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Abstract
Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
Keywords
RAF/MEK/ERK PATHWAY, PHASE-II, CONTROLLED TRIAL, CLINICAL-TRIALS, ANGIOGENESIS, MANAGEMENT, BEVACIZUMAB, COMBINATION, ACTIVATION, APOPTOSIS

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MLA
Llovet, Josep M, Sergio Ricci, Vincenzo Mazzaferro, et al. “Sorafenib in Advanced Hepatocellular Carcinoma.” NEW ENGLAND JOURNAL OF MEDICINE 359.4 (2008): 378–390. Print.
APA
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., Cosme de Oliveira, A., et al. (2008). Sorafenib in advanced hepatocellular carcinoma. NEW ENGLAND JOURNAL OF MEDICINE, 359(4), 378–390. Presented at the 43rd Annual meeting of the American Society of Clinical Oncology.
Chicago author-date
Llovet, Josep M, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard, Edward Gane, Jean-Frederic Blanc, Andre Cosme de Oliveira, et al. 2008. “Sorafenib in Advanced Hepatocellular Carcinoma.” New England Journal of Medicine 359 (4): 378–390.
Chicago author-date (all authors)
Llovet, Josep M, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard, Edward Gane, Jean-Frederic Blanc, Andre Cosme de Oliveira, Armando Santoro, Jean-Luc Raoul, Alejandro Forner, Myron Schwartz, Camillo Porta, Stefan Zeuzem, Luigi Bolondi, Tim F Greten, Peter R Galle, Jean-François Seitz, Ivan Borbath, Dieter Haussinger, Tom Giannaris, Minghua Shan, Marius Moscovici, Dimitris Voliotis, Jordi Bruix, the SHARP Investigators Study Group, and Hans Van Vlierberghe. 2008. “Sorafenib in Advanced Hepatocellular Carcinoma.” New England Journal of Medicine 359 (4): 378–390.
Vancouver
1.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, et al. Sorafenib in advanced hepatocellular carcinoma. NEW ENGLAND JOURNAL OF MEDICINE. 2008;359(4):378–90.
IEEE
[1]
J. M. Llovet et al., “Sorafenib in advanced hepatocellular carcinoma,” NEW ENGLAND JOURNAL OF MEDICINE, vol. 359, no. 4, pp. 378–390, 2008.
@article{1228582,
  abstract     = {Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma.
Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety.
Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group.
Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.},
  author       = {Llovet, Josep M and Ricci, Sergio and Mazzaferro, Vincenzo and Hilgard, Philip and Gane, Edward and Blanc, Jean-Frederic and Cosme de Oliveira, Andre and Santoro, Armando and Raoul, Jean-Luc and Forner, Alejandro and Schwartz, Myron and Porta, Camillo and Zeuzem, Stefan and Bolondi, Luigi and Greten, Tim F and Galle, Peter R and Seitz, Jean-François and Borbath, Ivan and Haussinger, Dieter and Giannaris, Tom and Shan, Minghua and Moscovici, Marius and Voliotis, Dimitris and Bruix, Jordi and SHARP Investigators Study Group, the and Van Vlierberghe, Hans},
  issn         = {0028-4793},
  journal      = {NEW ENGLAND JOURNAL OF MEDICINE},
  keywords     = {RAF/MEK/ERK PATHWAY,PHASE-II,CONTROLLED TRIAL,CLINICAL-TRIALS,ANGIOGENESIS,MANAGEMENT,BEVACIZUMAB,COMBINATION,ACTIVATION,APOPTOSIS},
  language     = {eng},
  location     = {Chicago, IL, USA},
  number       = {4},
  pages        = {378--390},
  title        = {Sorafenib in advanced hepatocellular carcinoma},
  url          = {http://www.nejm.org/toc/nejm/359/4},
  volume       = {359},
  year         = {2008},
}

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