Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies
| Autor: | John O'Quigley, L. Djafari, Hervé Rubie, M-A Raquin, Birgit Geoerger, Gilles Vassal, Pascal Chastagner, M Wartelle, Geoffrey P. Margison, D. Frappaz, F Pein, Anne Geoffray, François Doz, J-C. Gentet, Amanda J. Watson, Dominique Couanet |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Adult
Male Oncology Cancer Research medicine.medical_specialty Pathology Adolescent Maximum Tolerated Dose medicine.medical_treatment Dacarbazine cisplatin paediatric phase I/II temozolomide Neutropenia O(6)-Methylguanine-DNA Methyltransferase Neoplasms Internal medicine Glioma Clinical Studies Antineoplastic Combined Chemotherapy Protocols medicine Humans Child Neoplasm Staging Salvage Therapy Cisplatin Chemotherapy Temozolomide business.industry Infant O-6-methylguanine-DNA methyltransferase medicine.disease CRM Treatment Outcome Drug Resistance Neoplasm Child Preschool Female Neoplasm Recurrence Local MGMT business medicine.drug Alkyltransferase |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6602740 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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