Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945

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.

Fig. 1

Progression free survival (PFS) and overall survival (OS) for the midline HGG cohort. The x-axis is time (months) and the y-axis represents the proportion of surviving patients

Fig. 2

Extent of surgical resection and survival. a PFS (p = 0.26) and b OS (p = 0.55). Chemotherapy regimen and survival. c PFS (p = 0.48) and d OS (p = 0.49). Solid line Regimen A or nonrandomized to Regimen A (prednisone, CCNU and vincristine); Dotted line Regimen B or non-randomized to Regimen B

Fig. 3

Anatomic site and survival curves. Primary tumor site and a PFS (p = 0.59) or c OS (p = 0.39). Number of involved sites and b PFS (p = 0.0013) or d OS (p = 0.0084)

Fig. 4

Tumor histology and survival curves for a PFS or b OS. Solid line anaplastic astrocytoma (AA, WHO III); dashed line glioblastoma multiforme (GBM, WHO IV); dotted line diagnoses discordant for pediatric HGG. c, d Comparing changed diagnoses following central review to those patients with an unchanged diagnosis (p < 0.01). Diagnosis changed, dotted line; diagnosis unchanged, solid line