Phase II Trial of Systemic Continuous Fluorouracil and Subcutaneous Recombinant Interferon Alfa-2b for Treatment of Hepatocellular Carcinoma

Patt, Yehuda Z.; Hassan, Manal M.; Lozano, Richard D.; Brown, Thomas; Vauthey, Jean Nicolas; Curley, Steven A.; Ellis, Lee M.

doi:10.1200/jco.2003.10.103

Cited by 180 publications

(150 citation statements)

References 35 publications

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“…Their combination of IFN-a and 5-FU has been shown previously to be highly effective clinically (Sakon et al, 2002;Patt et al, 2003;Obi et al, 2006). This is supported by our own observation that combination therapy with IFN-a and 5-FU induced significantly more apoptosis and tumour growth inhibition than monotherapy.…”

Section: Discussionsupporting

confidence: 72%

“…Recent studies have suggested that these patients may be effectively treated by combination therapy involving subcutaneous (s.c.) administration of interferon (IFN)-a and intrahepatic administration of 5-fluorouracil (5-FU) (Sakon et al, 2002;Obi et al, 2006). A Phase II trial has also revealed that continuous 5-FU infusion combined with thrice-weekly treatment with IFN-a effectively treats HCC, perhaps because the drugs together play a neoadjuvant role (Patt et al, 2003). Comprehensive genetic analyses with PCR arrays have revealed that this method may be useful for predicting whether combination chemotherapy with IFN-a and 5-FU can successfully treat HCC (Kurokawa et al, 2004).…”

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confidence: 99%

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Combination therapy with PEG-IFN-α and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53

et al. 2007

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When the tumour suppressor p53 is activated by DNA damage, it stimulates the transcription of its target genes, which then induce cell cycle arrest or apoptosis. Here, we examined the role p53 plays in the antitumour effect of combination treatment with pegylated interferon (PEG-IFN)-a and 5-fluorouracil (5-FU), which has been shown to effectively treat advanced hepatocellular carcinoma (HCC). Nude mice were injected subcutaneously with cultured HepG2 cells, in which p53 is functional. They were treated a week later with PEG-IFN and/or 5-FU for 7 weeks, after which we measured and examined their tumours. Combination groups showed significantly lower tumour volumes and higher tumour cell apoptosis than the other groups. Combination treatment and PEG-IFN monotherapy also significantly elevated the p53 protein and mRNA levels in the tumour but only combination treatment increased the degree of p53 phosphorylation at serine46 and induced p53-regulated apoptosis-inducing protein 1 (p53AIP1) expression. The antitumour effects of combination treatment is due in part to the elevation by PEG-IFN of p53 protein and mRNA expression and in part to the DNA damage that is generated by 5-FU, which induces p53 serine46 phosphorylation, which in turn upregulates p53AIP1 expression.

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 99%

Combination therapy with PEG-IFN-α and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53

et al. 2007

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“…The effectiveness of the combination therapy of 5-FU and interferon-a on advanced HCC has been reported. 34,35 It is noted that the dose of 5-FU used in this study is 40 mg kg À1 daily for 3 days, which is much less than the amount of 5-FU used in other cases. Generally, 5-FU was given at 60-66 mg kg À1 daily in treatment of either human HCC or gastric tumors in animals.…”

Section: Discussionmentioning

confidence: 87%

Therapeutic effect of α-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice

Chen

Yip

et al. 2010

Gene Ther

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Previous studies have shown that the application of Ad/AFPtBid significantly and specifically killed hepatocellular carcinoma (HCC) cells in culture and subcutaneously implanted in mice. This study was to test the therapeutic efficacy of Ad/AFPtBid in an orthotopic hepatic tumor model. Four weeks after implantation of tumor cells into the liver, nude mice were treated with Ad/ AFPtBid alone or in combination with 5-fluorouracil (5-FU). Serum a-fetoprotein (AFP) was measured as a marker for tumor progression. The results showed that Ad/AFPtBid significantly inhibited Hep3B tumor growth. Ad/AFPtBid and 5-FU in combination was more effective than either agent alone. Tumor tissues of Ad/AFPtBid alone or combination treatment groups showed a decrease in cells positive for proliferation cell nuclear antigen, but an increase in apoptosis. Ad/AFPtBid did not suppress the hepatic tumor formed by non-AFP-producing hepatoma SK-HEP-1 cells or colorectal adenocarcinoma DLD-1 cells. The survival rate was higher in mice treated with Ad/AFPtBid plus 5-FU than those treated with either agent alone. No acute toxic effect was observed in mice receiving Ad/AFPtBid. Collectively, Ad/AFPtBid can specifically target and effectively suppress the AFP-producing orthotopic liver tumor in mice without obvious toxicity, indicating that it is a promising tool in combination with chemotherapeutic agents for treatment of AFP-producing HCC.

