Gefitinib is one of the first molecularly targeted agents to be evaluated in the treatment of newly diagnosed brain tumors of childhood. Because the PBTC previously reported that a subset of high-grade intrinsic BSG overexpresses EGFR in the context of gene amplification,21
there was a strong rationale to examine the safety and efficacy of an EGFR inhibitor such as gefitinib in these tumors.
The current study demonstrated that administration of gefitinib with irradiation in children with BSGs was generally well tolerated, with an acceptable incidence of ITH, which has been a concern with other growth factor receptor inhibitors.44
The rate of ITH attributed to the study drug (7%) compares favorably with other studies involving radiation plus conventional43
or molecularly targeted chemotherapy.44
Other toxicities were generally mild and reversible. The pharmacokinetics of gefitinib are similar to those in the phase I component of this study,33
paralleling results for children with solid tumors.45
Wide interpatient variation was noted in gefitinib apparent oral clearance, maximal plasma concentrations, and area under the concentration–time curve. No relationship was apparent between ABCG2 single nucleotide polymorphisms and gefitinib absorption rate. Maximal serum concentrations were within the range at which inhibition of EGFR tyrosine kinase activity has been noted in in vitro studies.46
Although a previous study questioned whether EGFR inhibitory concentrations could be achieved in adult gliomas with oral gefitinib therapy,28
another report suggested that gefitinib undergoes preferential distribution from the blood into brain tumor tissue.47
However, a recent study demonstrated that transport of gefitinib across the blood-brain barrier may be significantly limited by active efflux proteins.48
Given the potentially distinctive features of brainstem gliomas and the impracticality of sampling to obtain tissue drug levels, it remains unknown whether effective drug concentrations were achieved in the brainstem tumor site.
Although PFS and OS data from this study are consistent with the generally disappointing therapeutic results observed for these tumors, they appear nominally more favorable than some other recent reports, albeit within the range of outcomes observed. In particular, the 2-year survival rate of 19.6 ±5.9% compares with a rate of 3% in a recent trial of topotecan plus irradiation,6
3 ±2% in a study involving radiation, etoposide, and vincristine,7
6.8 ±3.8% in a trial of imatinib plus irradiation,44
5.5 ±3.1% in a trial of zarnestra plus irradiation (unpublished data), 9.2 ±2.7% in a pooled analysis of the HIT (Hirntumor-Studie)-GBM database,49
14 ±5% in a large institutional review,50
and 14 ±5.4% in a previous study of hyperfractionated irradiation administered to a dose of 7200 cGy.3
In most of these studies, longer-term survival rates have been less than 5%. Although 3 of 43 patients (7.0%) in the current study remain progression free with 36 months of follow-up, one of these cases had atypical features, and 2 of these patients were younger than 5 years of age, of potential relevance in light of observations from some prior reports that younger children with BSGs appeared to have a more favorable outcome.49,51,52
Moreover, it is known that stringency of entry criteria in terms of duration and type of symptoms and imaging definitions required for protocol eligibility can also influence outcome interpretations,1
and it is thus important to emphasize that inferences cannot be made regarding efficacy of the regimen employed in this study versus those in other reports that may have used somewhat different criteria. Finally, since data were not systematically collected on second-line therapy among patients who had progressive disease, the impact of such interventions on the OS data cannot be assessed.
In the absence of molecular data in these tumors, it is impossible to know whether the long-term survivors had lesions that were within the small subset of BSGs that exhibit EGFR
Studies in other tumor types indicate that tumors with activating mutations or amplification of EGFR
are more likely to have favorable responses to EGFR inhibitors than tumors without EGFR
alterations, particularly in the absence of other molecular features, such as PTEN
deletions, which counteract sensitivity to EGFR blockade.23–26
In view of the intriguing, albeit small, percentage of patients with long-term disease control in the current study, there is some rationale to consider strategies to combine targeted therapy with molecular characterization of BSGs in future trials, to define molecular features that correlate with therapeutic efficacy. Because EGFR kinase domain mutations, which are associated with the greatest sensitivity to EGFR inhibitors,53
are uncommon in malignant gliomas,28
including those arising in children,54
it remains to be determined whether other molecular alterations involving EGFR signaling pathways may occur selectively in treatment responders.