Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation

P. De Simone, L. Crocetti, D. Pezzati, I. Bargellini, D. Ghinolfi, P. Carrai, G. Leonardi, C. Della Pina, D. Cioni, L. Pollina, D. Campani, C. Bartolozzi, Riccardo Lencioni, F. Filipponi

Research output: Contribution to journalArticle

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Abstract

Background Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. Results Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). Conclusions Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

Original languageEnglish (US)
Pages (from-to)241-244
Number of pages4
JournalTransplantation Proceedings
Volume46
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

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Liver Transplantation
Hepatocellular Carcinoma
Safety
Recurrence
Therapeutics
Everolimus
sorafenib
TOR Serine-Threonine Kinases
Hand-Foot Syndrome
Asthenia
Hoarseness
Neoplasms
Proto-Oncogene Proteins c-akt
Survival
Alopecia
Anorexia
Tacrolimus
Pruritus
Hypothyroidism
Exanthema

ASJC Scopus subject areas

  • Surgery
  • Transplantation
  • Medicine(all)

Cite this

Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. / De Simone, P.; Crocetti, L.; Pezzati, D.; Bargellini, I.; Ghinolfi, D.; Carrai, P.; Leonardi, G.; Della Pina, C.; Cioni, D.; Pollina, L.; Campani, D.; Bartolozzi, C.; Lencioni, Riccardo; Filipponi, F.

In: Transplantation Proceedings, Vol. 46, No. 1, 2014, p. 241-244.

Research output: Contribution to journalArticle

De Simone, P, Crocetti, L, Pezzati, D, Bargellini, I, Ghinolfi, D, Carrai, P, Leonardi, G, Della Pina, C, Cioni, D, Pollina, L, Campani, D, Bartolozzi, C, Lencioni, R & Filipponi, F 2014, 'Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation', Transplantation Proceedings, vol. 46, no. 1, pp. 241-244. https://doi.org/10.1016/j.transproceed.2013.10.035
De Simone, P. ; Crocetti, L. ; Pezzati, D. ; Bargellini, I. ; Ghinolfi, D. ; Carrai, P. ; Leonardi, G. ; Della Pina, C. ; Cioni, D. ; Pollina, L. ; Campani, D. ; Bartolozzi, C. ; Lencioni, Riccardo ; Filipponi, F. / Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. In: Transplantation Proceedings. 2014 ; Vol. 46, No. 1. pp. 241-244.
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abstract = "Background Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. Results Seven patients (100{\%} male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6{\%}), cyclosporine (CsA) in 2 (28.6{\%}), and EVL monotherapy in 3 (42.8{\%}). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4{\%}) were alive, 4 of them (57.1{\%}) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3{\%}) and sepsis in the other (14.3{\%}). EVL monotherapy was achieved in 6 patients (85.7{\%}), whereas 1patient (14.3{\%}) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4{\%}), hypertension in 1 (14.3{\%}), alopecia in 1 (14.3{\%}), hypothyroidism in 1 (14.3{\%}), diarrhea in 2 (28.6{\%}), pruritus in 1 (14.3{\%}), abdominal pain in 1 (14.3{\%}), rash in 1 (14.3{\%}), asthenia in 3 (42.8{\%}), anorexia in 3 (42.8{\%}), and hoarseness in 2 (28.6{\%}). Adverse events led to temporary SORA discontinuation in 2 patients (28.6{\%}) and to SORA dose reduction in 3 (42.8{\%}). Conclusions Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.",
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TY - JOUR

T1 - Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation

AU - De Simone, P.

AU - Crocetti, L.

AU - Pezzati, D.

AU - Bargellini, I.

AU - Ghinolfi, D.

AU - Carrai, P.

AU - Leonardi, G.

AU - Della Pina, C.

AU - Cioni, D.

AU - Pollina, L.

AU - Campani, D.

AU - Bartolozzi, C.

AU - Lencioni, Riccardo

AU - Filipponi, F.

PY - 2014

Y1 - 2014

N2 - Background Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. Results Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). Conclusions Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

AB - Background Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. Results Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). Conclusions Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

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