Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane monitoring and tumor regression.
OBJECTIVE
To define a mitotane dose for pediatric patients with adrenocortical cancer (ACC) that maintains therapeutic plasma levels (TL) between 14 and 20 microg/mL and to verify its antitumor efficacy in association with 8 cycles of cisplatin, etoposide, and doxorubicin (CED).


METHODS
Powdered mitotane was dissolved in a medium chain triglyceride oil and administered to 11 children with ACC (2.4 to 15.4 y of age); an initial low dose was increased to 4 g/m2/d. Ten of the 11 children had a germline TP53 R337H mutation. Mitotane plasma levels were determined using high-performance liquid chromatography.


RESULTS
The mitotane dose to maintain TL in 7 patients ranged from 1.0 to 5.3 g/m2/d. Six children reached mitotane levels of 10 microg/mL in 3.6 months (1.5 to 5.0 mo), whereas 5 children took 8 months (6.5 to 12.5 mo). Minor to partial tumor remission was found in 5 patients (<1 y) and complete remission was found in 2 patients. Of the 3 patients who are alive at the time of report, 1 patient has been without disease for 16 months, and 2 patients have progressive disease. All patients had recurrent metastatic disease (2 to 9 times). Mitotane toxic effects were nausea, diarrhea, vomiting, neurologic alterations, gynecomastia, a rare case of hypertensive encephalopathy, and CED-related hematologic toxic effects.


CONCLUSIONS
Mitotane daily dose to maintain TL is variable and monitoring should start 1.5 months after the beginning of treatment. CED combined with mitotane is the best available pharmacologic treatment for ACC, but further studies are required to characterize different profiles of therapeutic response.
Zancanella
Patrícia
P
Center for Molecular Genetics and Cancer Research-CEGEMPAC, Department of Pediatrics, Federal University of Paraná, and Division of Pediatric Oncology, Erasto Gaertner Hospital, Liga Paranaense de Combate ao Câncer, Curitiba, PR, CEP, Brazil.
Pianovski
Mara A D
MA
Oliveira
Brás H
BH
Ferman
Sima
S
Piovezan
Gislaine C
GC
Lichtvan
Leniza L
LL
Voss
Suely Z
SZ
Stinghen
Sérvio Túlio
ST
Callefe
Luiz G
LG
Parise
Guilherme A
GA
Santana
Maria Helena A
MH
Figueiredo
Bonald C
BC
D000284:Administration, Oral; D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery; D018268:Adrenocortical Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008939:Mitotane / Q000008:administration & dosage* / Q000009:adverse effects; D009367:Neoplasm Staging; D011446:Prospective Studies; D012074:Remission Induction; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
D005047:Etoposide; D008939:Mitotane; D004317:Doxorubicin; D002945:Cisplatin