.26, 27 We aimed to assess IFN's efficacy on overall survival, tumor response and local tumor progression in HCC patients.

Overall survival

In the two studies, the period of follow-up for overall survival was defined as the time from randomization to patient death or last follow-up. We planned to analyze IFN's effect on one-, three-year overall survival of HCC patients. Unfortunately, data on three-year survival were available in one study27 but unavailable in the other study.26 So, we only evaluated IFN's effect on one-year survival in HCC patients finally. IFN seemingly improved one-year survival in both two studies. Pooled estimate from the two studies indicated IFN-treated patients had higher rate of one-year survival than no antitumor treated patients; the difference did not reach significant level (RR = 1.61; 95% CI = 0.96–2.69; p = 0.072; Fig. 5) without heterogeneity in the data (χ2 = 0.00, I2 = 0.0%, p = 0.951).

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Figure 5. Meta-analysis of RCTs evaluating the effect of IFN on overall one-year survival in advanced HCC patients. The fixed effect model was applied. RR and 95% CI for each study are plotted on the graph. The blocks indicate the estimate of RR, and their size relates to the size of the individual study. The diamond indicates the overall estimate from the meta-analysis. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Download figure to PowerPoint

Tumor response and local tumor progression

The definitions of tumor response and local tumor progression were not unified among the two studies included in the meta-analysis. Therefore, quantitative analysis could not be performed for tumor response and local tumor progression among HCC patients.

Sensitivity analysis and publication bias

Sensitivity analysis and publication bias estimate were mainly used to evaluate the reliability of meta-analysis results, especially which showed statistical significance.28

Sensitivity analysis

We used different methods to conduct sensitivity analysis on meta-analysis result regarding IFN's effect on HCC risk reduction in HCV-infected patients. First, according to the method by Han and Pan,29 after we deleted the data of low-quality study,21 we reanalyzed the data of remaining articles, the RR was 0.44 (95% CI = 0.28–0.68; p = 0.000), similar to the RR of 0.39 (95% CI = 0.26–0.59; p = 0.000). Second, we performed sensitivity analysis by applying different effect models, as described in the article by E et al.28; combined RRs were calculated with a fixed effect model and a random effect model, and the results were compared; the RR with a fixed effect model was also similar as that with a random effect model (RR = 0.39; 95% CI = 0.26–0.59; p = 0.000 vs. RR = 0.38; 95% CI = 0.25–0.57; p = 0.000). Thus, sensitivity analysis performed by using different methods all indicated that the results of current meta-analysis were comparatively reliable.

Publication bias

Assessment of publication bias by using Egger's test (statistical significance was set at p < 0.05)30 suggested no evidence for significant publication bias in these included studies (p = 0.594).

Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

To date, several meta-analyses have been conducted to evaluate the effect of IFN on HCC occurrence in chronic viral hepatitis patients.10–12 However, the results of these meta-analyses were inconsistent even when they discussed the same topic. For example, Camma et al.10 reported that IFN did not affect the rate of HCC in HBV-related liver cirrhosis, while in the study by Sung et al.,12 the authors concluded that IFN significantly reduced HCC risk in HBV-infected patients with cirrhosis. Besides, in these meta-analyses, data were extracted mainly from the nonrandomized trials. However, nonrandomized trials may experience many problems that can reduce their internal and external validity, and their lack of precision and reliability can lead to significant inherent biases toward false positive results.31 Thus, a major reason for the inconsistence or instability of previous analysis results may be attributed to the inappropriate selection of related studies, at least in part. Moreover, in Camma et al.'s study, the authors aimed to evaluate the preventive effect of IFN on HCC in viral cirrhosis; while they included some study with only one-year mean follow-up duration, notably, to assess the preventive efficacy of IFN on disease progression, at least two-year follow-up period was needed.22, 32 Considering meta-analysis is traditionally applied and best confined to RCTs,33 and discordant results of available clinical trials and limitations of previous meta-analyses are existing, it is, therefore, necessary to carry out a quantitative analysis to assess the real effect of IFN on HCC development and progression in HCV- or HBV-associated chronic hepatitis patients based on RCTs to provide a more comprehensive understanding of the available data rather than just considering individual clinical trials.

