Temozolomide for Pediatric High-Grade Gliomas

Abstract

Introduction: Pediatric high-grade gliomas, excluding those arising in the brain stem which is frequently not histologically confirmed, comprise approximately 5% to 10% of all childhood brain tumors. Within the subgrouping are anaplastic astrocytomas and glioblastoma multiforme [1, 2]. Other subtypes may occur such as malignant oligodendrogliomas or oligoastrocytomas, but are much less common in pediatrics, compared with tumors arising in adults [1, 2]. Overall prognosis for pediatric high-grade gliomas is poor, although some studies have suggested somewhat higher survival rates than those seen in patients with similar tumors in adults [3–5]. The validity of early pediatric clinical studies has been questioned, as on central pathologic reviews, one study of pediatric high-grade astrocytomas reporting apparently better overall survival rates was contaminated by the inclusion of patients with low-grade neoplasms [4]. In general, 2-year survival rates have ranged from 10% to 30% for patients with supratentorial pediatric high-grade gliomas, and the single most independent prognostic factor across pediatric-age groups has been the degree of surgical resection; with patients undergoing a total resection or near-total resection having a better prognosis [3–5]. Recent studies have demonstrated a survival advantage for patients greater than 21 years of age with highgrade gliomas treated with temozolomide during and after tumor site radiotherapy [6, 7]. In adults with glioblastoma multiforme, the addition of temozolomide to radiation resulted in a 26% 2-year overall survival rate compared with 10% for those treated with radiation alone [6]. Temozolomide is an alkylating agent whose primary mechanism of cytotoxicity is alkylation at the 06 position of guanine. In the adult studies, the survival benefit was most apparent in patients whose tumors had methylation of the methylguanine DNA methyltransferase (MGMT) promoter, which is thought to result in diminished MGMT activity [8]. The MGMT gene encodes a DNArepair enzyme, which reduces the efficacy of alkylating chemotherapies. To determine if a similar survival rate could be seen in children, a study was undertaken by the Children’s Oncology Group (COG).