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

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.

Fig. 1

PRISM flow chart of study selection. After selection and filtering of a total of 4883 studies, 215 studies were included in this study, of which 20 clinical studies were evaluated for inclusion in the subsequent qualitative analysis and no clinical study was suited for meta-analysis. 49 preclinical studies were qualitatively analysed, of which 29 studies were included in the meta-analysis.

Fig. 2

Effect of RT on BBB permeability in clinical studies - qualitative analysis. Analysing clinical studies, the absence or presence of RT-induced BBB permeability was evaluated (A) and subgrouped by disease type (B), Biological effective dose (C), BBB disruption detection method D), and duration of patient follow-up (E), showing differential effects.

Fig. 3

Effect of RT on BBB permeability in preclinical studies - qualitative analysis. Analysing preclinical studies, the absence or presence of RT-induced BBB permeability was evaluated (A), and subgrouped by animal model used (B), Biological effective dose (C), BBB disruption detection method (D), and duration of follow-up (E), showing differential effects.

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