Imaging progression after radiotherapy for IDH mutant low-grade glioma: Sometimes it is best to stay calm and stay the course

The difficulty in distinguishing benign radiation-related imaging changes from progressive glioma using standard brain MRI sequences and other conventional imaging methods is a challenge in optimizing the care of individual patients and impairs rapid screening of novel agents for effectiveness. This has been actively studied for patients with high-grade glioma where imaging progression during the first several months after therapy may actually be a consequence of treatment and associated with improved outcomes. This clinical problem is potentially more consequential in patients with low-grade glioma who will have a high prior probability of long-term tumor control with standard treatment, are at risk of premature abandonment of highly effective therapies, may demonstrate not only short-term but also late imaging changes a decade or more later, and could experience toxicities of salvage treatments that may be given long before they are necessary.

In this issue of Neuro-Oncology Practice, the research reported by Sutherland et al. confirms that progression of T2/FLAIR (Fluid-Attenuated Inversion Recovery) abnormality in brain MRI of low-grade glioma patients observed within the first 2 years after administration of radiation therapy has a high probability of representing treatment-related pseudoprogression and not requiring alteration of the therapeutic plan.¹ During the first year after treatment, T2/FLAIR progression defined by Response Assessment in Neuro-Oncology (RANO) criteria as ≥ 25% increase in FLAIR volume occurred in 75% of patients. Only 1 of 12 patients with T2/FLAIR progression in the first year demonstrated continual progression judged to be a true failure of the treatment. A long follow-up period is necessary to exclude true progression as these imaging changes stabilized at the median of 18.4 months after treatment. This study supports a cautious approach when continuing progression on FLAIR MRI is observed in the first year or more after treatment of a non-enhancing low-grade glioma.

This article described T2/FLAIR progression, but a separate question is the development of new areas of contrast enhancement which, although a potential consequence of radiotherapy, may also reflect the transformation of the tumor to a higher-grade process necessitating intervention. Radiation-induced contrast enhancement is thought to be more common after particle radiation (proton) rather than photon.² Never-the-less, given the low probability of early failure of treatment to control IDH-mutant low-grade glioma, new contrast enhancement occurring in the first 1–2 years post treatment may also be monitored with consideration of biopsy or therapy modification based on symptoms and evolution of imaging findings. Moreover, the location of the new enhancement with respect to the radiation field and the tumor location should be considered. Contrast enhancement has been observed in select cases to progress for a year or more and then stabilize/resolve.

Long-term imaging effects of treatment, not addressed in this study, may occur several years later and similarly, be difficult to distinguish from disease progression. These can include diffuse progressive white matter injury within the radiated region; focal necrosis with contrast enhancement, edema, and mass effect; cystic changes; and microhemorrhage.³ Prospectively collected data reported over 30 years ago demonstrated radiation dose-related white matter changes first appearing at the median of 14 months after therapy in 42% of glioma patients who survived more than 18 months.⁴ These changes can appear a decade or more after therapy. A series of 124 patients irradiated for nasopharyngeal cancers with no known central nervous system tumor were monitored for imaging changes in radiation-exposed temporal lobes with a significant proportion showing imaging effects. The median time to first detection after radiation of white matter changes was 66 months (range 12–216 months), for contrast-enhanced lesions was 72 months (range 12–192 months), and that for cysts was 117 months (range 48–216 months).⁵

The data presented by Sutherland et al. specific to low-grade glioma and other data describing the imaging effects of cranial radiation suggests that caution is warranted before presuming short- or long-term imaging changes actually confirm disease progression, since standard MRI is unreliable even when applying the RANO consensus guidelines. We recommend follow-up over several scans to confirm continued disease progression, whether FLAIR abnormality or contrast enhancement, prior to considering biopsy to confirm the nature of the process. The observation of rapid progression with mass effect and/or development of associated focal symptoms justifies resection or biopsy to assess the presence of active disease, transformation to a higher grade, and acquisition of new molecular characteristics. Prudent initiation of new therapy without histopathologic confirmation is appropriate when biopsy/resection is not feasible and the pace and location of progression portends injury to neurologic function that justifies treatment in the setting of this uncertainty.

The work of Sutherland et al emphasizes the need to investigate novel imaging techniques or combined approaches that may better address this difficult clinical uncertainty. In recent years, several imaging modalities have shown promising capabilities in distinguishing radiation effects from disease progression. Amide proton transfer is a type of chemical exchange saturation transfer that has shown encouraging diagnostic performance in discerning treatment effects from disease progression in both high- and low-grade gliomas.⁶ Furthermore, amino acid positron emission tomography (PET) imaging has emerged as a valuable diagnostic modality as the uptake of radiolabeled amino acids is not limited to blood–brain barrier disruption, allowing the identification of non-enhancing glioma subregions.⁷ Notably, dynamic ¹⁸F-fluorethyltyrosine (¹⁸F-FET) PET has demonstrated potential use in astrocytic low-grade gliomas by identifying high-risk low-grade glioma at the time of diagnosis and distinguishing radiation-induced changes from tumor progression post therapy.^8,9 More recently, 18F-Fluciclovine PET either alone or in combination with multiparametric MRI accurately differentiated pseudoprogression from tumor progression in glioblastoma patients.¹⁰ Its use in pediatric low-grade gliomas is currently under study (NCT05555550). The ECOG-ACRIN GABLE trial (EAF223) is a platform study to test the effectiveness of promising imaging and/or blood biomarkers to distinguish pseudoprogression (NCT06319027), though confined to high-grade glioma. These and other novel imaging approaches require validation in prospective multicenter studies.

Conflict of interest statement. Lawrence Kleinberg: Research support: Novartis, Incyte, and Novocure. Consulting: Novocure, Servier. Solmaz Sahebjam: Consulting: Telix Pharmaceuticals, Pliant Therapeutics.

Funding

None declared.