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- Title
Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.
- Authors
Geoerger, B.; Vassal, G.; Doz, F.; O'Quigley, J.; Wartelle, M.; Watson, A. J.; Raquin, M.-A.; Frappaz, D.; Chastagner, P.; Gentet, J.-C.; Rubie, H.; Couanet, D.; Geoffray, A.; Djafari, L.; Margison, G. P.; Pein, F.
- 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.
- Subjects
CHILDHOOD cancer; CANCER treatment; DRUG therapy; CISPLATIN; ANTINEOPLASTIC agents; DNA repair; CANCER relapse; CLINICAL trials; COMPARATIVE studies; DRUG resistance in cancer cells; DRUG dosage; DRUG toxicity; RESEARCH methodology; MEDICAL cooperation; RESEARCH; TRANSFERASES; TUMORS; TUMOR classification; EVALUATION research; TREATMENT effectiveness; SALVAGE therapy; DACARBAZINE
- Publication
British Journal of Cancer, 2005, Vol 93, Issue 5, p529
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/sj.bjc.6602740