What Effect Does Radiotherapy Have on Healthy Brain Tissue?

Radiotherapy (RT) plays a significant role in curative and palliative management of primary and secondary brain tumors.¹ However, the unfortunate side effect is that healthy tissue is irradiated alongside the tumor, leading to brain tissue damage and cognitive impairment.

In fact, around 50–90% of brain tumor patients that survive at least 6 months after RT experience some form of cognitive decline, such as memory loss.² Recently, in our systematic review conducted at the University of Manchester and published in the journal Neuro-Oncology Advances, we examined damage to the normal brain tissue after brain irradiation.³

Limitations identified in past evaluations of radiation-induced damage

We aimed to shed light on the factors that influence the magnitude of damage to the normal neurovascular unit (NVU) – the parts of the brain that regulate cerebral blood flow, enabling nutrient delivery to activated neurons – following irradiation and to determine when changes of the vasculature and neural tissue occur.

It is assumed that vascular damage after brain irradiation could contribute to cognitive dysfunction, thus efforts have been made by different groups to examine the impact of radiation on the blood–brain barrier (BBB) – the vascular component of the NVU – or the wider NVU (i.e. the vascular and neural tissue compartments).^4–10 When Hart et al. (2022) systematically analyzed studies published before April 2020, they found that in both clinical and pre-clinical studies, brain irradiation increased BBB permeability at acute, delayed and late-delayed timepoints, ¹¹ indicating that vascular changes can occur and exist long-term. Since they only focused on the effects of low linear energy transfer (LET) photons on the vascular component, we decided to conduct a systematic review to reveal the impact of various ionizing radiation (IR) types on the entire NVU.

Damage extent varies with radiation dose, dose rate and delivery technique

Recognizing the need for a wider analysis of the impact of IR on normal brain tissue, we analyzed the outputs from 6,883 studies using PubMed and Web of Science databases.

The review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines,¹² and the studies that met the inclusion criteria (n = 82) were classified and quantitatively analyzed.

Our key findings were:

• Brain irradiation causes widespread effects on all components that make up the NVU, i.e. the endothelial cell layer, pericytes, astrocytes, microglia, extracellular matrix, neurons and oligodendrocytes.
• Damage is more severe with higher doses, low LET radiation, broader beams, lower dose rates and in tumor-bearing animal models.
• Changes in the vasculature and neural compartments occur at acute (up to one-month post-IR in preclinical and clinic settings), delayed (one-to-three months post-IR in preclinical or one-to-six months post-RT in clinic) and late (≥ three months post-IR in preclinical or ≥ six months post-RT in clinic)^8,10,13 time windows.

IR-related chronic vascular changes could contribute to cognitive decline

Damage extent is more severe with low LET radiation, higher doses, lower dose rates and with broader beams. As expected, most studies concluded that higher doses result in more severe damage to the entire NVU and that damage appears faster than when lower doses are used. There were few comparable studies that investigated other factors, such as fractionation, high/low LET, tumor presence in the model irradiated and dose rate.

Another key finding is that changes or damage to both the vasculature and neural tissue can occur at acute, delayed and late time windows after irradiation. Even though the neural tissue is the central element for maintaining proper cognition,¹⁴ these findings indicate that the chronic changes in the vasculature could contribute to cognitive decline, which normally occurs as a late side effect. 

Our work has provided a detailed overview of various changes that occur in the vasculature and neural compartments of the normal tissue after brain irradiation, when they occur and some key factors that determine damage severity.

We also identified crucial gaps in the field that need to be addressed or considered in future studies to increase relatability to clinical settings. These gaps relate to radiation (i.e. type, dose, source, dose rate and delivery method), animal models (tumor-bearing compared to non-tumor-bearing), techniques employed to examine changes and the timelines chosen.

Our findings were, however, limited by the majority of the studies being rodent models (89%) that used whole or partial brain irradiation at large, single doses. This differs from the therapeutic management of brain tumors in the clinic and does not reveal the differences in management of different patients (age, tumor location, tumor size etc.).

Moreover, the predominant model used was non-tumor-bearing rodents; out of the 69 in vivo studies, 61 used healthy (non-tumor-bearing) subjects. This limits our understanding of how the tumor impacts normal tissue toxicity, and how the tumor's presence may interact with cognition.

Equally important, this review focused on studies that used RT only, yet in clinical settings, it is often given as a combination with chemotherapy, surgery and immunotherapy. Despite providing detailed non-confounded effects of IR on the NVU of the normal brain tissue, they show an incomplete picture in relation to clinical outcomes.

Real-world clinical application

Since cognitive dysfunction has been reported in the presence ^15–17 or absence of tumors ^18–20 and before or after RT treatment,^21–24 studies that compare IR effects and behavioral outcomes in tumor-bearing and naïve models are needed to address clearly how normal tissue toxicities drive long-term neurocognitive changes, independent of the tumor.

Also, future studies that combine RT with novel imaging, such as magnetic resonance imaging (MRI) would help to reveal NVU changes in real time,²⁵ which can provide a broader understanding of when the normal tissue and cognitive changes occur.

Reference: Nakkazi A, Forster D, Whitfield GA, Dyer DP, Dickie BR. A systematic review of normal tissue neurovascular unit damage following brain irradiation-factors affecting damage severity and timing of effects. Neurooncol Adv. 2024; 6(1):vdae098. doi:10.1093/noajnl/vdae098

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