1. ¹Department of Pediatrics, Institut Gustave Roussy, Villejuif, France
2. ²UPRES EA 3535 'Pharmacology and New Treatments in Cancer', Institut Gustave Roussy, Villejuif, France
3. ³Institut Curie, Paris, France
4. ⁴Information Systems, Institut Gustave Roussy, Villejuif, France
5. ⁵Cancer Research-UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, UK
6. ⁶Centre Léon Bérard, Lyon, France
7. ⁷Hôpital d'Enfants, Nancy, France
8. ⁸Hôpital de La Timone, Marseille, France
9. ⁹Hôpital Purpan, Toulouse, France
10. ¹⁰Department of Radiology, Institut Gustave Roussy, Villejuif, France
11. ¹¹Hopital Lenval, Department of Radiology, Nice, France
12. ¹²Schering-Plough, Levallois, France

Correspondence: Dr B Geoerger, Department of Pediatrics, UPRES EA 3535 'Pharmacology and New Treatments in Cancer', Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: geoerger@igr.fr

Received 21 April 2005; Revised 13 July 2005; Accepted 14 July 2005; Published online 23 August 2005.

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 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 5 temozolomide in heavily treated, and 200 mg m^-2 5 temozolomide in less-heavily pretreated children.