title: Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.
abstract: There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.
authors.affiliation: Gastrointestinal Cancer Unit, Spanish National Cancer Research Center, Fuenlabrada University Hospital, Camino del Molino 2, Fuenlabrada, Madrid, Spain. cgomezm@cnio.es
authors.forename: Carlos
authors.initials: C
authors.lastname: Gomez-Martin
authors.forename: Javier
authors.initials: J
authors.lastname: Bustamante
authors.forename: Javier F
authors.initials: JF
authors.lastname: Castroagudin
authors.forename: Magdalena
authors.initials: M
authors.lastname: Salcedo
authors.forename: Elena
authors.initials: E
authors.lastname: Garralda
authors.forename: Milagros
authors.initials: M
authors.lastname: Testillano
authors.forename: Ignacio
authors.initials: I
authors.lastname: Herrero
authors.forename: Ana
authors.initials: A
authors.lastname: Matilla
authors.forename: Bruno
authors.initials: B
authors.lastname: Sangro
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D015331:Cohort Studies; D003967:Diarrhea / Q000139:chemically induced / Q000453:epidemiology; D018450:Disease Progression; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015994:Incidence; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077157:Sorafenib; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007166:Immunosuppressive Agents; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus