Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma

Llovet, Josep M.; Sala, María; Castells, L.; Suárez, Yanette; Vilana, R.; Bianchi, L.; Ayuso, Carmen; Vargas, Vı́ctor; Rodés, Joan; Bruix, Jordi

doi:10.1002/hep.510310111

Cited by 254 publications

(153 citation statements)

References 34 publications

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“…Several treatments of unresectable HCC, such as immunotherapy with interferon, 78,80 antiandrogen therapy, 65 internal radiation, 55 and arterial 47,52 or systemic chemotherapy, 74,76 have also been evaluated in comparison with conservative management. However, none included a sufficient number of patients to guarantee a robust analysis.…”

Section: Discussionmentioning

confidence: 99%

Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

2003

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There is no standard treatment for patients with unresectable hepatocellular carcinoma (HCC). Survival benefits derived from medical interventions are controversial. The aim of this systematic review was to assess the evidence of the impact of medical treatments on survival. Randomized controlled trials (RCTs) that were published as full papers assessing survival for primary treatments of HCC were included. MEDLINE, the Cochrane Library, CANCERLIT, and a manual search from 1978 to May 2002 were used. The primary end point was survival, and the secondary end point was response to treatment. Estimates of effect were calculated according to the random effects model. Sensitivity analysis included methodological quality. We identified 61 randomized trials, but only 14 met the criteria to perform a meta-analysis assessing arterial embolization (7 trials, 545 patients) or tamoxifen T he incidence of hepatocellular carcinoma (HCC) is increasing worldwide. 1 Liver cancer is the fifth most common cancer in the world and the third most common cause of cancer-related death. 2 Cohort studies and cost-efficiency modeling have suggested that surveillance of well-defined cirrhotic patients may decrease tumor-related mortality. However, only 30% of patients benefit from curative therapies such as resection, transplantation, or percutaneous ablation 3 and achieve 5-year survival rates of 50% to 75%. 4 Most patients with HCC are diagnosed at intermediate to advanced stages, and there is no standard treatment for these patients. 3,4 The most reliable method to show survival advantages is to perform large randomized controlled trials (RCTs) that include more than 1,000 patients comparing treatment versus no treatment in a well-defined strata of individuals. 5-10 These investigations are lacking in patients with HCC. On the contrary, several medical interventions have been tested in the setting of small RCTs. However, the reduced size of these studies may cause questions of their statistical power when detecting survival differences, which, as in many areas of health care and oncology, are unlikely to be large. This raises the need for a systematic meta-analysis assessment, with a major role to integrate valid information and provide estimates of treatment effects when RCTs themselves are not of sufficient size. 9,10 Two systematic reviews published years ago 11,12 suggested a potential benefit for at Abbreviations: HCC, hepatocellular carcinoma; RCT, randomized controlled trial; OR, odds ratio; CI, confidence interval.

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Section: Discussionmentioning

confidence: 99%

Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

2003

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“…IFN-a was the first cytokine to be used clinically in human cancers. It is of note that although the benefit derived from IFN-a on established HCCs remains rather disappointing (Llovet et al, 2000), several clinical studies have suggested that IFN-a might prevent HCC development in HBV-or HCV-related cirrhosis, although the data remain controversial and no clear mechanism has been described in these studies (Ikeda et al, 1998;Nishiguchi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

et al. 2003

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The role of interferon-a (IFN-a) remains unclear in prevention of virus-induced hepatocellular carcinoma in humans. We have investigated it herewith in the X/myc transgenic mouse model of Hepadnavirus-related hepatocarcinogenesis because of upregulation of c-myc oncogene in the liver. We have demonstrated that IFN-a can downregulate dose-dependently hepatocyte proliferation and c-myc overexpression at early premalignant stages, while it does not affect either hepatocyte apoptosis or telomerase activity at these steps. However, continuous and long-term administration of IFN-a dose-dependently delays tumor onset in dysplastic livers and increases overall survival of animals, more efficiently whether started before the onset of dysplasia. The present study therefore highlights that early preventive administration of IFN-a can slow down evolution towards hepatocellular carcinoma via repression of c-myc and hepatocyte proliferation at premalignant steps in experimental cmyc-induced hepatocarcinogenesis. However, the transient effect observed in this study emphasizes a need to clarify the possible mechanisms of acquired resistance and subsequent therapeutic escape. Our experimental model may be a pertinent tool to explore antioncogenic properties of IFN-a in human cirrhotic livers showing c-myc upregulation.

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“…However, there were significant treatment-related toxicities in patients who received high-dose interferon. On the other hand, when a lower dosage (3 × 10 6 IU/m 2 , three times weekly) of interferon was used instead, there was no demonstrable clinical benefit [30] .…”

Section: Hormonal Therapymentioning

confidence: 99%

Evolution of systemic therapy of advanced hepatocellular carcinoma

Yau¹,

Chan²,

Epstein³

et al. 2008

WJG

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Hepatocellular carcinoma (HCC) commonly occurs in hepatitis B endemic areas, especially in Asian countries. HCC is highly refractory to cytotoxic chemotherapy. This resistance is partly related to its tumor biology, pharmacokinetic properties, and both intrinsic and acquired drug resistance. There is no convincing evidence thus far that systemic chemotherapy improves overall survival in advanced HCC patients. Other systemic approaches, such as hormonal therapy and immunotherapy, have also disappointing results. Recently, encouraging results have been shown in using sorafenib in the treatment of advanced HCC patients. In this review, we concisely summarize the evolution of developments in the systemic therapy of advanced HCC.

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Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma

Cited by 254 publications

References 34 publications

Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

Evolution of systemic therapy of advanced hepatocellular carcinoma

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