title: Natural history, management and pharmacokinetics of everolimus-induced-oral ulcers: insights into compliance issues.
abstract: BACKGROUND
  Oral ulcers is a well-recognised adverse event (AE) of mTOR inhibitors. Paradoxically, little is known about its natural history, risk factors, and basic management.
  
  
  METHODS
  AEs of 79 patients prospectively enrolled in 6 phase I-II studies testing everolimus were reviewed. The following parameters were analysed: incidence, severity, duration and associated AE. The association between OU and everolimus dose, pharmacokinetics and the effectiveness of empiric treatments were explored.
  
  
  RESULTS
  OU, grade 3-4 OU, prolonged time under OU and RCOU (recurrent and chronic oral ulcer) were observed in 72% 11%, 30% and 25% patients, respectively. Patients with antecedent of prior chemotherapy, with PS 1, or receiving everolimus in combination tended to present higher rates of prolonged time under OU and of grade 3-4 OU. As everolimus daily dose increased, the median time to OU was shorter, the median duration was longer and OU incidence tended to increase. Simultaneously, OU tended to be associated with higher everolimus exposure. None of the empiric treatments appeared effective against OU (preventive or curative intent).
  
  
  CONCLUSIONS
  Everolimus-induced OU is a frequent, recurrent and sometimes harmful complication. A dose effect relationship is displayed. Its daily management remains challenging. OU represents a key issue in the compliance of mTOR inhibitors.
authors.affiliation: SITEP (Phase 1 Unit), Department of Medicine, Institut Gustave Roussy, Villejuif, France. chferte@hotmail.com
authors.forename: Charles
authors.initials: C
authors.lastname: Ferté
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.forename: Meriem
authors.initials: M
authors.lastname: Zizi
authors.forename: Daniel Barrios
authors.initials: DB
authors.lastname: Gonzales
authors.forename: Aicha
authors.initials: A
authors.lastname: Goubar
authors.forename: Carlos
authors.initials: C
authors.lastname: Gomez-Roca
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.forename: Tarek
authors.initials: T
authors.lastname: Sahmoud
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D009067:Mouthwashes / Q000627:therapeutic use; D019226:Oral Ulcer / Q000139:chemically induced* / Q000628:therapy; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009067:Mouthwashes; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus