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dc.contributor.authorGeoerger, B
dc.contributor.authorVassal, G
dc.contributor.authorDoz, F
dc.contributor.authorO'Quigley, J
dc.contributor.authorWartelle, M
dc.contributor.authorWatson, Amanda J
dc.contributor.authorRaquin, M-A
dc.contributor.authorFrappaz, D
dc.contributor.authorChastagner, P
dc.contributor.authorGentet, J-C
dc.contributor.authorRubie, H
dc.contributor.authorCouanet, D
dc.contributor.authorGeoffray, A
dc.contributor.authorDjafari, L
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorPein, F
dc.date.accessioned2009-08-04T17:20:59Z
dc.date.available2009-08-04T17:20:59Z
dc.date.issued2005-09-05
dc.identifier.citationDose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies. 2005, 93 (5):529-37 Br. J. Canceren
dc.identifier.issn0007-0920
dc.identifier.pmid16136028
dc.identifier.doi10.1038/sj.bjc.6602740
dc.identifier.urihttp://hdl.handle.net/10541/76280
dc.description.abstractCisplatin 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.
dc.language.isoenen
dc.subjectCancer Recurrenceen
dc.subjectCancer Stagingen
dc.subjectCanceren
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols
dc.subject.meshChild
dc.subject.meshChild, Preschool
dc.subject.meshCisplatin
dc.subject.meshDacarbazine
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshInfant
dc.subject.meshMale
dc.subject.meshMaximum Tolerated Dose
dc.subject.meshNeoplasm Recurrence, Local
dc.subject.meshNeoplasm Staging
dc.subject.meshNeoplasms
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshSalvage Therapy
dc.subject.meshTreatment Outcome
dc.titleDose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pediatrics, Institut Gustave Roussy, Villejuif, France. geoerger@igr.fren
dc.identifier.journalBritish Journal of Canceren
html.description.abstractCisplatin 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.


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