Beyond tumor volume: connectomic measures of tumor burden provide superior prognostic information across tumor compartments in glioblastoma

Background

Glioblastoma (GBM) interacts with distributed brain networks, suggesting that its prognostic impact may extend beyond local tumor burden, yet imaging-based prognostic assessment remains largely focused on tumor volume. Despite more than 30 years of research, the association between tumor volume and survival remains inconsistent. Brain-wide tractography-derived measures may capture additional prognostic information, but their robustness remains uncertain.

Methods

We analyzed 999 patients with newly diagnosed GBM pooled from multiple cohorts. For each of five tumor compartments, we quantified volume and derived tract-density measures by mapping the compartment onto a normative tractogram. Associations with overall survival (OS) were evaluated using log-rank tests across stratification percentiles and survival horizons, with the Benjamini–Bogomolov procedure accounting for multiple testing within and across compartments. Cox models assessed associations after adjustment for clinical covariates.

Results

Associations between tumor volume and OS varied across compartments and stratification thresholds, with only contrast-enhancing volume consistently associated with survival. Tract-density measures showed more consistent associations across survival horizons, tissue compartments, and stratification thresholds. The whole-tumor tract-density measure yielded the most parsimonious model and remained associated with OS after adjustment for age, MGMT promoter methylation status, and extent of resection.

Conclusions

The prognostic value of tumor volume in GBM depends strongly on the compartment assessed and the stratification threshold. Brain-wide tractography-derived measures provide more consistent survival associations across compartments and retain prognostic information after adjustment for established clinical factors. These findings support moving beyond local volumetric assessment to incorporate connectomic biomarkers into prognostic modeling in GBM.

Key Points

• Tumor volume shows inconsistent prognostic value for GBM survival, except for the contrast-enhancement volume.

• A brain-wide tractography-derived measure, the lesion-tract density index, shows robust survival associations across tumor compartments.

• Whole-tumor lesion-tract density yields the most parsimonious survival model.