Abstract

Functional MRI may identify critical windows of opportunity for drug delivery and distinguish between early treatment responders and non-responders. Using diffusion-weighted, dynamic contrast-enhanced, and dynamic susceptibility contrast MRI, as well as pro-angiogenic and pro-inflammatory blood markers, we prospectively studied the physiologic tumor-related changes in fourteen newly diagnosed glioblastoma patients during standard therapy. 153 MRI scans and blood collection were performed before chemoradiation (baseline), weekly during chemoradiation (week 1–6), monthly before each cycle of adjuvant temozolomide (pre-C1-C6), and after cycle 6. The apparent diffusion coefficient, volume transfer coefficient (Ktrans), and relative cerebral blood volume (rCBV) and flow (rCBF) were calculated within the tumor and edema regions and compared to baseline. Cox regression analysis was used to assess the effect of clinical variables, imaging, and blood markers on progression-free (PFS) and overall survival (OS). After controlling for additional covariates, high baseline rCBV and rCBF within the edema region were associated with worse PFS (microvessel rCBF: HR = 7.849, p = 0.044; panvessel rCBV: HR = 3.763, p = 0.032; panvessel rCBF: HR = 3.984; p = 0.049). The same applied to high week 5 and pre-C1 Ktrans within the tumor region (week 5 Ktrans: HR = 1.038, p = 0.003; pre-C1 Ktrans: HR = 1.029, p = 0.004). Elevated week 6 VEGF levels were associated with worse OS (HR = 1.034; p = 0.004). Our findings suggest a role for rCBV and rCBF at baseline and Ktrans and VEGF levels during treatment as markers of response. Functional imaging changes can differ substantially between tumor and edema regions, highlighting the variable biologic and vascular state of tumor microenvironment during therapy.

Highlights

  • Functional magnetic resonance imaging (MRI) may identify critical windows of opportunity for drug delivery and distinguish between early treatment responders and non-responders

  • We did not find any significant correlations between imaging and blood markers (Supplementary Table 6). In this prospective trial evaluating 153 MRI scans in newly diagnosed GBM patients treated with standard CRT and adjuvant TMZ, we performed an in-depth analysis to determine if certain MR imaging and peripheral blood markers at different treatment time points predicted clinical outcome

  • Our study revealed 1) a suggestive association between high baseline/pre-treatment microvascular rCBF and panvascular relative cerebral blood volume (rCBV) and rCBF within the edema region of interest (ROI) and an increased risk of disease progression; 2) a statistically significant association between high week 5 and pre-C1 Ktrans values in the tumor ROI and worse Progression-free survival (PFS); and 3) a statistically significant association between high week 6 VEGF levels and worse overall survival (OS)

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Summary

Introduction

Functional MRI may identify critical windows of opportunity for drug delivery and distinguish between early treatment responders and non-responders. Dynamic contrast-enhanced (DCE) MRI, a type of perfusion-weighted imaging, has the ability to measure vessel permeability and may represent a potential tool to identify time points when the blood-brain barrier (BBB) is permeable and permissive to drug delivery. In this prospective single-center study, we studied the functional MRI changes in patients with newly diagnosed GBM treated with six weeks of concurrent fractionated radiation (RT) and daily temozolomide (“chemoradiation” (CRT)) and adjuvant monthly temozolomide (TMZ; collectively referred to as “standard therapy”) at multiple time points. The goal of this exploratory study was to obtain a detailed understanding of the impact of treatment on tumor physiology and vascular state and identify time points during which treatment could be optimized

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