Magnetic resonance imaging (MRI) is the most used imaging modality in patients with brain tumours. However, conventional MRI, including T1 weighted and T2 weighted sequences, has its limitations in distinguishing progression or tumour recurrence from nonspecific post-treatment changes, because pathological contrast enhancement could reflect either tumour regrowth or reactive changes after radiotherapy (RT).
Pseudoprogression (PsP) and radiation necrosis (RN) are the most common radiological entities after brain tumor irradiation. Pseudoprogression is defined as a new or enlarging contrast enhancement occurring early after the end of RT (e.g., < 12 weeks for glioblastoma, 6-12 months for lower grade gliomas) in the absence of tumor progression. These findings typically occur within the RT high dose areas (> 45 Gy) and regress or stabilize without any change of treatment. The underlying mechanism of PsP is a partial break-down of the blood brain barrier. Radiation necrosis (RN) occurs from around 6 months to several years post RT and reflects more severe, extensive and permanent tissue and vascular damage. The incidence of PsP in patients with gliomas has been reported to range from 10 to 40 % (Abbasi et al., 2018). There are conflicting results regarding the association between MGMT methylated status and higher risk of PsP in patients with glioblastoma (Brandes et al., 2008) (Wick et al., 2016). Recently, a meta-analysis including 424 low grade glioma patients demonstrated higher incidence of PsP after proton therapy (PT) compared to photons (Lu, Welby, Laack, Mahajan, & Daniels, 2020). Contrast enhancing lesions occurring after PT were described as multifocal, patchy (e.g., < 1 cm in ) and located at the distal end of the proton beam (Ritterbusch, Halasz, & Graber, 2021). Similarly, higher rates of asymptomatic radiological changes after PT were reported in meningioma patients (Song et al., 2021).
Quantification of PsP and RN
Perfusion weighted imaging (PWI) such as dynamic susceptibility contrast (DSC) and dynamic contrast enhancement (DCE) are the most commonly used advanced imaging techniques to distinguish PsP from the true progression based on the underlying pathophysiology that tumoral neovascularisation is associated with hyperperfusion, whereas inflammatory and other reactive treatment related changes are not. PWI parameters can separate viable tumour from treatment changes with sensitivities and specificities within a range of 80–90%. However, almost all imaging studies are small, retrospective, and biased. (Langen, Galldiks, Hattingen, & Shah, 2017) (van Dijken, van Laar, Holtman, & van der Hoorn, 2017) (Patel et al., 2017). There are still ongoing efforts to standardize acquisition and postprocessing of PWI (Boxerman et al., 2020). Amino acid PET is another imaging technique used to differentiate tumour progression from treatment related changes. The uptake of amino acid tracers is independent of the blood-brain- barrier, thus providing additional value of tissue metabolism. Several studies have repeatedly reported a high diagnostic accuracy (in the range of 80-90%) of amino acid PET using the tracers FET and FDOPA in patients with predominantly glioblastoma through the use of the tumour to normal brain tissue ratios (Langen et al., 2017).
Microstructural changes of normal-appearing brain
Late delayed radiation brain injury (RBI) may result in progressive and irreversible cognitive deterioration. The knowledge on underlying mechanism of late delayed RBI is still limited, but white matter damage (e.g., demyelination and axonal degradation) and vascular damage most likely play an important role. One of the best methods for evaluating white matter degradation is diffusion tensor imaging (DTI). DTI makes use of the fact that within the brain water molecules preferentially move along the long axis of myelinated fibers, leading to unequal diffusion (anisotropy) in that direction. The most prominent effects of radiation induced white matter injury are decreasing fractional anisotropy, increasing mean diffusivity, and increasing radial diffusivity. Data on dose- and time-dependency of radiation-induced diffusion changes are heterogenous. The strongest dose-dependence has been found within corpus callosum, fornix and cingulum (Connor et al., 2017). There is only very limited evidence on predictive value of radiation induced diffusion changes on the cognitive outcome (Chapman et al., 2012; Witzmann, Raschke, & Troost, 2021). Radiation-induced vascular changes can be detected with PWI (Witzmann et al., 2021).