Abstract Background The combination of temozolomide (TMZ) and lomustine (CCNU) with radiation (RT) is the only treatment regimen to show a significant survival benefit in pediatric high-grade glioma (PHGG). However, it is unknown which PHGG subgroups benefit. We previously presented evidence that patients with hemispheric PHGG benefit, while patients with midline PHGG do not. Here, we present updated findings, including molecular characterization of a subset of our cohort. Methods We have now developed a cohort of 22 PHGG patients treated with RT/TMZ/CCNU, along with 101 control patients who received RT, RT/TMZ, or RT with TMZ and/or bevacizumab, through the Children’s Brain Tumor Network. We linked molecular data from Cavatica wherever available. We also tested a panel of cytotoxic and targeted agents in combination with TMZ/CCNU in PHGG patient-derived cell lines. Results RT/TMZ/CCNU was associated with improved overall survival (OS) compared to controls for the entire cohort (651 vs. 424d, p = 0.046) and for hemispheric tumors (750 vs. 486d, p = 0.05) but not for midline tumors (458 vs. 352d, p = 0.36). The regimen was not associated with improved OS in the limited subset with molecularly characterized tumors (8 cases, 40 controls) for H3-mutant or H3-wild-type tumors. Other factors associated with improved OS on univariate analysis included non-H3-mutant tumors, hemispheric location, and gross/near-total resection. Hemispheric location was the only significant factor on multivariable analysis. In preclinical testing, vinblastine and imatinib showed promising synergy with CCNU/TMZ in PHGG cell lines. Discussion In this updated PHGG cohort, patients with hemispheric PHGG had a significant survival benefit from RT/TMZ/CCNU treatment, while those with midline PHGG did not. Molecular characterization of additional PHGG treated with these therapies is critical to the impact of these findings in determining which PHGG patients and subtypes should receive RT/TMZ/CCNU as a treatment backbone and baseline for future preclinical combination studies and clinical trials.
Zahedi et al. (Fri,) studied this question.