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

Michael Iv; Lewis Naya; Sajal Sanan; Samuel L Van Buskirk; Seema Nagpal; Reena P Thomas; Lawrence D Recht; Chirag B Patel

doi:10.1177/19714009231207083

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

Neuroradiol J. 2024 Feb;37(1):107-118. doi: 10.1177/19714009231207083. Epub 2023 Nov 6.

Authors

Michael Iv¹, Lewis Naya², Sajal Sanan³, Samuel L Van Buskirk⁴, Seema Nagpal⁵, Reena P Thomas⁵, Lawrence D Recht⁵, Chirag B Patel^{6

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Affiliations

¹ Division of Neuroradiology, Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
² Stanford Cancer Institute, Stanford, CA, USA.
³ School of Medicine, University of Washington, Seattle, WA, USA.
⁴ Department of Psychology, University of Texas at San Antonio, San Antonio, TX, USA.
⁵ Division of Neuro-Oncology, Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Cancer Biology Program, The University of Texas MD Anderson Cancer Center, University of Texas at Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA.
⁸ Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center-University of Texas at Houston Graduate School of Biomedical Sciences (GSBS), USA.

Abstract

Background and objective: 200 kHz 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.

Methods: 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 (V_p), volume of extravascular extracellular space (EES) per volume of tissue (V_e), blood-brain barrier (BBB) permeability (K^trans), and time constant for gadolinium reflux from EES back into the vascular system (K_ep). Between-group comparisons were performed using rank-sum analysis, and bootstrapping evaluated likely reproducibility of the results.

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), K^trans (+54.6% [1768.4%] vs -26.9% [61.2%], p = 0.024), V_e (+111.0% [518.1%] vs -13.0% [22.5%], p = 0.048), and V_p (+98.8% [2172.4%] vs -24.6% [53.3%], p = 0.024) compared to temozolomide-only.

Conclusion: 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.

Keywords: blood-brain barrier; glioblastoma; magnetic resonance imaging; neuro-oncology; neuroimaging; perfusion imaging; permeability; tumor treating fields.

MeSH terms

Blood-Brain Barrier / diagnostic imaging
Blood-Brain Barrier / pathology
Brain Neoplasms* / diagnostic imaging
Brain Neoplasms* / therapy
Cerebral Blood Volume
Contrast Media
Glioblastoma* / drug therapy
Glioblastoma* / therapy
Humans
Magnetic Resonance Imaging / methods
Reproducibility of Results
Temozolomide / therapeutic use

Substances

Temozolomide
Contrast Media