title: Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.
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.
authors: Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy. Electronic address: p.desimone@ao-pisa.toscana.it.
authors: P
authors: P
authors: De Simone
authors: Radiology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: L
authors: L
authors: Crocetti
authors: Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy.
authors: D
authors: D
authors: Pezzati
authors: Radiology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: I
authors: I
authors: Bargellini
authors: Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy.
authors: D
authors: D
authors: Ghinolfi
authors: Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy.
authors: P
authors: P
authors: Carrai
authors: Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy.
authors: G
authors: G
authors: Leonardi
authors: Radiology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: C
authors: C
authors: Della Pina
authors: Radiology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: D
authors: D
authors: Cioni
authors: Pathology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: L
authors: L
authors: Pollina
authors: Pathology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: D
authors: D
authors: Campani
authors: Radiology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: C
authors: C
authors: Bartolozzi
authors: Radiology Department, University of Pisa Medical School Hospital, Pisa, Italy.
authors: R
authors: R
authors: Lencioni
authors: Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy.
authors: F
authors: F
authors: Filipponi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D016208:Databases, Factual; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D017093:Liver Failure / Q000188:drug therapy* / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D061214:Patient Safety; D018579:Patient Selection; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012189:Retrospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077157:Sorafenib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus