Blood-brain barrier permeability following conventional photon radiotherapy - A systematic review and meta-analysis of clinical and preclinical studies

Elvin't Hart; Zelda Odé; Marc P P Derieppe; Lucianne Groenink; Martijn W Heymans; René Otten; Maarten H Lequin; Geert O R Janssens; Eelco W Hoving; Dannis G van Vuurden

doi:10.1016/j.ctro.2022.04.013

Blood-brain barrier permeability following conventional photon radiotherapy - A systematic review and meta-analysis of clinical and preclinical studies

Clin Transl Radiat Oncol. 2022 May 4:35:44-55. doi: 10.1016/j.ctro.2022.04.013. eCollection 2022 Jul.

Affiliations

¹ Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
² Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The UMC Utrecht Brain Center, Utrecht, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
³ Department of Epidemiology and Data Science, Amsterdam University Medical Center, De Boelelaan 1089a, 1081 HV Amsterdam, The Netherlands.
⁴ University Library, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands.
⁵ Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
⁶ Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Abstract

Radiotherapy (RT) is a cornerstone treatment strategy for brain tumours. Besides cytotoxicity, RT can cause disruption of the blood-brain barrier (BBB), resulting in an increased permeability into the surrounding brain parenchyma. Although this effect is generally acknowledged, it remains unclear how and to what extent different radiation schemes affect BBB integrity. The aim of this systematic review and meta-analysis is to investigate the effect of photon RT regimens on BBB permeability, including its reversibility, in clinical and preclinical studies. We systematically reviewed relevant clinical and preclinical literature in PubMed, Embase, and Cochrane search engines. A total of 69 included studies (20 clinical, 49 preclinical) were qualitatively and quantitatively analysed by meta-analysis and evaluated on key determinants of RT-induced BBB permeability in different disease types and RT protocols. Qualitative data synthesis showed that 35% of the included clinical studies reported BBB disruption following RT, whereas 30% were inconclusive. Interestingly, no compelling differences were observed between studies with different calculated biological effective doses based on the fractionation schemes and cumulative doses; however, increased BBB disruption was noted during patient follow-up after treatment. Qualitative analysis of preclinical studies showed RT BBB disruption in 78% of the included studies, which was significantly confirmed by meta-analysis (p < 0.01). Of note, a high risk of bias, publication bias and a high heterogeneity across the studies was observed. This systematic review and meta-analysis sheds light on the impact of RT protocols on BBB integrity and opens the discussion for integrating this factor in the decision-making process of future RT, with better study of its occurrence and influence on concomitant or adjuvant therapies.

Keywords: AVM, Arteriovenous malformations; BBB, Blood-brain barrier; Blood-brain barrier; CT, Computed tomography; Dose Fractionation; EB, Evans Blue; LC-MS, Liquid chromatography-mass spectrometry; MRI, Magnetic resonance imaging (MRI); NMR, Nuclear magnetic resonance; NSCLC, Non-small cell lung cancer; PET, Positron emission tomography; Permeability; RT, Radiotherapy; Radiotherapy; Radiotherapy Dosage; SRS, Stereotactic radiosurgery; WBRT, Whole-brain RT.

Publication types

Review