title: Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly.
abstract: Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations >14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.
authors.affiliation: Medicina Interna I, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Daffara
authors.forename: Silvia
authors.initials: S
authors.lastname: De Francia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Reimondo
authors.forename: Barbara
authors.initials: B
authors.lastname: Zaggia
authors.forename: Emiliano
authors.initials: E
authors.lastname: Aroasio
authors.forename: Francesco
authors.initials: F
authors.lastname: Porpiglia
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Angela
authors.initials: A
authors.lastname: Termine
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Carlo
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Alberto
authors.initials: A
authors.lastname: Angeli
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy*; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007037:Hypothyroidism / Q000209:etiology; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D009367:Neoplasm Staging; D011446:Prospective Studies; D015996:Survival Rate; D013739:Testosterone / Q000378:metabolism; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013739:Testosterone; D008939:Mitotane; D006854:Hydrocortisone