In this meta-analysis, we first evaluated the effect of nonmaintenance IFN on HCC risk in patients with HCV infection. The pooled data demonstrated a significant overall risk reduction of HCC in patients with IFN treatment (p = 0.000); subgroup analysis showed that IFN also reduced incidence of HCC in patients with HCV-related cirrhosis significantly (p = 0.000). Although the analysis results were positive, the reasons for the differences between IFN treated and untreated patients were still not very clear. Studies showed SVR was the best marker for HCV clearance in treating HCV infection, and achievement of SVR was often associated with reduced liver-related morbidity and mortality in patients with HCV.34, 35 In this study, we also compared HCC incidence in patients treated with IFN based on SVR and NR. Our analysis result showed that HCC risk was lower in IFN-treated patients who achieved SVR than those who were nonresponders. Nevertheless, it should be noted that SVR was an important but not the only determining factor contributing to HCC risk reduction in HCV-infected patients treated with antiviral agents. Recent report demonstrated that some cirrhotic patients without SVR did not develop HCC if histological regression of cirrhosis was achieved; it indicated that histological improvement may also play an important role in HCC risk reduction besides achievement of SVR.36 From these mentioned earlier, we suggest that patients who achieved SVR or histological improvement (if without SVR) may have lower risk to develop HCC than those who did not achieve either SVR or histological improvement; especially, the population who achieved both SVR and histological improvement may benefit most from IFN treatment in terms of HCC risk reduction. Unfortunately, in the present study, we failed to make detailed comparisons of HCC risk between patients who had histological improvement and those who did not obtain histological improvement owing to lack of some essential data in the included studies. Thus, the earlier analysis and speculation still need further confirmation. Moreover, it should also be noted that some patients with SVR were still at risk for HCC development during long-term follow-up (although the incidence may be low); the reason for this may be partly attributed to the potential low-level viremia undetectable by the available assaying techniques in these patients.37 Therefore, it is important that HCV-infected patients should still keep with regular screening for HCC, even after obtaining SVR. Based on the above analysis, we wanted to know more about the effect of maintenance IFN on HCC risk in nonresponders to initial IFN-based antiviral therapy. Pooled data from two studies (HALT-C trial and the trial by Fartoux et al.)22, 23 indicated that the benefit in terms of HCC risk reduction was not in favor of maintenance IFN therapy (p = 0.864). Recently, two large RCTs (which were excluded from our meta-analysis because they did not meet our inclusion criteria), CO-PILOT and Evaluation of Pegintron in Control of Hepatitis C Cirrhosis (EPIC3),9, 38 also reported results on maintenance IFN therapy and HCC risk in nonresponders. In the CO-PILOT trial,9 patients who were nonresponders to initial IFN-based antiviral therapy were randomized to receive either PEG-IFN alfa-2b or colchicine for four years; while in the EPIC3 trial,38 nonresponders were randomized to receive either PEG-IFN alfa-2b or no treatment for up to three years. Data from the CO-PILOT and EPIC3 trials demonstrated no overall benefit of maintenance IFN therapy on occurrence of clinical events (HCC, etc.), which also confirmed our current analysis result. In theory, maintenance IFN therapy can reduce HCC development based on histological improvement of liver fibrosis or cirrhosis owing to its prolonged anti-inflammatory effect. Possible explanations for these observed negative results may mainly include the following three points. First, the doses of PEG-IFN used in the three large trials were significantly lower than the standard doses (HALT-C: 90 μg/week PEG-IFN alfa-2a, half the standard dose; CO-PILOT and EPIC3: 0.5 μg/kg/week PEG-IFN alfa-2b, one-third the standard dose); these low PEG-IFN doses might not have enough efficacy to inhibit virus replication; moreover, the power of reducing liver fibrosis or cirrhosis progression might also be weak. (In the HALT-C trial, the histological regression of liver fibrosis or cirrhosis was not evident between the treatment and control groups.) Second, in these trials, the patients did not receive long-term ribavirin with PEG-IFN administration; combination treatment might be more potent than monotherapy in suppressing virus replication, decreasing disease progression and improving clinical outcomes. Third, the mean follow-up period was relatively short in these trials. Particularly, in the trial by Fartoux et al.,22 the mean follow-up was only 24 months. Extended period of follow-up might be more effective and objective in assessing clinical outcomes of these patients. However, it should also be noticed that if full-dose PEG-IFN or ribavirin was included in the maintenance regimen, the rate of complications associated with maintenance therapy would be higher. Thus, further explorations on the benefit of IFN-based single-drug or multidrug maintenance regimen on HCC risk reduction in nonresponders were required.

