O-6-Methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: Results from the CCG-945 cohort

Department of Neurosurgery, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center and the Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.
Journal of Clinical Oncology (Impact Factor: 17.88). 08/2006; 24(21):3431-7. DOI: 10.1200/JCO.2006.05.7265
Source: PubMed

ABSTRACT O6-methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined.
We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens.
Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% +/- 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% +/- 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location.
Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.
    Journal of Neuro-Oncology 11/2014; 121(3). DOI:10.1007/s11060-014-1669-x · 3.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We analyzed the prognostic factors of Korean pediatric patients with supratentorial high-grade glioma (HGG). Between 1997 and 2011, 62 patients with 34 glioblastomas and 28 anaplastic gliomas were surgically operated at nine institutions. The male-to-female ratio was 33 to 29 and the median age was 12 years (range 1-18). The prognostic significance of tumor location, extent of removal, pathologic grade, treatment method, and pattern of recurrence was analyzed. The median progression-free survival (PFS) and overall survival (OS) were 9.3 (±0.8) and 17.8 (±1.9) months, respectively. Glioblastoma and anaplastic glioma showed OSs of 15.9 (±1.3) and 19.6 (±2.4) months, respectively. Based on the univariate analysis, gross total removal (GTR) and initial combined chemoradiotherapy improved PFS (p = 0.012 and p = 0.003) and OS (p = 0.030 and p = 0.013), respectively. Cerebrospinal fluid (CSF) dissemination showed poor OS (p = 0.001). Based on the multivariate analysis, GTR and initial combined chemoradiotherapy resulted in an improved PFS [(hazard ratio 0.360; 95 % CI 0.177-0.733; p = 0.005) and (hazard ratio 0.458; 95 % CI 0.230-0.911; p = 0.026), respectively]. GTR, initial combined chemoradiotherapy, and no CSF seeding resulted in an improved OS [(hazard ratio 0.417; 95 % CI 0.201-0.861; p = 0.018), (hazard ratio 0.406; 95 % CI 0.206-0.800; p = 0.009), and (hazard ratio 0.288; 95 % CI 0.148-0.563; p = 0.000), respectively]. No significant difference in PFS and OS was observed between glioblastoma and anaplastic glioma. CSF dissemination was observed in 22 patients (35.5 %) during total follow-up. Pediatric anaplastic glioma showed poor survival, similarly to glioblastoma. GTR and initial combined chemoradiotherapy were associated with improved survival.
    Journal of Neuro-Oncology 11/2014; DOI:10.1007/s11060-014-1653-5 · 3.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pediatric high-grade gliomas are rare tumors with poor outcomes and incompletely defined management. We conducted a multi-institutional retrospective study to evaluate association of clinical, pathologic, and treatment characteristics with outcomes. Fifty-one patients treated from 1984 to 2008 at the Ohio State University or University of Michigan were included. Histologic subgroups were compared. Log-rank and stepwise Cox proportional hazard modeling were used to analyze progression-free survival (PFS) and overall survival (OS) within the whole group, grade III subgroup, grade IV subgroup, and sub-total resection/biopsy subgroup. Median OS was 27.6 months. Grade III histology, complete tumor resection, and cerebral tumor location correlated with improved PFS and OS. Temozolomide use and chemotherapy after radiotherapy or chemoradiation (CRT) were associated with better PFS while seizure at presentation was associated with better OS. In multivariate analysis, complete resection and chemotherapy following radiotherapy or CRT were independent predictors for improved PFS and OS. For grade III and IV subgroups, complete resection was associated with improved OS (grade III) and seizure presentation was associated with improved OS (grade IV). In the incompletely resection subgroup, temozolomide use and concurrent CRT independently correlated with improved PFS, while higher radiation dose (≥59.4 Gy) and adjuvant chemotherapy were independently associated with improved OS. Total resection and receiving chemotherapy adjuvant to radiation or CRT are most closely associated with improved PFS and OS. For higher risk incompletely resected patients, temozolomide use and treatment intensification with concurrent CRT, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes.
    Frontiers in Oncology 02/2015; 5:28. DOI:10.3389/fonc.2015.00028