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“…Separate Note on FL-HCC [43][44][45][46][47][48][49][50] Because the analysis of the literature shows that NC-HCC and FL-HCC are still perceived differently on account of their different clinical presentations, courses, imaging results, and outcomes, some brief remarks about this tumor variant are made here.…”

Section: Resultsmentioning

confidence: 99%

“…48 There is some indication that adjuvant chemotherapy (a combination of 5-fluorouracil and interferon) may be useful and more applicable in these patients because they present with normal residual liver tissue. 49,50 In conclusion, at the request of the consensus conference committee, we have examined the reported results of partial liver resection and transplantation in NC-HCC patients. Although the reported experience, especially in the field of LT, is small, the (surprisingly) high tumor recurrence rate after liver resection and the few reports of successful outcomes after LT for intrahepatic recurrence after partial resection in these patients may indicate that NC-HCC is an underused indication for LT.…”

Section: Resultsmentioning

confidence: 99%

Place of liver transplantation in the treatment of hepatocellular carcinoma in the normal liver

et al. 2011

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Hepatocellular carcinoma (HCC) is a relatively common cancer and occurs mainly in patients with liver cirrhosis (85%-95%). A significant number of cases are, however, diagnosed in normal and noncirrhotic/nonfibrotic livers. In contrast to HCC in a cirrhotic liver, noncirrhotic hepatocellular carcinoma (NC-HCC) predominantly occurs in young and healthy female patients in their 30s, and the diagnosis is frequently made at an advanced stage in the absence of a clear etiological factor. [1][2][3] The same holds true for the uncommon fibrolamellar hepatocellular carcinoma (FL-HCC) variant. [1][2][3] Several studies have shown that the 3-year overall survival (OS) rates with different pharmaceutical, radiological, and surgical therapies for HCC (if they are adequately performed) are approximately 60%. 4 After 3 years, the results of these treatments start to diverge substantially with respect to OS and, most importantly, with respect to disease-free survival (DFS). Long-term follow-up (5-10 years) has clearly shown that surgical resection is the only curative treatment for any kind of HCC. [2][3][4][5] With respect to very long-term DFS (>5 years), liver transplantation (LT) offers the best results. 2,4-6 In order to be successful, surgery has to be adapted to the tumor, the underlying condition of the patient, and the patient's liver. Liver resection and LT should have complementary roles rather than competing ones, and they should be associated with each other instead of being opposed. 5 Partial resection for HCC can be considered only for patients with well-compensated cirrhosis or fibrosis or with normal liver tissue. For patients with decompensated liver disease, cirrhosis, or a technically unresectable tumor, LT offers the best chance for a cure. This option indeed addresses the tumor as well as the underlying liver disease.Despite the extensive experience with LT for the treatment of HCC in patients with cirrhosis, the experience with LT for the treatment of NC-HCC is anecdotal and is limited to situations in which resection is not possible.The aims of this study were as follows: (1) to analyze the results from recent series of partial liver resections for NC-HCC, (2) to compare these results with the results of LT for the same condition; and (3) to propose an adaptation of the therapeutic algorithm for NC-HCC on the basis of these analyses.

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Phase II Trial of Systemic Continuous Fluorouracil and Subcutaneous Recombinant Interferon Alfa-2b for Treatment of Hepatocellular Carcinoma

Abstract: Continuous IV FU and thrice-weekly SC rIFNalpha2b are an effective treatment, especially for FLHCC, and may have a neoadjuvant role in this disease. This regimen has activity in HCC and can be tolerated even by cirrhotic patients.

Cited by 180 publications

References 35 publications

Combination therapy with PEG-IFN-α and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53

Combination therapy with PEG-IFN-α and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53

Therapeutic effect of α-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice

Place of liver transplantation in the treatment of hepatocellular carcinoma in the normal liver

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