Temozolomide in paediatric high-grade glioma: a key for combination therapy?

Temozolomide (TMZ) is an oral methylating agent that belongs to the imidazotetrazine class of drugs. It is metabolised into monomethyl triazeno imidazole carboxamide (MTIC) (Stevens et al, 1987), which is also the cytotoxic metabolite of dimethyl triazeno imidazole carboxamide (DTIC, dacarbazine). The cytotoxic effect of MTIC is caused by alkylation of deoxyguanosine nucleotides, mostly at the O6 position, leading to DNA mismatch (G–T match instead of G–C match) (Catapano et al, 1987), DNA strand breaks and subsequently apoptosis (Tentori et al, 1997). Several phase I studies with TMZ single drug have been published in adults and children with solid tumours (Newlands et al, 1992; O'Reilly et al, 1993; Dhodapkar et al, 1997; Brock et al, 1998; Estlin et al, 1998; Nicholson et al, 1998; Brada et al, 1999), showing haematological dose-limiting toxicity (DLT). Maximally tolerated doses (MTD) were between 150 and 250 mg m−2 day−1 when using the once daily oral administration on 5 consecutive days every 4 weeks, depending on whether or not patients had been previously treated with nitrosureas (Dhodapkar et al, 1997) or craniospinal irradiation (CSI) (Nicholson et al, 1998). In children, the MTD is 180 mg m−2 day−1 for patients with previous CSI (Nicholson et al, 1998) and 200–215 mg m−2 day−1, respectively for patients without prior CSI (Estlin et al, 1998; Nicholson et al, 1998, respectively). The reports of phase II trials of TMZ using comparable administration regimens of 150–200 mg m−2 day−1 × 5 every 28 days in adults with recurrent or progressive grade III or grade IV (oligodendro-) glioma showed objective response rates varying from 8, 11, 23, 35 and 44%, respectively (Brada et al, 2001; Bower et al, 1997; Brandes et al, 2001; Yung et al, 1999; Chinot et al, 2001, respectively). A phase II clinical trial by the UKCCSG New Agents Group/SFOP ‘Groupe de Pharmacologie’ with this regimen of TMZ in paediatric patients with recurrent or progressive high-grade glioma showed a lower response rate of 12% for supratentorial high-grade glioma and 6% for brainstem glioma, respectively (Lashford et al, 2002). In this study, the response rate was evaluated after two cycles of TMZ. Despite the low response rate, several patients improved clinically suggesting that TMZ is a good palliative treatment in patients with malignant glioma. We report here a single institution experience using TMZ in children with (recurrent) grade III or IV glioma, focussing on clinical improvement, response rate, progression-free survival (PFS) and toxicity.