In the current meta-analysis, we also compared the effect of nonmaintenance IFN on HCC risk between treated and untreated patients with HBV infection. Pooled data from two studies24, 25 (which all used standard IFN for treatment of chronic HBV infection) showed that HCC occurred less frequently in the IFN-treated patients, the difference was close to significant level (p = 0.056); nevertheless, the difference might be significant if the follow-up period extended or the sample size enlarged. Notably, the oral nucleoside analog lamivudine, as an alternative to standard IFN therapy, has been reported to be effective in reducing HCC incidence in Asian patients with chronic HBV infection in recent years.39 The tolerability and safety of lamivudine are excellent, but its prolonged use will induce drug resistance because of the emergence of tyrosine, methionine, aspartate, aspartate (YMDD) mutations (which has occasionally been related to severe, and even fatal, flares of hepatitis).40 More recently, PEG-IFN has taken the place of standard IFN in the treatment of chronic HBV infection. Studies show that PEG-IFN is superior in efficacy to either standard IFN or lamivudine therapy on the basis of hepatitis B e antigen or hepatitis B s antigen clearance, HBV DNA suppression and normalization of alanine aminotransferase levels.41–44 However, whether PEG-IFN can exert better effect than standard IFN or lamivudine on HCC risk reduction in HBV-infected patients still needs further investigation.

Besides the earlier evaluations about IFN's efficacy on HCC development in HCV or HBV-infected patients, we also conducted pooled analysis to assess IFN's therapeutic effect on advanced HCC patients, mainly focusing on patient survival. Theoretically, IFN treatment may benefit HCC patients because IFN not only possesses antitumor properties, including antiproliferative, antiangiogenic, and immunomodulatory effects, but also has antiviral activities with clearance or suppression of HCV or HBV.3, 45 In the present analysis, pooled data on one-year overall survival from two studies suggested a trend in favor of IFN therapy. However, whether long-term survival of HCC patients (e.g., three-year survival) can be significantly improved by IFN remains unknown. Unfortunately, we failed to assess IFN's benefit on long-term survival of HCC patients owing to some insufficient data in this analysis. In addition, notable is that in the two selected studies,26, 27 one reported overall positive survival benefit in IFN-treated Chinese patients (mostly HBV-related HCC),26 while this result was not confirmed by the other report in Western patients (mostly HCV-related HCC).27 From this, it seems that different etiologies of HCC may influence IFN's therapeutic effect. In summarizing data from the studies evaluating IFN's effect on postsurgical recurrence and survival in HCC patients with chronic HBV or HCV infection, Clavien46 also concluded that IFN therapy might be more effective in inhibiting tumor recurrence and improving overall survival in HBV-associated HCC patients than that in HCV-associated HCC patients. The reasons for these discrepant findings between HBV- and HCV-related HCC remain unclear. It is also a pity that we failed to perform subanalysis to assess IFN's efficacy on overall survival based on different etiologies of HCC because of limited studies included. So, further exploration on this issue may be worthwhile. Furthermore, it is also worth noting that PEG-IFN has many advantages over standard IFN in the treatment of chronic HCV or HBV infection, as mentioned earlier.41, 42, 47 Therefore, whether PEG-IFN can more efficiently improve survival of HCV or HBV-related HCC patients than standard IFN also awaits further research.

