- Email: [email protected]
Management of hepatocellular carcinoma recurrence after liver transplant is far from perfect
The American Journal of Surgery xxx (2017) 1e2
Contents lists available at ScienceDirect
The American Journal of Surgery journal homepage: www.americanjournalofsurgery.com
Letter to the Editor
Management of hepatocellular carcinoma recurrence after liver transplant is far from perfect
Keywords: Hepatocellular carcinoma Recurrence Sorafenib Liver transplant
Financial support This study was not supported by any pharmaceutical company or grants; the cost was borne by the authors. References
We read with interest the recent subgroups analysis of the Gideon registry reporting Sorafenib to have an adequate safety profile as treatment of recurrent hepatocellular carcinoma (HCC) after liver transplant (LT).1 However, so far the published observational studies on HCC recurrence after LT treated with sorafenib, reported contradictory results in terms of both efficacy and safety and the opportunity of such treatment has been long debated. In fact, while some studies emphasize the potential efficacy over best supportive care, others report a concern about safety.2e20 To resolve uncertainties, a meta-analysis of published studies was recently reported.21 Overall 1-year survival ranged from 18% to 90%. Tumour progression was the main cause of death. The pooled estimate of 1-year survival was 63%. Moreover, there was a significant heterogeneity among studies.21 Interestingly, the second cause of death in the metaanalysis was bleeding, reported only in patients undergoing mTor inhibitor therapy.21 This unexpected data reinforces the concern about bleeding with the combination of sorafenib and m-Tor inhibitor previously underlined and, generally, the risk of serious adverse events potentially correlated to drug to drug interaction, an issue already reported for sorafenib in different clinical contexts.22e24 Overall, since sorafenib is nowadays the only systemic therapy effective for HCC,25e28 these data would suggest not to avoid sorafenib as treatment of HCC recurrence after LT, but to strictly select patients for sorafenib and follow them carefully. However, the association with m-Tor inhibitors should be discouraged. Finally, albeit sorafenib could theoretically be useful as treatment of such a difficult to treat population, management of HCC recurrence after LT is still far from perfect. Conflict of interest We declare we do not have any conflict of interest.
1. Martin 2nd RC, Bruenderman E, Cohn A, et al. Sorafenib use for recurrent hepatocellular cancer after resection or transplantation: observations from a US regional analysis of the GIDEON registry. Am J Surg. 2017;213:688e695. 2. Dharancy S, Romano O, Lorho R, et al. Tolerability and efficacy of sorafenib in recurrent hepatocellular carcinoma after liver transplantation: a case control study. Hepatology. 2008;48:310A. 3. Feun LG, Levi D, Moon J, et al. Sorafenib in hepatocellular carcinoma patients after liver transplantation. J Clin Oncol. 2009;29:15. 4. Kim R, El-Gazzaz G, Tan A, et al. Safety and feasibility of using sorafenib in recurrent hepatocellular carcinoma after orthotopic liver transplantation. Oncology. 2010;79(1-2):62e66. http://dx.doi.org/10.1159/000319548. 5. Tan WF, Qiu ZQ, YU Y, et al. Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation. Acta Pharmacol Sin. 2010;31:1643e1648. 6. Valdivieso A, Bustamante J, Gastaca M, Uriarte JG, et al. Management of hepatocellular carcinoma recurrence after liver transplantation. Transpl Proc. 2010;42:660e662. 7. Yoon DH, Ryoo BY, Ryu MH, et al. Sorafenib for recurrent hepatocellular carcinoma after liver transplantation. J Clin Oncol. 2010;40:768e773. 8. Pfiffer TE, Seehofer D, Nicolaou A, et al. Recurrent hepatocellular carcinoma in liver transplant recipients: parameters affecting time to recurrence, treatment options and survival in the sorafenib era. Tumori. 2011;97:436e441. 9. Gomez-Martin C, Bustamante J, Castroagudin JF, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl. 2012;18:45e52. 10. Sotiropoulos GC, Nowak KW, Fouzas I, et al. Sorafenib treatment for recurrent hepatocellular carcinoma after liver transplantation. Transpl Proc. 2012;44: 2754e2756. 11. Staufer K, Fischer L, Seegers B, et al. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transpl Int. 2012;25: 1158e1164. 12. Vitale A, Boccagni P, Kertusha X, et al. Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation? Transpl Proc. 2012;44: 1989e1991. 13. Weinmann A, Niederle IM, Koch S, et al. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Dig Liver Dis. 2012 May;44(5): 432e437. 14. Pfeiffenberger J, Koschny R, Hoffmann K, et al. Sorafenib treatment is save and may affect survival of recurrent hepatocellular carcinoma after liver transplantation. Langenbeck's Archiv Surg. October 2013;398:1123e1128. 15. Sposito C, Mariani L, Germini A, et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol. 2013;59:59e66. 16. Waghray A, Balci B, El-Gazzaz G, et al. Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation. Clin Transpl. 2013;27:555e561. 17. Zavaglia C, Airoldi A, Mancuso A, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation:
http://dx.doi.org/10.1016/j.amjsurg.2017.04.004 0002-9610/© 2017 Elsevier Inc. All rights reserved.
