title: Rapidly progressing high o,p'DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results.
abstract: BACKGROUND
  It has been reported that the therapeutic threshold of mitotane, plasma level above 14 microg/ml, is achieved within 3-5 months after o,p'DDD treatment initiation in patients with adrenocortical carcinoma (ACC).
  
  
  OBJECTIVE
  We evaluated pharmacokinetic and tolerance of a high-dose schedule of pure o,p'DDD treatment given in 500-mg tablets of mitotane (Lysodren, Bristol-Myers Squibb, HRA Pharma, Paris, France) in four patients with ACC and two patients with Cushing's syndrome-related endocrine tumours. It was administered at a starting dosage of 3 g/day, which was rapidly increased to 6-9 g/day within 2 weeks according to digestive tolerance and then adjusted according to tolerance and plasma o,p'DDD monitoring. Patients were followed up until they reached the therapeutic threshold of mitotane, and toxicity was recorded. A relationship between o,p'DDD dose and plasma level was sought.
  
  
  RESULTS
  The highest starting dosage given ranged between 6 and 9 g a day, during the first two weeks. The daily maintenance dose ranged 4.5-9 g during the next 2 weeks and 3-9 g by the second month of treatment. The therapeutic threshold was reached in all four patients who received o,p'DDD treatment for at least 1 month. Among these four patients, the toxic threshold (plasma mitotane level > 20 microg/ml) was even reached at 6 weeks of therapy in three patients. Grade 1, 2 or 3 toxicity was observed in 3, 2 and 1 patients, respectively. Toxicity resolved after reduction or discontinuation of o,p'DDD therapy. A significant linear correlation was found between plasma mitotane dose and plasma level.
  
  
  CONCLUSIONS
  These results suggest that a high-dose o,p'DDD therapeutic schedule is feasible with an acceptable toxicity and may shorten the time required to reach the therapeutic schedule from 3-5 months to 4 weeks. These patients require a close follow-up, combining clinical and plasma o,p'DDD level monitoring every second week. A confirmatory study is ongoing.
authors.affiliation: Department of Nuclear Medicine and Endocrinological Oncology, Gustave-Roussy Institute, Villejuif, France.
authors.forename: Antongiulio
authors.initials: A
authors.lastname: Faggiano
authors.forename: Sophie
authors.initials: S
authors.lastname: Leboulleux
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
mesh_terms: D018268:Adrenocortical Carcinoma / Q000097:blood / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D002648:Child; D003480:Cushing Syndrome / Q000097:blood / Q000188:drug therapy*; D003632:Dichlorodiphenyldichloroethane / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D003632:Dichlorodiphenyldichloroethane