A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma
Introduction
Brain stem gliomas constitute 10–20% of childhood central nervous system tumours. The majority are diffuse gliomas, most commonly astrocytomas of the pons. Patients usually present with a short duration of symptoms, including long tract, cranial nerve and cerebellar deficits. Most patients have a rapidly progressive and fatal course and die within 18 months of diagnosis, with a median survival of only 8–11 months.1
The mainstay of therapy includes early use of corticosteroids and conventional fractionated radiotherapy, which usually provide transient clinical improvement, but are not curative. Radiotherapy allows steroid reduction or discontinuation in many patients.1 Despite numerous collaborative studies aimed at improving the treatment for diffuse intrinsic brain stem gliomas (DIBSGs) in children, survival rates remain dismal. New approaches to treatment are needed. Studies evaluating enhanced delivery of radiotherapy utilising acceleration or hyperfractionation show no survival benefits over conventional fractionated radiotherapy.1, 2, 3 Numerous phase I/II trials of neo-adjuvant, concomitant or adjuvant radiosensitising agents, such as topotecan,4 etanidazole,5 cisplatin6 and carboplatin,7 have failed to demonstrate reliable clinical efficacy.
Despite these disappointing results, radiosensitisation is still an area of considerable interest in paediatric DIBSGs. Temozolomide (TMZ) (Temodal®), an orally administered cytotoxic alkylating agent that readily crosses the blood–brain barrier,8 is another potential radiosensitiser. Combining TMZ and radiotherapy causes 2- to 3-fold increase in cell kill in vitro when compared to radiotherapy alone, likely by synchronising the cell cycle in G2-M arrest—a radiosensitive phase.9, 10 With the Stupp regimen, TMZ has been used in combination with radiotherapy to successfully improve outcomes for adults with glioblastoma.11, 12
TMZ has traditionally been administered in a standard 5-day schedule every 28 days at maximum tolerated dose: 200 mg/m2 in paediatric studies.13, 14 An alternative is the metronomic dosing schedule. Although there is no consensus on the definition of ‘metronomic’, it broadly refers to frequent drug administration at a relatively low dose, without extended rest periods. For the purpose of this study, it refers to daily administration, with only short breaks between cycles. Metronomic TMZ has been tested in adult malignant gliomas15, 16 and paediatric brain tumours.17, 18 Response and survival rates were similar to the 5-day regimen.
Metronomic dosing of TMZ has several benefits, including increasing plasma exposure levels to 1.5- to 2-fold higher than those seen in the 5-day regimen over a similar time period, with no increased toxicity.15, 18 In addition, frequent, low-dose administration of chemotherapy may exert anti-angiogenic effects in various brain tumours.20 Despite the extent of vascularity in DIBSG being largely unknown, anti-angiogenic approaches are still an area of interest in these very treatment-resistant tumours. Potential serum markers of angiogenesis, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular cell adhesion molecule-1 (VCAM-1), inter-cellular adhesion molecule-1 (ICAM-1) and endoglin, are elevated in patients with various malignancies, including brain tumours.21
In a preceding phase I study of metronomic TMZ monotherapy for recurrent paediatric brain tumours, Baruchel et al. report two complete and two partial responses to therapy.18 These promising findings, combined with the need for new treatment strategies in DIBSG, provided rationale for the current study piloting a novel treatment regimen for these patients: administration of metronomic TMZ concomitantly with standard radiotherapy, followed by daily metronomic TMZ monotherapy.
Section snippets
Patient eligibility
Patients aged 18 years or younger were eligible for inclusion, provided that they had a newly diagnosed diffuse intrinsic lesion centred in the brain stem, confirmed by MRI. Patients were required to have at least two of three typical brainstem symptoms (cranial nerve deficit, long tract signs or ataxia) and a clinical history no longer than 6 months.
Additional eligibility criteria included Karnofsky or Lansky Performance Status of >60% or >50%, respectively, and life expectancy >12 weeks.
Patient characteristics
Between April 2005 and July 2007, 15 children with newly diagnosed DIBSGs were enrolled in five centres across Canada. The study group consisted of six males and nine females with a median age of 6.4 years (range 2.4–12.3). The median time to treatment after diagnosis was 7 days (range 2–47). All patients were being treated with corticosteroids at the start of the study. Patients completed a median of three 6-week courses of therapy (range 1–5), the first of which was the induction cycle with
Discussion
Metronomic low-dose TMZ with concurrent radiotherapy was assessed in 15 paediatric patients with DIBSGs. Myelosuppression was the predominant toxicity. Lymphopaenia was most common, occurring in all induction and maintenance cycles. Previous studies of metronomic TMZ monotherapy have also demonstrated high rates of prolonged lymphopaenia,18, 19 suggesting that this is an effect of the TMZ itself, rather than its combination with radiotherapy. Infections associated with immune suppression have
Role of funding sources
The study was supported by Schering-Plough and b.r.a.i.n.child, and was sponsored by the principal investigator. Decision to submit to EJC was made by the principal investigator.
Conflict of interest statement
None declared.
Acknowledgements
The study was funded by b.r.a.i.n.child (Brain Tumour Research Assistance and Information Network). Temozolomide was provided by Schering-Plough Canada.
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