White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma

Abstract

Importance: The prognosis of overall survival (OS) in patients with glioblastoma (GBM) may depend on the underlying structural connectivity of the brain.

Objective: To examine the association between white matter tracts affected by GBM and patients' OS by means of a new tract density index (TDI).

Design, setting, and participants: This prognostic study in patients with a histopathologic diagnosis of GBM examined a discovery cohort of 112 patients who underwent surgery between February 1, 2015, and November 30, 2020 (follow-up to May 31, 2023), in Italy and 70 patients in a replicative cohort (n = 70) who underwent surgery between September 1, 2012, and November 30, 2015 (follow-up to May 31, 2023), in Germany. Statistical analyses were performed from June 1, 2021, to May 31, 2023. Thirteen and 12 patients were excluded from the discovery and the replicative sets, respectively, because of magnetic resonance imaging artifacts.

Exposure: The density of white matter tracts encompassing GBM.

Main outcomes and measures: Correlation, linear regression, Cox proportional hazards regression, Kaplan-Meier, and prediction analysis were used to assess the association between the TDI and OS. Results were compared with common prognostic factors of GBM, including age, performance status, O6-methylguanine-DNA methyltransferase methylation, and extent of surgery.

Results: In the discovery cohort (n = 99; mean [SD] age, 62.2 [11.5] years; 29 female [29.3%]; 70 male [70.7%]), the TDI was significantly correlated with OS (r = -0.34; P < .001). This association was more stable compared with other prognostic factors. The TDI showed a significant regression pattern (Cox: hazard ratio, 0.28 [95% CI, 0.02-0.55; P = .04]; linear: t = -2.366; P = .02). and a significant Kaplan-Meier stratification of patients as having lower or higher OS based on the TDI (log-rank test = 4.52; P = .03). Results were confirmed in the replicative cohort (n = 58; mean [SD] age, 58.5 [11.1] years, 14 female [24.1%]; 44 male [75.9%]). High (24-month cutoff) and low (18-month cutoff) OS was predicted based on the TDI computed in the discovery cohort (accuracy = 87%).

Conclusions and relevance: In this study, GBMs encompassing regions with low white matter tract density were associated with longer OS. These findings indicate that the TDI is a reliable presurgical outcome predictor that may be considered in clinical trials and clinical practice. These findings support a framework in which the outcome of GBM depends on the patient's brain organization.

Figure 1.. Calculation of Tracts Density Index (TDI) and Workflow of Analysis

A, Brain tumors were manually segmented and normalized to the Montreal Neurological Institute coordinate space through an entianomorphic normalization approach. B, The intersection between the 3-dimensional normalized tumor volume mask and the normative group average white matter density index map was calculated to compute a single average density value for each brain tumor. A mean and SD of the TDI is reported (bottom) along with a representation of the density distribution in the main white matter tracts from the probabilistic Johns Hopkins University White Matter Tractography Atlas (thresholded at 25% probability). C, Schematic of the set of analyses (regression, survival, and replicative) performed to assess the additional prognostic value of the TDI. ATR indicates anterior thalamic radiation; CST, corticospinal tract; hippo, hippocampus; IFOF, inferior fronto-occipital fasciculus; ILF, inferior longitudinal fasciculus; L, left side; R, right side; SLF, superior longitudinal fasciculus; UF, uncinate fasciculus; temp, temporal.

Figure 2.. Anatomic Distribution of Glioblastoma and Linear Correlations With Overall Survival and Progression-Free Survival in the 2 Cohorts

A, Frequency maps are overlaid on the white matter template (fsaverage). B, Independent component (IC) analysis (ICA) performed in the discovery and replicative data sets. The ICA maps between data sets show high spatial correlation with the number of components fixed to both 3 or 4. The ICA maps in the discovery data set show high spatial match with a third independent data set retrieved from the literature. A indicates anterior; Dim, dimensions; L, left side; Lat, lateral; P, posterior; R, right side.

Figure 3.. Association Among Overall Survival (OS), Prognostic Factors, and Tract Density Index (TDI) by Linear Regression, Kaplan-Meier, and Cox Regression Analyses

A, Stepwise removal of data (OS-wise) correlational analysis removes at each step the patient with the lowest OS score. Horizontal bar in the boxes indicates the median; lower and upper ends of the boxes, first and third quartiles; and whiskers, maximum and minimum values. Blue dotted line is significance at P < .05. B, Coefficient values are given for each factor. C, Patients were split into 2 subgroups according to the 25th and 75th percentiles of the TDI; corresponding curves were computed for both core edema density index (CE-TDI) and core density index (C-TDI). Shaded areas indicate 95% CI. D, Adjusted OS from the linear regression analysis in the discovery data set. At each step, the excluding threshold was set as 1 month of OS longer (0-12 months). Analysis was performed using only clinical and genetic variables (orange) and adding the CE-TDI (dark blue). MGMT indicates O⁶-methylguanine-DNA methyltransferase. ^aSignificant models.