Please cite this article in press as: Mancuso A, Maringhini AManagement of hepatocellular carcinoma recurrence after liver transplant is far from perfect, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.04.004
2
Letter to the Editor / The American Journal of Surgery xxx (2017) 1e2
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20.
21.
22.
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24. 25.
experience at a single center and review of the literature. Eur J Gastroenterol Hepatol. 2013;25:180e186. De Simone P, Crocetti L, Pezzati D, et al. Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Transpl Proc. 2014;46:241e244. Mancuso A, Mazzarelli C, Perricone G, et al. Sorafenib efficacy for treatment of HCC recurrence after Liver Transplantation is an open issue. J Hepatol. 2014;3: 261. Mancuso A, Perricone G. Time to resize the role of everolimus as treatment of hepatocellular carcinoma recurrence after liver transplant. Transpl Int. 2015;28:502. Mancuso A, Mazzola A, Cabibbo G, et al. Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplant: a systematic review and meta-analysis. Dig Liver Dis. 2015;47:324e330. Mancuso A, Airoldi A, Vigano R, et al. Fatal gastric bleeding during sorafenib treatment for hepatocellular carcinoma recurrence after liver transplantation. Dig Liver Dis. 2011;43:754. Mancuso A, Zavaglia C, Bai F, et al. Sorafenib hepatotoxicity seems to be enhanced by HAARTS interaction during treatment of advanced hepatocelluler carcinoma in HIV-infected patients. Alimentary Pharmacol Ther. 2013;38: 1414e1416. Mancuso A. Regorafenib for hepatocellular carcinoma progressing on sorafenib: just another starting point. AME Med J. 2017;2:31. Mancuso A. Management of hepatocellular carcinoma: enlightening the grey
zones. World J Hepatol. 2013;5:302e310. 26. Mancuso A, Perricone G. Hepatocellular carcinoma and liver transplantation: state-of-the-art. J Clin Transl Hepatol. 2014;2:176e181. 27. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378e390. 28. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10: 25e34.
Andrea Mancuso, M.D*, Alberto Maringhini, M.D Medicina Interna 1, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico - Di Cristina - Benfratelli, Piazzale Leotta 4, 90100, Palermo, Italy * Corresponding author. E-mail address: [email protected] (A. Mancuso).
28 March 2017
Please cite this article in press as: Mancuso A, Maringhini AManagement of hepatocellular carcinoma recurrence after liver transplant is far from perfect, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.04.004
Contents lists available at ScienceDirect
The American Journal of Surgery journal homepage: www.americanjournalofsurgery.com
Letter to the Editor
Management of hepatocellular carcinoma recurrence after liver transplant is far from perfect
Keywords: Hepatocellular carcinoma Recurrence Sorafenib Liver transplant
Financial support This study was not supported by any pharmaceutical company or grants; the cost was borne by the authors. References
We read with interest the recent subgroups analysis of the Gideon registry reporting Sorafenib to have an adequate safety profile as treatment of recurrent hepatocellular carcinoma (HCC) after liver transplant (LT).1 However, so far the published observational studies on HCC recurrence after LT treated with sorafenib, reported contradictory results in terms of both efficacy and safety and the opportunity of such treatment has been long debated. In fact, while some studies emphasize the potential efficacy over best supportive care, others report a concern about safety.2e20 To resolve uncertainties, a meta-analysis of published studies was recently reported.21 Overall 1-year survival ranged from 18% to 90%. Tumour progression was the main cause of death. The pooled estimate of 1-year survival was 63%. Moreover, there was a significant heterogeneity among studies.21 Interestingly, the second cause of death in the metaanalysis was bleeding, reported only in patients undergoing mTor inhibitor therapy.21 This unexpected data reinforces the concern about bleeding with the combination of sorafenib and m-Tor inhibitor previously underlined and, generally, the risk of serious adverse events potentially correlated to drug to drug interaction, an issue already reported for sorafenib in different clinical contexts.22e24 Overall, since sorafenib is nowadays the only systemic therapy effective for HCC,25e28 these data would suggest not to avoid sorafenib as treatment of HCC recurrence after LT, but to strictly select patients for sorafenib and follow them carefully. However, the association with m-Tor inhibitors should be discouraged. Finally, albeit sorafenib could theoretically be useful as treatment of such a difficult to treat population, management of HCC recurrence after LT is still far from perfect. Conflict of interest We declare we do not have any conflict of interest.
