title: Practical treatment using mitotane for adrenocortical carcinoma.
abstract: OBJECTIVE
  Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma.
  
  
  RESULTS
  Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences.
  
  
  CONCLUSIONS
  Mitotane concentration of 14-20  mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
authors.affiliation: aInternal Medicine I bPharmacology, Department of Clinical and Biological Sciences, University of Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
authors.forename: Barbara
authors.initials: B
authors.lastname: Zaggia
authors.forename: Barbara
authors.initials: B
authors.lastname: Allasino
authors.forename: Silvia
authors.initials: S
authors.lastname: De Francia
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000401:mortality; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008939:Mitotane / Q000008:administration & dosage* / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008939:Mitotane