To the best of our knowledge, this is the first meta-analysis that evaluates the effects of IFN on HCC development and progression in patients with chronic HCV or HBV infection based only on RCTs. We feel that our meta-analysis may add to current understanding of IFN's effect on HCC development and progression; however, some potential limitations may be evident. First, in this analysis, we selected studies from limited databases; moreover, the total number of included studies and the total sample size were also small; this might influence the validity of our analysis to some extent. Second, the fact that non-English studies were excluded in this analysis might be a source of potential publication bias in this study. However, it was reported that language restriction of a meta-analysis other than English did not result in any significant bias in the estimation of interventional effectiveness.48 Third, since our meta-analysis was conducted on aggregated data, strong recommendations at an individual patient level cannot be obtained. Owing to several limitations existing in the included studies and the current meta-analysis, our results should be interpreted with caution, and likewise, the conclusions of this meta-analysis should also be drawn cautiously.

In conclusion, despite some potential limitations, the present study suggests that nonmaintenance IFN can efficiently reduce HCC development in patients with chronic HCV infection; this effect is more evident in sustained viral responders, while maintenance IFN does not reduce HCC risk in nonresponders to initial antiviral therapy. Nevertheless, there is no solid proof to recommend use of IFN to reduce HCC development in HBV-infected patients, and the benefit of IFN treatment on tumor progression and survival of advanced HCC patients remains to be demonstrated by further studies.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The authors thank all the patients and clinical investigators who are involved in the studies included in this meta-analysis. This work was partly supported by the Anhui Provincial “115” Industrial Innovation Program.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  • 1
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74108.
  • 2
    Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 52938.
  • 3
    Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Mullhaupt B, Clavien PA. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009; 96: 97581.
  • 4
    Mazzella G, Accogli E, Sottili S, Festi D, Orsini M, Salzetta A, Novelli V, Cipolla A, Fabbri C, Pezzoli A, Roda E. Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. J Hepatol 1996; 24: 1417.
  • 5
    Imai Y, Kawata S, Tamura S, Yabuuchi I, Noda S, Inada M, Maeda Y, Shirai Y, Fukuzaki T, Kaji I, Ishikawa H, Matsuda Y, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group. Ann Intern Med 1998; 129: 949.
  • 6
    Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm SW. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology 1997; 26: 133842.
  • 7
    Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Fukuda M, Koida I, Arase Y, Chayama K, Murashima N, Kumada H. Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus: a pilot study. Cancer 1998; 82: 82735.
  • 8
    Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359: 242941.
  • 9
    Afdhal NH, Levine R, Brown R, Freilich B, O'Brien M, Brass C. Colchicine versus peginterferon alfa 2b long term therapy: results of the 4 year copilot trial. J Hepatol 2008; 48( Suppl 2): S4.
  • 10
    Camma C, Giunta M, Andreone P, Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach. J Hepatol 2001; 34: 593602.
  • 11
    Papatheodoridis GV, Papadimitropoulos VC, Hadziyannis SJ. Effect of interferon therapy on the development of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a meta-analysis. Aliment Pharmacol Ther 2001; 15: 68998.
  • 12
    Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008; 28: 106777.
  • 13
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 112.
  • 14
    Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Onkologie 2000; 23: 597602.
  • 15
    Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17: 281534.
  • 16
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 153958.
  • 17
    Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, Shiomi S, Seki S, Kobayashi K, Otani S. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995; 346: 10515.
  • 18
    Nishiguchi S, Shiomi S, Nakatani S, Takeda T, Fukuda K, Tamori A, Habu D, Tanaka T. Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis. Lancet 2001; 357: 1967.
  • 19
    Valla DC, Chevallier M, Marcellin P, Payen JL, Trepo C, Fonck M, Bourliere M, Boucher E, Miguet JP, Parlier D, Lemonnier C, Opolon P. Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment. Hepatology 1999; 29: 18705.
