title: Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.
abstract: Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.
authors.affiliation: Department of Pediatrics, Institut Gustave Roussy, Villejuif, France. geoerger@igr.fr
authors.forename: B
authors.initials: B
authors.lastname: Geoerger
authors.forename: G
authors.initials: G
authors.lastname: Vassal
authors.forename: F
authors.initials: F
authors.lastname: Doz
authors.forename: J
authors.initials: J
authors.lastname: O'Quigley
authors.forename: M
authors.initials: M
authors.lastname: Wartelle
authors.forename: A J
authors.initials: AJ
authors.lastname: Watson
authors.forename: M-A
authors.initials: MA
authors.lastname: Raquin
authors.forename: D
authors.initials: D
authors.lastname: Frappaz
authors.forename: P
authors.initials: P
authors.lastname: Chastagner
authors.forename: J-C
authors.initials: JC
authors.lastname: Gentet
authors.forename: H
authors.initials: H
authors.lastname: Rubie
authors.forename: D
authors.initials: D
authors.lastname: Couanet
authors.forename: A
authors.initials: A
authors.lastname: Geoffray
authors.forename: L
authors.initials: L
authors.lastname: Djafari
authors.forename: G P
authors.initials: GP
authors.lastname: Margison
authors.forename: F
authors.initials: F
authors.lastname: Pein
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000453:epidemiology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D016879:Salvage Therapy; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin; D000077204:Temozolomide