Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma

Petrini, Iacopo; Lencioni, Monica; Ricasoli, Miriam; Iannopollo, Mauro; Orlandini, Cinzia; Oliveri, Filippo; Bartolozzi, Carlo; Ricci, Sergio

doi:10.1007/s00280-011-1753-2

Cited by 65 publications

(42 citation statements)

References 27 publications

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“…In a phase Ⅱ trial with 39 advanced HCC patients, sorafenib in combination with 5-fluorouracil infusion showed an encouraging disease control rate with the stable disease (SD) rate of 46.2% for a median duration of 16.2 mo, median TTP of 8 mo and OS of 13.7 mo [46] . Metronomic chemotherapy using tegafur/uracil has been shown to enhance the anti-tumor effect of antiangiogenic agents in preclinical models.…”

Section: Combinational Therapy With Sorafenibmentioning

confidence: 99%

“…In a multicenter phase Ⅱ So.LAR. study with 50 ad- Combinational therapy 5-fluorouracil plus sorafenib [46] Phase Ⅱ 39 SD: 46.2%; median TTP: 8 mo; OS: 13.7 mo Tegafur/uracil plus sorafenib [47] Phase Ⅱ 53 Median PFS: 3.7 mo; median OS: 7.4 mo Octreotide plus sorafenib [48] Phase Ⅱ (So.LAR.) 50 SD: 66%; median TTP: 7.0 mo; median OS: 12 mo Doxorubicin plus sorafenib vs doxorubicin plus placebo [50] Phase Ⅲ 47 vs 49 Median TTP: 6.4 mo vs 2.8 mo; OS: 13.7 mo vs 6.5 mo; PFS: 6.0 mo vs 2.7 mo Erlotinib plus sorafenib vs erlotinib plus placebo [53,54] Phase Ⅲ (SEARCH) 362 Median TTP: 3.2 mo vs 4.0 mo; OS: 9.5 mo vs 8.5 mo Second-line treatments Sunitinib [55] Retrospective analysis 11 SD: 40%; median TTP: 3.2 mo Brivanib [56] Phase Ⅱ 46 SD: 41.3%; RR: 4.3%; DCR: 45.7%; median OS: 9.79 mo Tivantinib vs placebo [6] Phase Ⅱ 71 vs 36 Progressive disease: 65% vs 72%; TTP: 1.6 mo vs 1.4 mo Gemcitabine plus oxaliplatin [59] Retrospective analysis 18 Overall RR: 18.8%; SD: 18.8%; median PFS: 3.2 mo; OS: 4.7 mo Erlotinib plus bevacizumab [61] Phase controlled arm in this trial, the encouraging outcome was unable to justify that the efficacy was from sorafenib alone or the synergism with doxorubicin.…”

Section: Combinational Therapy With Sorafenibmentioning

confidence: 99%

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Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

163

152

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Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. Core tip: The primary resistance of hepatocellular carcinoma (HCC) to sorafenib is due to genetic heterogeneity. Thus, seeking predictive biomarkers and combining sorafenib with other anticancer agents for HCC have been launched with varying degrees of success. Sorafenib inhibits several kinase targets but it can also simultaneously or sequentially activate the addiction switches and compensatory pathways, inducing acquired resistance. Some other molecular targeted drugs have been used as second-line treatment for advanced HCC after the failure of sorafenib therapy. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms accounting for sorafenib resistance in HCC.Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5(7): 345-352 Available from:

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Section: Combinational Therapy With Sorafenibmentioning

confidence: 99%

Section: Combinational Therapy With Sorafenibmentioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

163

152

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“…Analysis of the cost-effectiveness of the treatments under investigation should also be an important consideration in future trials. Hsu et al [166] Tegafur/uracil Prospective phase Ⅱ 53 7.4 57 3.7 Prete et al [161] Long-acting octreotide Prospective phase Ⅱ 50 12 76 7 Abou-Alfa et al [165] PR- 104 Prospective phase Ⅰ 14 NR 50 NR Lee et al [164] S-1 fluoropyrimidines Prospective phase Ⅰ 20 10.4 52.9 3.9 Petrini et al [163] 5-Fluorouracil Prospective phase Ⅱ 39 13.7 48.7 7.5 Table 3 Combined sorafenib plus systemic anticancer therapy for unresectable hepatocellular carcinoma DCR: Disease control rate; NR: Not recorded; OS: Overall survival; PFS: Progression-free survival.…”

Section: Resultsmentioning

confidence: 99%

“…Several combinations of sorafenib with systemic chemotherapeutic agents have been evaluated, including sorafenib with doxorubicin [160] , octreotide [161] , oxaliplatin [162] , 5-fluorouracil [163] , S-1 fluoropyrimidines [164] , PR-104 [165] , tegafur/uracil [166] , cisplatin and gemcitabine [167] , and AVE 1642 (a human monoclonal antibody inhibiting the insulin-like growth factor-1 receptor) [168] (Table 3). Other ongoing phase Ⅱ trials include the combination of sorafenib with gemcitabine/ oxaliplatin [169] , modified FOLFOX [170] , or capecitabine/ oxaliplatin [171] .…”

Section: Sorafenib and Systemic Chemotherapymentioning

confidence: 99%

Recent advances in multidisciplinary management of hepatocellular carcinoma

Gomaa¹

2015

WJH

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“…In HCC, Petrini et al (10) reported that treatment with a combination of sorafenib and 5-FU improved the efficacy of systemic treatment in advanced HCC without side effects.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib inhibits cancer side population cells by targeting c-Jun N-terminal kinase signaling

Kim

Lee

Park

et al. 2012

Molecular Medicine Reports

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Abstract. Sorafenib is a systemic chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the anticancer effect of sorafenib in cancer stem cell-like cells, such as side population (SP) cells, in HCC and to analyze the signaling pathway for drug-resistance. To evaluate the anticancer effects of sorafenib, Huh7 and Huh-BAT cells were treated with sorafenib, fluorouracil (5-FU), and sorafenib plus 5-FU. These cells were examined for growth rates, the SP fraction, sphere-forming efficacy and expression of c-Jun N-terminal kinase (JNK) signaling molecules. Sorafenib and 5-FU treatment decreased growth rates in Huh7 and Huh-BAT cells; however, the treatments exerted different effects in SP cells and on the expression levels of JNK signaling molecules. Treatment with 5-FU increased the SP cell number and upregulated the expression of JNK signaling molecules. By contrast, sorafenib decreased the SP cell number and downregulated the expression of JNK signaling molecules. No significant differences in sphere-forming efficacy were observed subsequent to 5-FU and sorafenib treatment in Huh7 and Huh-BAT cells. These results indicate that sorafenib exerted anticancer effects in HCC and SP cells by targeting JNK signaling.

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Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma

Abstract: The results show an encouraging disease control rate, time to progression, and overall survival. The combination of sorafenib and 5-fluorouracil was feasible, and the side effects were manageable for patients carefully selected for liver function and performance status.

Cited by 65 publications

References 27 publications

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Recent advances in multidisciplinary management of hepatocellular carcinoma

Sorafenib inhibits cancer side population cells by targeting c-Jun N-terminal kinase signaling

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