mTOR inhibitors and sorafenib for recurrent heptocellular carcinoma after orthotopic liver transplantation
Authors: Oliver Waidmann, Wolf-Peter Hofmann, Stefan Zeuzem, Joerg Trojan
Journal: Journal of Hepatology (2010)

Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: A proof of principleJournal of HepatologyVol. 52Issue 5PreviewThe advent of molecular medicine that targets specific pathways is changing the therapeutic approach to hepatocellular carcinoma. For several aberrantly activated pathways in hepatocarcinoma, surrogate markers of activation can be assessed by immunohistochemistry, although associations with in vivo response to targeted therapies are still lacking. Full-Text PDF Open Access With interest we read the recent publication of the Milan group by Bhoori et al., describing a patient with a late recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation who was successfully treated with a combination of everolimus and sorafenib after initial failure of sorafenib [[1]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 general, the prognosis of recurrent HCC after orthotopic liver transplantation is fatal, especially in those patients presenting with early recurrence [[2]Valdivieso A. Bustamante J. Gastaca M. Uriarte J.G. Ventoso A. Ruiz P. et al.Management of hepatocellular carcinoma recurrence after liver transplantation.Transplant Proc. 2010; 42: 660-662Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. The majority of these patients present with metastatic disease and treatment options are very limited [[3]Graziadei I. Finkenstedt A. Nachbaur K. Zoller H. Mark W. Vogel W. Outcome of patients with recurrent hepatocellular carcinoma after liver transplantation.J Hepatol. 2010; 52: A214Google Scholar]. Sorafenib, a tyrosine kinase-inhibitor with anti-proliferative and anti-angiogenic activity, is currently the only approved systemic treatment in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage HCC [[4]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (9271) Google Scholar]. It inhibits downstream signaling of VEGFR-2 and -3, Flt-3, PDGFR, and FGFR-1 and blocks the Ras-Raf-MEK-ERK cascade by targeting the serine–threonine kinase Raf. Rapamycin and its analogues, e.g. sirolimus and everolimus, inhibit mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase (PI3K) signal transduction. mTOR inhibitors exhibit anti-tumor activity probably through reduced expression of hypoxia-inducible factor and subsequently VEGF and PDGF expression. The Milan group suggested a strong phosphorylation of the S6 protein, a downstream signal of mTOR, as a potential predictive biomarker for everolimus [[1]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], an inhibitor of mTOR approved as an immunosuppressant after solid organ transplantation as well as targeted therapy in renal cell cancer. The critical role of mTOR signaling for hepatocarcinogensis is well-documented preclinically [[5]Villanueva A. Chiang D.Y. Newell P. Peix J. Thung S. Alsinet C. et al.Pivotal role of mTOR signaling in hepatocellular carcinoma.Gastroenterology. 2008; 135: 1972-1983Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar] and inhibition of the mTOR pathway after liver transplantation for HCC leads to higher survival rates in some groups of patients [[6]Toso C. Merani S. Bigam D.L. Shapiro A.M. Kneteman N.M. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma.Hepatology. 2010; 51: 1237-1243Crossref PubMed Scopus (259) Google Scholar]. The results of the SILVER study, comparing relapse-free survival rates in this population either treated with sirolimus or mTOR-inhibitor-free immunosuppression are anticipated in the near future [[7]Schnitzbauer A.A. Zuelke C. Graeb C. Rochon J. Bilbao I. Burra P. et al.A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma.BMC Cancer. 2010; 10: 190Crossref PubMed Scopus (133) Google Scholar]. Targeting the Ras pathway with the multikinase inhibitor sorafenib in addition to mTOR inhibition has synergistic effects on tumor growth in xenograft mice [[8]Newell 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]. These data form the current rational to switch patients with recurrent HCC after liver transplantation from calcineurin inhibitors to mTOR inhibitors like sirolimus or everolimus, and additionally to start sorafenib. However, even in patients without liver transplantation, the toxicity of sorafenib can severely impact quality of life [9Welker M.W. Lubomierski N. Gog C. Herrmann E. Engels K. Vogl T.J. et al.Efficacy and safety of sorafenib in advanced hepatocellular carcinoma under daily practice conditions.J Chemother. 2010; 22: 205-211PubMed Google Scholar, 10Blanchet B. Billemont B. Barete S. Garrigue H. Cabanes L. Coriat R. et al.Toxicity of sorafenib: clinical and molecular aspects.Expert Opin Drug Saf. 2010; 9: 275-287Crossref PubMed Scopus (44) Google Scholar] and up to now only anecdotal data on the use of sorafenib after liver transplantation are available [[2]Valdivieso A. Bustamante J. Gastaca M. Uriarte J.G. Ventoso A. Ruiz P. et al.Management of hepatocellular carcinoma recurrence after liver transplantation.Transplant Proc. 2010; 42: 660-662Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. Although sorafenib and mTOR inhibitors have different targets, side-effects of both drugs overlap (e.g. fatigue, diarrhea, skin toxicity) and therefore can lead to unacceptable toxicity. Dose finding studies for the combination of sorafenib with mTOR inhibitors have not been published and it remains speculative if side-effects of either drug could be boosted by the other. Herein, we present our experience with recurrent HCC after liver transplantation in three patients who were treated with sorafenib and an mTOR inhibitor (Table 1). Hepatic recurrence occurred in all three patients, and additionally two presented with extrahepatic metastasis. After diagnosis of recurrence, two out of the three patients were switched from cyclosporine to everolimus (1 mg twice daily) or sirolimus (2 mg daily). Patient 3 was already switched to sirolimus before because of cyclosporine-induced nephrotoxicity. Dose titration with sorafenib (starting dose 200 mg twice daily) was initiated in patient 1 concomitantly and in patient 2 after one month. In patient 1 the sorafenib dose was elevated to 400 mg twice daily after three weeks but had to be reduced to the starting dose because of the development of grade 3 hand–foot-syndrome and fatigue. Upon follow-up CT scanning after 3 months, a stable disease was documented; however, after 5 months progression was documented and sorafenib was stopped permanently. Patient 2 had to temporarily stop sorafenib because of grade 3 hand–foot-syndrome. Since side-effects re-occurred after re-exposure even in a very low dose (200 mg every second day) sorafenib was permanently stopped. Patient 3 developed grade 3 fatigue and his performance status worsened rapidly. He was admitted to the hospital three weeks after the initiation of sorafenib treatment with a sepsis. Although sorafenib was stopped immediately, he died of multiorgan-failure one week later.Table 1Patients with recurrent HCC after liver transplantation treated with sorafenib and everolimus or sirolimus.∗Incidental diagnosis in explant; ∗∗standard exception MELD; ∗∗∗alive. Open table in a new tab ∗Incidental diagnosis in explant; ∗∗standard exception MELD; ∗∗∗alive. In summary, our preliminary experience indicates that combination treatment with an mTOR inhibitor and sorafenib is possible only in selected patients after liver transplantation. Even under close monitoring and careful dose titration of an mTOR inhibitor followed by sorafenib, major toxicity, predominantly severe hand–foot-syndrome, occurred in two of three patients. The authors who have taken part in this study declared a relationship with the manufacturers of the drugs involved. O. Waidmann received a travel grant from Bayer Health Care. S. Zeuzem and J. Trojan received research funding and served on the advisory board for Bayer Health Care.