Josep M. Llovet, M.D., Sergio Ricci, M.D., Vincenzo Mazzaferro, M.D., Philip Hilgard, M.D., Edward Gane, M.D., Jean-Frédéric Blanc, M.D., Andre Cosme de Oliveira, M.D., Armando Santoro, M.D., Jean-Luc Raoul, M.D., Alejandro Forner, M.D., Myron Schwartz, M.D., Camillo Porta, M.D., Stefan Zeuzem, M.D., Luigi Bolondi, M.D., Tim F. Greten, M.D., Peter R. Galle, M.D., Jean-François Seitz, M.D., Ivan Borbath, M.D., Dieter Häussinger, M.D., Tom Giannaris, B.Sc., Minghua Shan, Ph.D., Marius Moscovici, M.D., Dimitris Voliotis, M.D., Jordi Bruix, M.D., for the SHARP Investigators Study Group
Background No effective systemic therapy exists for patientswith advanced hepatocellular carcinoma. A preliminary studysuggested that sorafenib, an oral multikinase inhibitor of thevascular endothelial growth factor receptor, the platelet-derivedgrowth factor receptor, and Raf may be effective in hepatocellularcarcinoma.
Methods In this multicenter, phase 3, double-blind, placebo-controlledtrial, we randomly assigned 602 patients with advanced hepatocellularcarcinoma who had not received previous systemic treatment toreceive either sorafenib (at a dose of 400 mg twice daily) orplacebo. Primary outcomes were overall survival and the timeto symptomatic progression. Secondary outcomes included thetime to radiologic progression and safety.
Results At the second planned interim analysis, 321 deaths hadoccurred, and the study was stopped. Median overall survivalwas 10.7 months in the sorafenib group and 7.9 months in theplacebo group (hazard ratio in the sorafenib group, 0.69; 95%confidence interval, 0.55 to 0.87; P<0.001). There was nosignificant difference between the two groups in the mediantime to symptomatic progression (4.1 months vs. 4.9 months,respectively, P=0.77). The median time to radiologic progressionwas 5.5 months in the sorafenib group and 2.8 months in theplacebo group (P<0.001). Seven patients in the sorafenibgroup (2%) and two patients in the placebo group (1%) had apartial response; no patients had a complete response. Diarrhea,weight loss, hand–foot skin reaction, and hypophosphatemiawere more frequent in the sorafenib group.
Conclusions In patients with advanced hepatocellular carcinoma,median survival and the time to radiologic progression werenearly 3 months longer for patients treated with sorafenib thanfor those given placebo. (ClinicalTrials.gov number, NCT00105443
[ClinicalTrials.gov]
.)
Source Information
The affiliations of the authors and the names of the investigators in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) Investigators Study Group are listed in the Appendix.
Address reprint requests to Dr. Llovet or Dr. Bruix at the Barcelona Clínic Liver Cancer Group, Liver Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain, or at jmllovet{at}clinic.ub.es or jbruix{at}clinic.ub.es.
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