Warren P. Mason

PURPOSE: Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers. METHODS: Four hundred seventy-eight patients with clinical high-risk LGG (WHO grade 2) were randomly assigned to standard radiotherapy (RT; 28 × 1.8 Gy) or dose-dense temozolomide (TMZ; 75 mg/m ² once daily × 21/28 days, up to 12 cycles). RESULTS: There was no significant difference in progression-free survival or overall survival (OS) between study arms. Analyzable tumor tissue in 73% (351/478) of patients allowed for post hoc reclassification according to the 2021 WHO pathologic criteria. In astrocytoma, IDHmt/1p/19q noncodeleted (n = 178), median OS was similar, 6.6-6.7 years irrespective of arm (0.67-1.44, P = .93). In oligodendroglioma, IDHmt/1p/19q codeleted (n = 109), median OS was 12.9 years (9.4-not reached) with RT and 14.9 years (10.1-number of events not reached) with TMZ (hazard ratio [HR], 0.88 [0.52-1.49], P = .63). In 64 tumors without isocitrate dehydrogenase (IDH) mutations, survival favored the TMZ arm: OS 2.5 (1.8-3.3) versus 4.7 (2.2-7.2) years (HR, 0.47 [0.27-0.82], P = .0068). Patients age 40 years and older fared better than patients younger than 40 years, challenging the current notion of age alone as a negative prognostic factor. CONCLUSION: The assigned initial treatment modality did not affect progression-free survival or OS, regardless of the molecular subtype. Combined-modality therapy was not tested in this trial but has since become a standard of care for IDH-mutant astrocytoma. With emerging novel therapeutic options, rational treatment strategies tailored at the individual clinical and pathologic recurrence risk profiles will be needed. The validity of an age cutoff as prognostic factor is challenged when tumors are molecularly classified.

Purpose:Brain tumor location is known to affect survival, but there is a lack of methodologic tools for systematically studying the complex interplay between brain tumor location, prognostic variables, treatment schemes, and survival.Experimental Design:A total of 592 prospectively enrolled patients with newly diagnosed glioblastoma from the phase III AVAglio trial, randomized to postsurgical chemoradiation with or without bevacizumab, were retrospectively analyzed. Statistical parametric mapping was conducted with multivariate Cox proportional hazards models at the voxel-wise level, incorporating dedicated interaction variables to evaluate the impact of baseline tumor volume and treatment arm on survival for different tumor locations from magnetic resonance imaging (MRI) scans, with subsequent cluster-based correction for multiple testing and mathematical estimation of regional survival curves.Results:Tumor location in the right prefrontal cortex was an independent favorable prognostic factor [median hazard ratio (HR) = 0.57] for survival, whereas tumor involvement in left hemisphere eloquent areas with language and visual functions was unfavorable (median HR = 1.69). Larger presurgical tumor volumes were associated with shorter survival independent of tumor location (HR = 1.005), but the effect was larger for tumor locations including eloquent structures (HR ranging 1.008–1.015), whereas nonsignificant for anterior frontal locations. Bevacizumab seemed to grant a survival benefit when specific brain regions were involved or spared by the tumor, but this result was not confirmed after correction for multiple testing.Conclusions:This workflow allows to map the survival effects of variables onto specific brain tumor locations, revealing location dependency of prognostic variables such as tumor volume, and potentially of treatment schemes, with relevant implications in risk stratification and clinical management.