Tumor-associated alterations in white matter connectivity have prognostic significance in MGMT-unmethylated glioblastoma

Purpose: We investigated the prognostic significance of tumor-associated white matter (TA-WM) tracts in glioblastoma (GBM) using magnetic resonance-diffusion tensor imaging (MR-DTI). We hypothesized that (1) TA-WM tracts harbor microscopic disease not targeted through surgery or radiotherapy (RT), and (2) the greater the extent of TA-WM involvement, the worse the survival outcomes. Methods: We studied a retrospective cohort of 76 GBM patients. TA-WM tracts were identified by MR-DTI fractional anisotropy (FA) maps. For each patient, 22 TA-WM tracts were analyzed and each tract was graded 1–3 based on FA. A TA-WM score (TA-WMS) was computed based on number of involved tracts and corresponding FA grade of involvement. Kaplan–Meier statistics were utilized to determine survival outcomes, log-rank test was used to compare survival between groups, and Cox regression was utilized to determine prognostic variables. Results: For the MGMT-unmethylated cohort, there was a decrease in OS for increasing TA-WMS (median OS 16.5 months for TA-WMS 0–4; 13.6 months for TA-WMS 5–8; 7.3 months for TA-WMS > 9; p = 0.0002). This trend was not observed in the MGMT-methylated cohort. For MGMT-unmethylated patients with TA-WMS > 6 and involvement of tracts passing through brainstem or contralateral hemisphere, median OS was 8.3 months versus median OS 14.1 months with TA-WMS > 6 but not involving aforementioned critical tracts (p = 0.003 log-rank test). For MGMT-unmethylated patients, TA-WMS was predictive of overall survival in multivariate analysis (HR = 1.14, 95% CI 1.03–1.27, p = 0.012) while age, gender, and largest tumor dimension were non-significant. Conclusion: Increased TA-WMS and involvement of critical tracts are associated with decreased overall survival in MGMT-unmethylated GBM.