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Figure 1: Pseudoprogression in a Right Frontal Anaplastic Astrocytoma, Treated With Surgery and Temozolomide Chemoradiotherapy in 2007; and a Second Surgery Followed by Chemotherapy in February 2008 Due to Tumoral Progression

AB Glial Cells

Oligodendrocytes are extremely sensitive to radiation. Their destruction is associated with radiological evidence of demyelination and reactive astrocytic gliosis in peri-lesional white matter.1,4,5,7,10,13,18

There is

sufficient loss of cellular components to account for the observed brain atrophy with hydrocephalus ex vacuo seen after RT.4,7,10,19

Other Mechanisms

The fibrinolytic enzyme system may also play a role in RN. Decreased tissue plasminogen activator and elevated urokinase plasminogen activator levels have been observed. Their effect on blood vessels may contribute to cytotoxic oedema and tissue necrosis.7,10

The potential

role of autoimmune vasculitis in the response of the central nervous system to radiation-induced damage needs further investigation.7,10,17 Damage from ChT may occur earlier and be more severe if capillary permeability or cell metabolism are altered.5,6

Therefore, RT CD

may enhance the efficacy of ChT by maximising drug uptake and activating parallel pathways, leading to an increase of endothelial cell death.6

This is particularly true for TMZ,5 demyelination and necrosis.4 Radiation-induced Brain Injury

The adverse effects of RT on the brain are classified into three types: acute injury, subacute injury and pseudoprogression, and late radiation-induced injury.

E Acute Injury

Acute injury occurs during radiation or just after completion of RT,1,4,6,17 presenting as transient worsening of symptoms1 increased intracranial pressure.6

and signs of Use of the currently recommended

low fraction doses means that symptoms are mostly transient and reversible and can usually be alleviated by corticosteroids.6 generally needed as it has little prognostic significance.1,6,17

MR is not

At follow-up contrast-enhanced axial T1-weighted imaging, surgical changes in the tumoral bed were observed (A). New areas of enhancement in the occipital lobes (B) and posterior fossa (C) are depicted (open arrows), mimicking leptomeningeal spread. No signs of leptomeningeal spread were found at lumbar puncture and spine magnetic resonance, and no changes in therapy were made. Four months later, those enhancement foci were no longer present (D and E). These findings suggest pseudoprogression.

Pathophysiology of Radiation-induced Injury The events leading to radiation-induced injury are the result of a complex, dynamic interplay between the various cells within the irradiated volume (tumoral, endothelial and glial cells).6

Endothelial Cell Injury

In acute stages, radiation-induced endothelial cell death results in a breakdown of the blood–brain barrier with vasodilatation and increased capillary permeability, which manifests as vasogenic oedema, hypoxia and ischaemia.1,4–6,10,18

In chronic stages, vascular hyalinisation, fibrinoid

necrosis and thrombosis lead to the development of cytotoxic oedema, infarction and necrosis.1,4,6,10,13,19

usually interspersed Further histological

The extension and confluence of

multiple peri-vascular necrotic foci result in large serpiginous or ‘geographic’ zones of parenchymal necrosis,4,10,20 with tumour cells of unclear viability.2,6,18

changes include inflammatory peri-vascular infiltration, low-grade haemorrhage, dystrophic calcifications and malformation-like aggregates of dilated vessels.18


Subacute Injury and Pseudoprogression Subacute injury occurs within the first 12 weeks of completion of RT,1,4–7,17,21

Corticosteroids are sometimes needed to control symptoms. Improvement usually occurs within a few weeks or months, sometimes spontaneously.1,6,17

presenting as somnolence, fatigue or worsening of pre-existing neurological focal deficits, although patients may remain asymptomatic.5

noted immediately after treatment. These findings may mimic recurrence or progression5

MR findings vary from non-enhancing white matter hyperintensities on T2-weighted imaging, representing oedema, to new enhancing lesions or enlargement of pre-existing lesions at first post-radiation MR,6

and may have an impact on

management, resulting in premature discontinuation of effective adjuvant therapy4–6,21

trials on recurrent gliomas.21

Therefore, this radiation effect has been called pseudoprogression or therapy-induced necrosis.5,6

and inappropriate patient selection for clinical such that ChRT is likely

to enhance vascular permeability (and therefore gadolinium enhancement),5,6

along with hypoxia, axonopathy, white-matter

At follow-up, most pseudoprogressive

lesions either stabilise or decrease in terms of size and area of enhancement without any change in therapy (see Figure 1),6,19 although some lesions may progress to RN. Hence, pseudoprogression can be considered as a continuum between subacute injury and true RN.6


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