Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma.

Abstract

200kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans. Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. At each timepoint, the difference between T1 pre- versus post-contrast tumor volume (ΔT1) and these pMRI metrics were evaluated: normalized and standardized relative cerebral blood volume (nRCBV, sRCBV); fractional plasma volume (Vp), volume of extravascular extracellular space (EES) per volume of tissue (Ve), blood-brain barrier (BBB) permeability (Ktrans), and time constant for gadolinium reflux from EES back into the vascular system (Kep). Between-group comparisons were performed using rank-sum analysis, and bootstrapping evaluated likely reproducibility of the results. Among 13 pMRI datasets (11 nGBM, 2 recurrent GBM), therapies included temozolomide-only (n = 9) and temozolomide + TTFields (n = 4). No significant differences were found in patient or tumor characteristics. Compared to temozolomide-only, temozolomide + TTFields did not significantly affect the percent-change in pMRI metrics from baseline to 2 months. But during the 2- to 6-month period, temozolomide + TTFields significantly increased the percent-change in nRCBV (+26.9% [interquartile range 55.1%] vs -39.1% [37.0%], p = 0.049), sRCBV (+9.5% [39.7%] vs -30.5% [39.4%], p = 0.049), Ktrans (+54.6% [1768.4%] vs -26.9% [61.2%], p = 0.024), Ve (+111.0% [518.1%] vs -13.0% [22.5%], p = 0.048), and Vp (+98.8% [2172.4%] vs -24.6% [53.3%], p = 0.024) compared to temozolomide-only. Using pMRI, we provide initial in-human validation of pre-clinical studies regarding the effects of TTFields on tumor blood volume and BBB permeability in GBM.