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

Abstract

This report describes a single-centre study with temozolomide (TMZ) (200 mg m À2 day À1 Â 5 per cycle of 28 days) in children with (recurrent) high-grade glioma. Magnetic resonance imaging was performed every two cycles. In all, 20 patients were treated between 1998 and 2001 after the UKCCSG/SFOP TMZ phase II trial. All patients had measurable disease. Totally, 15 patients had a relapse after surgery7radiotherapy7chemotherapy. Overall, five patients received TMZ after surgery or biopsy, awaiting radiotherapy. There were one clinically malignant grade II glioma, 11 grade III and eight grade IV gliomas. Seven tumours had oligodendroglial features. Mean age at start of TMZ was 12.0 years (range 3 -20.5 years). In total, eight patients had 48 cycles (range 3 -30). One VGPR (currently in CR after surgery), three PRs (with a PFS of 4, 4 and 11 months, respectively) and one MR (PFS 14 months) were observed. Three out of five responses occurred after 44 courses. The overall response rate was 20%. Median progression-free survival (PFS) was 2.0 months (range 3 weeks -34 þ months). PFS rate was 20% after 6 months. Median overall survival (OS) was 10 months. Nine patients showed a clinical improvement. Three patients vomitted shortly after TMZ administration, eight patients (13 cycles) experienced grade III/IV thrombocytopenia, occurring predominantly during the fourth week of the first two cycles. Five patients experienced neutropenia, and three patients febrile neutropenia. TMZ is a well-tolerated ambulatory treatment for children with malignant glial tumours. This drug warrants further study in these highly chemoresistant tumours and should be studied either as upfront therapy or in combination therapy. (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 O 6 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 À2 day À1 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 À2 day À1 for patients with previous CSI (Nicholson et al, 1998) and 200 -215 mg m À2 day À1 , 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 À2...

Molecular characteristics of pediatric non-ependymal, non‑pilocytic gliomas associated with resistance to temozolomide

“…Verschuur et al treated 20 children with recurrent high-grade gliomas, including 11 grade III and 8 grade IV gliomas. Progression-free survival at 6 months was 18 and 12.5% for each grade (5). Those figures are less favorably compared to those reported in adult studies (1,2).…”

Prognosis of pediatric high-grade gliomas with temozolomide treatment: a retrospective, multicenter study

“…In contrast to adult HGGs, it has been reported that pediatric HGGs have a poor response to adjuvant temozolomide and more increased side effects [2,4,9,11,20], with objective response rates of 12 and 20 % [9,20]. One study reported that there was no objective response and SD was obtained in 29 % of the patients [11].…”

Phase I study of temozolomide in combination with thiotepa and carboplatin with autologous hematopoietic cell rescue in patients with malignant brain tumors with minimal residual disease

“…Adverse side effects occurred in o50% of the cohort with the most common side effects consisting of bacteremia, nausea/vomiting, elevated transaminases and decreased performance, supporting previous studies citing the favorable toxicity profile of temozolomide. 9,13 On the basis of the results of this study, we conclude that increased doses of temozolomide are feasible when given with AHCR. As with many high-dose chemotherapy trials, efficacy of treatment will need to be analyzed in the context of multimodal therapy, but the combination of temozolomide, thiotepa and carboplatin with AHCR may improve survival in patients with recurrent malignant brain tumors, in particular those with highgrade gliomas in second or third complete response and those with minimal residual disease.…”

“…9 When administered daily at 200 mg/m 2 for 5 days every 28 days, temozolomide showed a tolerable toxicity profile in children, with myelosuppression being the most common side-effect reported. 9,13 The current study builds upon prior research with high-dose chemotherapy and AHCR 4,[14][15][16][17][18][19][20] with the addition of temozolomide in place of etoposide. 4,15 The primary objective of this study was to define the maximum tolerated dose (MTD) of temozolomide administered twice daily in combination with myeloablative 1 doses of thiotepa and carboplatin with AHCR in patients with either recurrent high-grade brain tumors with minimal residual disease or those with newly diagnosed brain tumors with minimal residual disease following conventional therapy.…”