  • 20
    Bernardinello E, Cavalletto L, Chemello L, Mezzocolli I, Donada C, Benvegnu L, Merkel C, Gatta A, Alberti A. Long-term clinical outcome after beta-interferon therapy in cirrhotic patients with chronic hepatitis C. TVVH Study Group. Hepatogastroenterology 1999; 46: 321622.
  • 21
    Soga K, Shibasaki K, Aoyagi Y. Effect of interferon on incidence of hepatocellular carcinoma in patients with chronic hepatitis C. Hepatogastroenterology 2005; 52: 11548.
  • 22
    Fartoux L, Degos F, Trepo C, Goria O, Cales P, Tran A, Buffet C, Poynard T, Capron D, Raabe JJ, Roulot D, Naveau S, et al. Effect of prolonged interferon therapy on the outcome of hepatitis C virus-related cirrhosis: a randomized trial. Clin Gastroenterol Hepatol 2007; 5: 5027.
  • 23
    Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, Curto TM, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009; 136: 13848.
    Direct Link:
  • 24
    Mazzella G, Saracco G, Festi D, Rosina F, Marchetto S, Jaboli F, Sostegni R, Pezzoli A, Azzaroli F, Cancellieri C, Montagnani M, Roda E, et al. Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial. Am J Gastroenterol 1999; 94: 224650.
    Direct Link:
  • 25
    Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999; 29: 9715.
  • 26
    Lai CL, Lau JY, Wu PC, Ngan H, Chung HT, Mitchell SJ, Corbett TJ, Chow AW, Lin HJ. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology 1993; 17: 38994.
  • 27
    Llovet JM, Sala M, Castells L, Suarez Y, Vilana R, Bianchi L, Ayuso C, Vargas V, Rodes J, Bruix J. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology 2000; 31: 548.
  • 28
    E Y, He N, Wang Y, Fan H. Percutaneous transluminal angioplasty (PTA) alone versus PTA with balloon-expandable stent placement for short-segment femoropopliteal artery disease: a metaanalysis of randomized trials. J Vasc Interv Radiol 2008; 19: 499503.
  • 29
    Han RF, Pan JG. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006; 67: 121623.
  • 30
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 62934.
  • 31
    Sacks H, Chalmers TC, Smith H, Jr. Randomized versus historical controls for clinical trials. Am J Med 1982; 72: 23340.
  • 32
    Shiffman ML, Hofmann CM, Contos MJ, Luketic VA, Sanyal AJ, Sterling RK, Ferreira-Gonzalez A, Mills AS, Garret C. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology 1999; 117: 116472.
  • 33
    Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Meta-analyses of randomized controlled trials. N Engl J Med 1987; 316: 4505.
  • 34
    Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 133574.
  • 35
    Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010; 8: 2808.
  • 36
    Mallet V, Gilgenkrantz H, Serpaggi J, Verkarre V, Vallet-Pichard A, Fontaine H, Pol S. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008; 149: 399403.
  • 37
    Gerotto M, Dal Pero F, Bortoletto G, Ferrari A, Pistis R, Sebastiani G, Fagiuoli S, Realdon S, Alberti A. Hepatitis C minimal residual viremia (MRV) detected by TMA at the end of Peg-IFN plus ribavirin therapy predicts post-treatment relapse. J Hepatol 2006; 44: 837.
  • 38
    Bruix J, Poynard T, Colombo M, Schiff E, Reichen J, Burak K, Heathcote EJL, Berg T, Poo-Ramirez JL, Brandao Mello C, Guenther R, Niederau C, et al. Pegintron maintenance therapy in cirrhotic (Metavir F4) HCV patients, who failed to respond to interferon/ribavirin therapy: final results of the EPIC3 cirrhosis maintenance trial. J Hepatol 2009; 50( Suppl 1): S22.
  • 39
    Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 152131.
  • 40
    Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, Brown N, Woessner M, Boehme R, Condreay L. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003; 36: 68796.
  • 41
    Chu CM, Liaw YF. Hepatitis B virus-related cirrhosis: natural history and treatment. Semin Liver Dis 2006; 26: 14252.
  • 42
    Buster EH, Hansen BE, Buti M, Delwaide J, Niederau C, Michielsen PP, Flisiak R, Zondervan PE, Schalm SW, Janssen HL. Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis. Hepatology 2007; 46: 38894.
  • 43
    Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352: 268295.
  • 44
    Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351: 120617.
  • 45
    Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol 1984; 2: 33652.
  • 46
    Clavien PA. Interferon: the magic bullet to prevent hepatocellular carcinoma recurrence after resection? Ann Surg 2007; 245: 8435.
  • 47
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 97582.
  • 48
    Moher D, Pham B, Klassen TP, Schulz KF, Berlin JA, Jadad AR, Liberati A. What contributions do languages other than English make on the results of meta-analyses? J Clin Epidemiol 2000; 53: 96472.