1. Martin 2nd RC, Bruenderman E, Cohn A, et al. Sorafenib use for recurrent hepatocellular cancer after resection or transplantation: observations from a US regional analysis of the GIDEON registry. Am J Surg. 2017;213:688e695. 2. Dharancy S, Romano O, Lorho R, et al. Tolerability and efficacy of sorafenib in recurrent hepatocellular carcinoma after liver transplantation: a case control study. Hepatology. 2008;48:310A. 3. Feun LG, Levi D, Moon J, et al. Sorafenib in hepatocellular carcinoma patients after liver transplantation. J Clin Oncol. 2009;29:15. 4. Kim R, El-Gazzaz G, Tan A, et al. Safety and feasibility of using sorafenib in recurrent hepatocellular carcinoma after orthotopic liver transplantation. Oncology. 2010;79(1-2):62e66. http://dx.doi.org/10.1159/000319548. 5. Tan WF, Qiu ZQ, YU Y, et al. Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation. Acta Pharmacol Sin. 2010;31:1643e1648. 6. Valdivieso A, Bustamante J, Gastaca M, Uriarte JG, et al. Management of hepatocellular carcinoma recurrence after liver transplantation. Transpl Proc. 2010;42:660e662. 7. Yoon DH, Ryoo BY, Ryu MH, et al. Sorafenib for recurrent hepatocellular carcinoma after liver transplantation. J Clin Oncol. 2010;40:768e773. 8. Pfiffer TE, Seehofer D, Nicolaou A, et al. Recurrent hepatocellular carcinoma in liver transplant recipients: parameters affecting time to recurrence, treatment options and survival in the sorafenib era. Tumori. 2011;97:436e441. 9. Gomez-Martin C, Bustamante J, Castroagudin JF, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl. 2012;18:45e52. 10. Sotiropoulos GC, Nowak KW, Fouzas I, et al. Sorafenib treatment for recurrent hepatocellular carcinoma after liver transplantation. Transpl Proc. 2012;44: 2754e2756. 11. Staufer K, Fischer L, Seegers B, et al. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transpl Int. 2012;25: 1158e1164. 12. Vitale A, Boccagni P, Kertusha X, et al. Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation? Transpl Proc. 2012;44: 1989e1991. 13. Weinmann A, Niederle IM, Koch S, et al. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Dig Liver Dis. 2012 May;44(5): 432e437. 14. Pfeiffenberger J, Koschny R, Hoffmann K, et al. Sorafenib treatment is save and may affect survival of recurrent hepatocellular carcinoma after liver transplantation. Langenbeck's Archiv Surg. October 2013;398:1123e1128. 15. Sposito C, Mariani L, Germini A, et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol. 2013;59:59e66. 16. Waghray A, Balci B, El-Gazzaz G, et al. Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation. Clin Transpl. 2013;27:555e561. 17. Zavaglia C, Airoldi A, Mancuso A, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation:
http://dx.doi.org/10.1016/j.amjsurg.2017.04.004 0002-9610/© 2017 Elsevier Inc. All rights reserved.
Please cite this article in press as: Mancuso A, Maringhini AManagement of hepatocellular carcinoma recurrence after liver transplant is far from perfect, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.04.004
2
Letter to the Editor / The American Journal of Surgery xxx (2017) 1e2
18.
19.
20.
21.
22.
23.
24. 25.
experience at a single center and review of the literature. Eur J Gastroenterol Hepatol. 2013;25:180e186. De Simone P, Crocetti L, Pezzati D, et al. Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Transpl Proc. 2014;46:241e244. Mancuso A, Mazzarelli C, Perricone G, et al. Sorafenib efficacy for treatment of HCC recurrence after Liver Transplantation is an open issue. J Hepatol. 2014;3: 261. Mancuso A, Perricone G. Time to resize the role of everolimus as treatment of hepatocellular carcinoma recurrence after liver transplant. Transpl Int. 2015;28:502. Mancuso A, Mazzola A, Cabibbo G, et al. Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplant: a systematic review and meta-analysis. Dig Liver Dis. 2015;47:324e330. Mancuso A, Airoldi A, Vigano R, et al. Fatal gastric bleeding during sorafenib treatment for hepatocellular carcinoma recurrence after liver transplantation. Dig Liver Dis. 2011;43:754. Mancuso A, Zavaglia C, Bai F, et al. Sorafenib hepatotoxicity seems to be enhanced by HAARTS interaction during treatment of advanced hepatocelluler carcinoma in HIV-infected patients. Alimentary Pharmacol Ther. 2013;38: 1414e1416. Mancuso A. Regorafenib for hepatocellular carcinoma progressing on sorafenib: just another starting point. AME Med J. 2017;2:31. Mancuso A. Management of hepatocellular carcinoma: enlightening the grey
zones. World J Hepatol. 2013;5:302e310. 26. Mancuso A, Perricone G. Hepatocellular carcinoma and liver transplantation: state-of-the-art. J Clin Transl Hepatol. 2014;2:176e181. 27. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378e390. 28. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10: 25e34.
Andrea Mancuso, M.D*, Alberto Maringhini, M.D Medicina Interna 1, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico - Di Cristina - Benfratelli, Piazzale Leotta 4, 90100, Palermo, Italy * Corresponding author. E-mail address: [email protected] (A. Mancuso).
28 March 2017
Please cite this article in press as: Mancuso A, Maringhini AManagement of hepatocellular carcinoma recurrence after liver transplant is far from perfect, The American Journal of Surgery (2017), http://dx.doi.org/10.1016/j.amjsurg.2017.04.004