Cerebral blood flow changes after radiation therapy identifies pseudoprogression in diffuse intrinsic pontine gliomas

Abstract

Background: The interval between progression and death in diffuse intrinsic pontine glioma (DIPG) is usually <6 months. However, reports of longer patient survival following radiotherapy, in the presence of radiological signs of progression, suggest that these cases may be comparable to pseudoprogression observed in adult glioblastoma. Our aim was to identify such cases and compare their multimodal MRI features with those of patients who did not present the same evolution.

Methods: Multimodal MRIs of 43 children treated for DIPG were retrospectively selected at 4 timepoints: baseline, after radiotherapy, during true progression, and at the last visit. The patients were divided into 2 groups depending on whether they presented conventional MRI changes that mimicked progression. The apparent diffusion coefficient, arterial spin labeling cerebral blood flow (ASL-CBF), and dynamic susceptibility contrast perfusion relative cerebral blood volume (DSCrCBV) and flow (DSCrCBF) values were recorded for each tumor voxel, avoiding necrotic areas.

Results: After radiotherapy, 19 patients (44%) showed radiological signs that mimicked progression: 16 survived >6 months following so-called pseudoprogression, with a median of 8.9 months and a maximum of 35.6 months. All 43 patients exhibited increased blood volume and flow after radiotherapy, but the 90th percentile of those with signs of pseudoprogression had a greater increase of ASL-CBF (P < 0.001). Survival between the 2 groups did not differ significantly. During true progression, DSCrCBF and DSCrCBV values increased only in patients who had not experienced pseudoprogression.

Conclusions: Pseudoprogression is a frequent phenomenon in DIPG patients. This condition needs to be recognized before considering treatment discontinuation. In this study, the larger increase of the ASL-CBF ratio after radiotherapy accurately distinguished pseudoprogression from true progression.

Figures

Fig. 1

Kaplan–Meier survival curves of the 2 groups: pseudoprogression (in red), controls (in blue). (A) Progression-free survival. (B) Overall survival.

Fig. 2

Longitudinal follow-up of an example case of pseudoprogression with 4 timepoints: at baseline, the week following the end of RT (after RT), at a follow-up examination 3 months after the end of RT, and finally at true progression 9 months after RT. (A–D) Axial T1-weighted images after contrast injection. (E–H) Sagittal T2 FLAIR images, (I–L) axial ASL-CBF, M-P, axial DSCrCBV, Q-T, axial ADC. Note the increase in contrast enhancement and volume of T2 FLAIR abnormalities after RT, associated with increased blood flow and decreased apparent diffusion. These changes reverted spontaneously by a follow-up examination 3 months later.

Fig. 3

Boxplot with whiskers representing the distribution of (A) ADC, (B) ASL-CBF, (C) DSCrCBV, and (D) DSCrCBF median values at baseline, after RT, during true progression, and at the last visit for all patients that showed pseudoprogression (in red) and those in the control group (in blue). Lines representing the underlying trend for each group were calculated by local nonparametric regression. Units: ADC in 103 µm2/s, ASL-CBF in mL/min per 100 g tissue.

Fig. 4

(A) Boxplot with whiskers representing the distribution of the 90th percentile ASL-CBF after RT values from control and pseudoprogression groups, in mL/min per 100 g tissue. (B) Boxplot with whiskers representing the distribution of after RT/baseline ratios of 90th percentile ASL-CBF values from control and pseudoprogression groups. (C) Receiver operating characteristic curve for identifying pseudoprogression using the after RT/baseline ratio of 90th percentile ASL-CBF values: area under the curve (AUC) = 0.98, best threshold = 1.92, specificity = 89%, sensitivity = 100%.