A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium

Abstract

This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m(2)/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 ±5.6 % and 9.3 ±4%, respectively. Overall survival rates were 56.4 ±7.6% and 19.6 ±5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with ≥36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents.

Figures

Fig. 1.

Progression-free (solid line) and overall survival (dashed line) of 43 patients receiving gefitinib 250 mg/m2/d during and after irradiation.

Fig. 2.

One long-term survivor had slightly atypical imaging features for a malignant brainstem glioma, with tumor involvement localized to the pontomedullary junction. Based upon tumor biopsy, the lesion was histologically demonstrated to be an anaplastic astrocytoma. Sagittal T1-weighted (A) and axial T2-weighted (B) MR images demonstrate a T1-hypointense and T2-hyperintense mass at the pontomedullary junction.

Fig. 3.

MR imaging of one of the 2 long-term survivors with typical imaging features of a diffuse intrinsic brainstem glioma. Sagittal T1-weighted (A) and axial T2-weighted (B) MR images demonstrate a T1-hypointense and T2-hyperintense mass in the pons surrounding the basilar artery with posterior mass effect on the fourth ventricle, moderate hydrocephalus, and tonsillar herniation.