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Sorafenib efficacy for treatment of HCC recurrence after liver transplantation is an open issue

2013; Elsevier BV; Volume: 60; Issue: 3 Linguagem: Inglês

10.1016/j.jhep.2013.10.030

1600-0641

Andrea Mancuso, Chiara Mazzarelli, Giovanni Perricone, Claudio Zavaglia,

Cancer Mechanisms and Therapy

Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: A case-control studyJournal of HepatologyVol. 59Issue 1PreviewThe efficacy of sorafenib in the post-liver transplantation (LT) setting has been scarcely studied. The aim of this study was to evaluate the efficacy of sorafenib, compared to best supportive care (BSC), in two cohorts of patients which presented with hepatocellular carcinoma (HCC) recurrence after LT. Full-Text PDF Reply to: “Sorafenib efficacy for treatment of HCC recurrence after liver transplantation is an open issue”Journal of HepatologyVol. 60Issue 3PreviewTo the Editor: Full-Text PDF Open Access To the Editor: We read with interest the case-control study on sorafenib treatment for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) recently published in the Journal of Hepatology [[1]Sposito C. Mariani L. Germini A. Reyes M.F. Bongini M. Grossi G. et al.Comparative efficacy of sorafenib vs. best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study.J Hepatol. 2013; 59: 59-66Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. The study reports the consecutive experience on 15 patients with no otherwise treatable HCC recurrence after LT, who underwent treatment with Sorafenib. Outcome was compared with those of 24 historical consecutive controls. Overall, an outcome benefit statistically attributed to sorafenib was reported for the former group. Despite some strong bias, namely the case-control design of the study and the different immunosuppressive regimes between the two groups, possibly affecting HCC outcome, the take home message of both the study and the accompanying Editorial seems to be that since sorafenib is already of proven efficacy for HCC recurrence treatment after LT, its indication should be added to the next guidelines [1Sposito C. Mariani L. Germini A. Reyes M.F. Bongini M. Grossi G. et al.Comparative efficacy of sorafenib vs. best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study.J Hepatol. 2013; 59: 59-66Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 2Toso C. Mentha G. Majno P. Integrating sorafenib into an algorithm for the management of post-transplant hepatocellular carcinoma recurrence.J Hepatol. 2013; 59: 3-5Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. However, overall evidence of sorafenib efficacy for HCC recurrence after LT is actually weak. Previous studies reported non homogeneous outcome after treatment of HCC recurrence after LT using sorafenib. In fact, despite the optimist results of some studies, more than one centre reported negative experiences [3Bhoori S. Toffanin S. Sposito C. Germini A. Pellegrinelli A. Lampis A. et al.Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle.J Hepatol. 2010; 52: 771-775Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 4Newell P. Toffanin S. Villanueva A. Chiang D.Y. Minguez B. Cabellos L. et al.Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo.J Hepatol. 2009; 51: 725-733Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 5Gangadhar T.C. Cohen E.E. Wu K. Janisch L. Geary D. Kocherginsky M. et al.Two drug interaction studies of sirolimus in combination with sorafenib or sunitinib in patients with advanced malignancies.Clin Cancer Res. 2011; 17: 1956-1963Crossref PubMed Scopus (38) Google Scholar, 6Zavaglia C. Airoldi A. Mancuso A. Vangeli M. Vigano R. Cordone G. et al.Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature.Eur J Gastroenterol Hepatol. 2013; 25: 180-186Crossref PubMed Scopus (56) Google Scholar, 7Staufer K. Fischer L. Seegers B. Vettorazzi E. Nashan B. Sterneck M. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation.Transpl Int. 2012; 25: 1158-1164Crossref PubMed Scopus (55) Google Scholar, 8Weinmann A. Niederle I.M. Koch S. Hoppe-Lotichius M. Heise M. Duber C. et al.Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.Dig Liver Dis. 2012; 44: 432-437Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 9Piguet A.C. Saar B. Hlushchuk R. St-Pierre M.V. McSheehy P.M. Radojevic V. et al.Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma.Mol Cancer Ther. 2011; 10: 1007-1017Crossref PubMed Scopus (68) Google Scholar]. In disagreement with the findings of the present study, we and others previously reported significant toxicity of sorafenib in the post-transplant setting [6Zavaglia C. Airoldi A. Mancuso A. Vangeli M. Vigano R. Cordone G. et al.Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature.Eur J Gastroenterol Hepatol. 2013; 25: 180-186Crossref PubMed Scopus (56) Google Scholar, 7Staufer K. Fischer L. Seegers B. Vettorazzi E. Nashan B. Sterneck M. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation.Transpl Int. 2012; 25: 1158-1164Crossref PubMed Scopus (55) Google Scholar]. In particular, one group reported grade 3–4 adverse events in 92% of 13 patients, resulting in sorafenib discontinuation in 77% [[6]Zavaglia C. Airoldi A. Mancuso A. Vangeli M. Vigano R. Cordone G. et al.Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature.Eur J Gastroenterol Hepatol. 2013; 25: 180-186Crossref PubMed Scopus (56) Google Scholar]. Our experience on 15 consecutive patients, as partially reported on 11, describes a high rate of intolerance or side-effects, causing drug discontinuation in 36% of 11 patients [[7]Staufer K. Fischer L. Seegers B. Vettorazzi E. Nashan B. Sterneck M. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation.Transpl Int. 2012; 25: 1158-1164Crossref PubMed Scopus (55) Google Scholar]. Moreover, one patient died because of massive gastrointestinal bleeding, as previously fully described [[10]Mancuso A. Airoldi A. Vigano R. Pinzello G. Fatal gastric bleeding during sorafenib treatment for hepatocellular carcinoma recurrence after liver transplantation.Dig Liver Dis. 2011; 43: 754Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar], suggesting the concern that everolimus and sorafenib interaction could facilitate gastrointestinal bleeding [[3]Bhoori S. Toffanin S. Sposito C. Germini A. Pellegrinelli A. Lampis A. et al.Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle.J Hepatol. 2010; 52: 771-775Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. In conclusion, we believe that there is not yet enough evidence to draw any definite conclusion on indication of sorafenib for HCC recurrence treatment after LT. Albeit difficult to perform, a multicenter prospective sorafenib vs. placebo controlled trial should be advocated. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.