Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma.
BACKGROUND
The prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient.


METHODS
A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3+3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (2) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (3) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10; (4) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7 years.


RESULTS
None of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3.


CONCLUSIONS
The recommended phase II dose in children is TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10 every 28 d. The combination was well tolerated and demonstrated antitumour activity.
Pediatric Oncology Division, Catholic University, A. Gemelli Hospital, Rome, Italy. ruggiero@rm.unicatt.it
Antonio
A
Ruggiero
Daniela
D
Rizzo
Giorgio
G
Attinà
Ilaria
I
Lazzareschi
Stefano
S
Mastrangelo
Palma
P
Maurizi
Roberta
R
Migliorati
Patrizia
P
Bertolini
Maria
M
Pastore
Cesare
C
Colosimo
Riccardo
R
Riccardi
D000284:Administration, Oral; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002648:Child; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008527:Medulloblastoma / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D000077204:Temozolomide; D016896:Treatment Outcome
D005047:Etoposide; D003606:Dacarbazine; D000077204:Temozolomide