Diffusely infiltrating brainstem gliomas (BSG) have been amongst the most therapeutically resistant paediatric brain tumors; 1- and 5-year progression-free survival (PFS) rates for these patients are less than 25% and 10%, respectively.1, 2
A paucity of data exist to document the histology and biology of these tumors; in the limited instances where tissue has been obtained, histology has shown high-grade or infiltrating glioma.3–7
More recent experience confirms the similarity of BSG to more accessible supratentorial malignant gliomas, a tumor setting where prognosis for children following incomplete resection is also quite poor with 1- and 5-year PFS rates of less than 50% and 20%, respectively.8–10
In view of these discouraging results, new therapeutic approaches are needed. Recent data demonstrate that a wide variety of tumors, including malignant gliomas, are driven to proliferate by aberrant activation of growth factor receptor-mediated signal transduction pathways.11,12
Constitutive activation of these pathways also contributes to tumor resistance to conventional therapeutic agents.
Cell signaling via the EGFR (also known as ERBB1) has been implicated in the development of adult and paediatric high-grade gliomas.13,14
EGFR amplification and over-expression affect 30%–50% of adult glioblastoma multiformes.13–16
In paediatric high-grade gliomas, available data suggest that while EGFR amplification occurs with low frequency,17,18
EGFR receptor over-expression is relatively common. Bredel et al
reported elevated expression of this receptor in 81% of paediatric STMG, with over half demonstrating over-expression in >90% of tumor cells.18
PBTC earlier showed that, EGFR protein is expressed to high levels and amplified in samples of childhood BSG.19
These data suggest that the EGFR constitutes a promising therapeutic target for paediatric STMG and BSG.
Gefitinib (ZD1839, Iressa™
, AstraZeneca), a low molecular weight synthetic molecule, is a potent and selective inhibitor of the EGFR tyrosine kinase that works by competing with adenosine triphosphate for its binding site, and blocking signal transduction pathways implicated in cancer cell proliferation, survival and other host-dependent processes thought to promote cancer growth.20
At the time this clinical trial (PBTC-007) was initiated, gefitinib had demonstrated preclinical evidence of antitumor activity alone and in combination with irradiation and had shown good antitumor activity in a wide range of human tumor xenografts after oral administration.
In both BSG and incompletely resected STMG, radiation therapy has demonstrated benefit.21
Preclinical studies have demonstrated radiosensitization with concurrent exposure to EGFR specific inhibitory agents, providing further rationale for trials of upfront combinations of EGFR inhibitors and concurrent irradiation.22
In adult phase I studies, gefitinib was well tolerated after either intermittent or continuous dosing.23–26
In these trials, dose-related toxicity was confined to the skin and gastrointestinal system; rarely, hepatic enzyme elevation occurred. Increasing intolerability was noted at daily doses of ≥600 mg. The combination of preclinical antitumor activity, known over-expression of the target pathway, and acceptable toxicity profile led us to study the agent in paediatric malignant gliomas.
The PBTC conducted a phase I trial of gefitinib in combination with radiation therapy in children with newly diagnosed BSG and incompletely resected STMG. The primary objectives were to define the safety of gefitinib administered orally once daily in combination with radiation therapy and to describe dose-limiting toxicities. Secondary objectives included characterizing the pharmacokinetic and pharmacogenetics of gefitinib in this patient population and to investigate EGFR expression and amplification in STMG.