title: Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection.
abstract: BACKGROUND
  Mitotane plasma concentrations ≥ 14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting.
  
  
  OBJECTIVE
  To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations ≥ 1 4 mg/l vs patients who did not.
  
  
  METHODS
  Retrospective analysis at six referral European centers.
  
  
  METHODS
  Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l.
  
  
  METHODS
  RFS (primary) and overall survival (secondary).
  
  
  RESULTS
  Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; P=0.007), while the risk of death was not significantly altered (HR: 0.59, 0.26-1.34; P=0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity.
  
  
  CONCLUSIONS
  Mitotane concentrations ≥ 14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.
authors.affiliation: Internal Medicine I, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Terzolo
authors.forename: A E
authors.initials: AE
authors.lastname: Baudin
authors.forename: A
authors.initials: A
authors.lastname: Ardito
authors.forename: M
authors.initials: M
authors.lastname: Kroiss
authors.forename: S
authors.initials: S
authors.lastname: Leboulleux
authors.forename: F
authors.initials: F
authors.lastname: Daffara
authors.forename: P
authors.initials: P
authors.lastname: Perotti
authors.forename: R A
authors.initials: RA
authors.lastname: Feelders
authors.forename: J H
authors.initials: JH
authors.lastname: deVries
authors.forename: B
authors.initials: B
authors.lastname: Zaggia
authors.forename: S
authors.initials: S
authors.lastname: De Francia
authors.forename: M
authors.initials: M
authors.lastname: Volante
authors.forename: H R
authors.initials: HR
authors.lastname: Haak
authors.forename: B
authors.initials: B
authors.lastname: Allolio
authors.forename: A
authors.initials: A
authors.lastname: Al Ghuzlan
authors.forename: M
authors.initials: M
authors.lastname: Fassnacht
authors.forename: A
authors.initials: A
authors.lastname: Berruti
mesh_terms: D000293:Adolescent; D000302:Adrenal Cortex / Q000187:drug effects* / Q000473:pathology / Q000601:surgery; D000306:Adrenal Cortex Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control / Q000601:surgery; D018268:Adrenocortical Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control / Q000601:surgery; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D009367:Neoplasm Staging; D012189:Retrospective Studies; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008939:Mitotane