Clinical Pilot Study of Intrahepatic Arterial Chemotherapy with Methotrexate, 5-Fluorouracil, Cisplatin and Subcutaneous Interferon-Alpha-2b for Patients with Locally Advanced Hepatocellular Carcinoma

Urabe, Takeshi; Kaneko, Shuichi; Matsushita, Eiki; Unoura, Masashi; Kobayashi, Kenichi

doi:10.1159/000011833

Cited by 88 publications

(70 citation statements)

References 20 publications

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“…thrombi in the major branches of the portal vein (Vp3 or 4), as our second report on this treatment. The efficacy of such treatment was 43.6% in our patients with highly advanced HCC, which was almost similar to the previous report of patients with the same stage HCC (Urabe et al, 1998). The prognosis of such patients is extremely poor and survival is generally limited to a few months after diagnosis, despite multimodal therapies even in cases suitable Figure 3 Immunohistochemical analysis of IFNAR2 expression in HCC tissues.…”

Section: Discussionsupporting

confidence: 88%

“…Patt et al (1993) reported 31% response rate in patients with unresectable advanced hepatoma and low alpha-fetoprotein (AFP) levels. Using intra-arterial infusion chemotherapy and systemic IFN-a, Urabe et al (1998) reported a response rate of 47% in patients with Vp3. In another study, Leung et al (1999) used cisplatin, doxorubicin, and IFN-a and reported that this treatment converted nine patients of 36 patients with inoperable HCC to become suitable for tumour resection, and none developed postoperative recurrence.…”

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confidence: 99%

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Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-α and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression

et al. 2005

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We previously reported the beneficial effects of combination therapy of interferon (IFN)-a/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumour thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than double the number of patients relative to the original report, and evaluates the role of IFN-a/type 2 interferon receptor (IFNAR2) expression on the response to the combination therapy. The study subjects were 55 patients with advanced HCC and tumour thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least two courses of IFN-a/5-FU without major complication. In the 55 patients, 24 (43.6%) showed objective response (eight (14.5%) showed complete response, 16 (29.1%) partial response), four (7.3%) showed no response, and 27 (49.1%) showed progressive disease. Immunohistochemically, IFNAR2 expression was detected in nine out of 13 (69.2%) patients. There was significant difference in the time-to-progression survival (P ¼ 0.0002) and the overall survival (Po0.0001) between IFNAR2-positive and -negative cases. There was a significant correlation between IFNAR2 expression and response to IFN-a/5-FU combination therapy in univariate analysis (P ¼ 0.0070). IFN-a/5-FU combination therapy is a promising modality for advanced HCC with tumour thrombi in the major portal branches and could significantly depend on IFNAR2 expression.

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-α and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression

et al. 2005

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“…The poor results may be the result of the huge tumor burden in the studies. [25][26][27][28] It has been postulated that postoperative adjuvant IFNs may inhibit the recurrence of HCC after operation. 29 In this study, therefore, the authors investigated the preventive benefit of IFN-␣ in inhibition of tumor growth and recurrence after curative resection in LCI-D20 model, with potential minimum tumor burden, at maximum tolerated doses for long duration (at daily dose of 3 ϫ 10 7 U/kg for 35 days).…”

Section: Discussionmentioning

confidence: 99%

High-lose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential

et al. 2000

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Postoperative recurrence of human hepatocellular carcinoma (HCC) is the major issue that must be addressed to further improve prognosis. This study was undertaken to investigate the effects of interferon-alfa-1b (IFN-␣-1b) on recurrent tumor and metastasis after curative resection in nude mice bearing an HCC xenograft with high metastatic potential. Tumor tissues from LCI-D20, a metastatic model of HCC in nude mice, were orthotopically implanted in 105 nude mice. Eleven days later, 64 mice underwent curative resection of liver tumors. IFN-␣ at different doses was administered subcutaneously to mice with or without resection. In mice without resection, when comparison was made among control, IFN 7.5 ؋ 10 6 U/kg/day, 1.5 ؋ 10 7 U/kg/day for treated groups, and 3 ؋ 10 7 U/kg/day; tumor volume was 8,475 mm 3 ؎ 2,636 mm 3 , 7,963 mm 3 ؎ 3,214 mm 3 , 769 mm 3 ؎ 287 mm 3 , and 13 mm 3 ؎ 9 mm 3 ; incidence of lung metastasis being 100%, 80%, 40%, and 0%; life span was 45 ؎ 4 days, 53 ؎ 8 days, 81 ؎ 6 days, and 105 ؎ 24 days, respectively. In mice with curative resection, when comparison was made among control, IFN 5 ؋ 10 5 U/kg/day, 1 ؋ 10 6 U/kg/day, 4 ؋ 10 6 U/kg/day, 7.5 ؋ 10 6 U/kg/day, 1.5 ؋ 10 7 U/kg/day, and 3 ؋ 10 7 U/kg/day for treated groups; incidence of recurrent tumor was 100%, 100%, 87.5%, 100%, 87.5%, 62.5%, and 12.5%; lung metastasis being 100%, 75%, 87.5%, 50%, 62.5%, 0%, and 0%, respectively. IFN-␣ inhibited neovascularization induced by LCI-D20 tumor specimens implanted into the micropocket of nude mice corneas. Hepatocellular carcinoma (HCC) is one of the most frequent fatal malignancies occurring in Asia and Africa. 1 In China, it is the second major cause of cancer death in males and the third in females. 2,3 Surgical resection is the most important treatment. Unfortunately, the postoperative recurrence rate remains high. 4,5 HCC is generally not sensitive to chemotherapy. HCC is a typical hypervascular tumor. Intrahepatic and lung metastases suggest its hematogenous dissemination. Recently, angiogenesis was proved to be an important factor influencing HCC metastases and recurrence. 6 Therefore, agents that inhibit angiogenesis maybe provide a new approach to suppress the tumor growth and recurrence of HCC. In addition to the well-documented, antiproliferative, and immunomodulatory effects of interferon (IFN), the antiangiogenic properties of IFN have been proven. [7][8][9][10][11] The systemic administration of IFN-␣ decreased the expression of angiogenic factors, such as bFGF, 12 inhibited the angiogenesis, and resulted in regression of human tumors. 13,14 This study evaluates whether IFN-␣-1b can suppress tumor growth, prolong animal life-span, and inhibit recurrence after resection by inhibition of angiogenesis.

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“…The response rate of advanced HCC to HAIC is approximately 30-40% (9)(10)(11)(12)(13)(14)(15)(16), and HAIC (as well as sorafenib) is recommended for treatment of advanced HCC, particularly in Japan (17,18). However, comparison of the effects of sorafenib with other treatment methods for HCC has not been Sorafenib and hepatic arterial infusion chemotherapy for unresectable advanced hepatocellular carcinoma: A comparative study carried out.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib and hepatic arterial infusion chemotherapy for unresectable advanced hepatocellular carcinoma: A comparative study

Hiramine

Uto

Imamura

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Sorafenib is a kinase-targeted drug that has high efficacy for advanced hepatocellular carcinoma (HCC). The aim of the present study was to determine whether sorafenib is more effective than hepatic arterial infusion chemotherapy (HAIC) for HCC. Twenty patients treated with sorafenib (sorafenib group) initiated at 800 mg/day and 45 patients treated with HAIC (HAIC group) for unresectable Child-Pugh A advanced HCC were investigated retrospectively. The treatment effect was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). As a result, the overall response rate was significantly lower in the sorafenib group than in the HAIC group (P=0.03), while the disease control and survival rates did not differ between the two groups. In the sorafenib group, treatment was discontinued in 19 patients, including 12 due to side effects. In subgroups of patients treated with sorafenib, the survival rate was significantly lower in patients (n=11) administered sorafenib for <60 days compared to those (n=9) treated for ≥60 days. A shorter treatment period (<60 days) was an independent risk factor for unfavorable survival [hazard ratio (HR), 3.34; 95% confidence interval (CI), 1.45-7.66 vs. HAIC], while survival in patients treated with sorafenib for ≥60 days did not differ from those treated with HAIC (HR, 0.79; 95% CI, 0.27-2.34). In conclusion, the disease control and survival rates of patients treated with sorafenib for advanced HCC were comparable to such rates in patients treated with HAIC.However, the prognosis was poor when long-term sorafenib treatment was not possible due to side effects, demonstrating the importance of patient selection for sorafenib treatment.

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Clinical Pilot Study of Intrahepatic Arterial Chemotherapy with Methotrexate, 5-Fluorouracil, Cisplatin and Subcutaneous Interferon-Alpha-2b for Patients with Locally Advanced Hepatocellular Carcinoma

Cited by 88 publications

References 20 publications

Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-α and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression

Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-α and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression

High-lose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential

Sorafenib and hepatic arterial infusion chemotherapy for unresectable advanced hepatocellular carcinoma: A comparative study

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