Brain metastases with poor vascular function are susceptible to pseudoprogression after stereotactic radiation surgery

Abstract

Purpose: This study aimed to investigate the hemodynamic status of cerebral metastases prior to and after stereotactic radiation surgery (SRS) and to identify the vascular characteristics that are associated with the development of pseudoprogression from radiation-induced damage with and without a radionecrotic component.

Methods and materials: Twenty-four patients with 29 metastases from non-small cell lung cancer or malignant melanoma received SRS with dose of 15 Gy to 25 Gy. Magnetic resonance imaging (MRI) scans were acquired prior to SRS, every 3 months during the first year after SRS, and every 6 months thereafter. On the basis of the follow-up MRI scans or histology after SRS, metastases were classified as having response, tumor progression, or pseudoprogression. Advanced perfusion MRI enabled the estimation of vascular status in tumor regions including fractions of abnormal vessel architecture, underperfused tissue, and vessel pruning.

Results: Prior to SRS, metastases that later developed pseudoprogression had a distinct poor vascular function in the peritumoral zone compared with responding metastases (P < .05; number of metastases = 15). In addition, differences were found between the peritumoral zone of pseudoprogressing metastases and normal-appearing brain tissue (P < .05). In contrast, for responding metastases, no differences in vascular status between peritumoral and normal-appearing brain tissue were observed. The dysfunctional peritumoral vasculature persisted in pseudoprogressing metastases after SRS.

Conclusions: Our results suggest that the vascular status of peritumoral tissue prior to SRS plays a defining role in the development of pseudoprogression and that advanced perfusion MRI may provide new insights into patients' susceptibility to radiation-induced effects.

Figure 1

Vascular characteristics prior to stereotactic radiation surgery across all patients. (a) Representative regions of interest of the tumor (red overlay), peritumoral (purple overlay), and pure edema (blue overlay) regions are shown in a patient with metastasis from non-small cell lung cancer. (b) Corresponding images of post-contrast T1-weighted, FLAIR, and blood volume-maps in the same patient. Median fractions of abnormal vessels, underperfused tissue, and macro- and microvessel pruning across all patients by tumor region (c), peritumoral region (d), and edema region (e). Boxplots (median values with interquartile range).

Figure 2

Poor vascular function associated with development of pseudoprogression. (a) When compared with responding metastases (green boxes), metastases that later developed pseudoprogression (blue boxes) displayed a higher fraction of macrovessel pruning (13% vs 37%; P < .01), microvessel pruning (18% vs 37%; P < 0.01), abnormal vessels (9% vs 29%; P < .05), and underperfused tissue (12% vs 38%; P < .001). Schematic illustration of functional pre-treatment vasculature found in responding metastases (b) compared with dysfunctional vasculature observed in metastases developing pseudoprogression (c). Boxplots (median with interquartile range); P-values from Mann-Whitney U test; Suppl. Table 2.

Figure 3

Vascular profiles related to pre-treatment tumor size and treatment outcome. (a) When compared with small metastases (purple boxes), large metastases (orange boxes) displayed a trend (non-significant) toward a higher fraction of macrovessel pruning (23% vs 36%; P-value not significant on the basis of Mann-Whitney U test), microvessel pruning (27% vs 34%; not significant), abnormal vessels (20% vs 28%; not significant), and underperfused tissue (23% vs 35%; not significant). (b) Within the group of small metastases (left), the responders displayed fractions within the normal range while higher fractions were generally observed in metastases that developed pseudoprogression. Similarly, for large metastases (right), a trend toward higher fractions was observed in pseudoprogressing metastases compared with responding metastases. Of note, no statistical test was performed due to the low number of metastases in each group. Boxplots (median with interquartile range); purple/orange dots (individual metastases).

Figure 4

Vascular signature of peritumoral zone is maintained after stereotactic radiation surgery (SRS). (a) For metastases that developed pseudoprogression, the fraction of abnormal vessels was higher than for responders at 3 months (P < .01) and 6 months after SRS (P < .001) and compared with normal brain tissue at 6 months (P < .05). (b) The fraction of underperfused tissue was higher in pseudoprogressing metastases compared with responding metastases at 3 months (P < .05) and 6 months (P < .01) and compared with normal brain tissue (P < .01). (c) The fraction of macrovessel pruning was higher in pseudoprogressing metastases compared with responding metastases at 6 months (P < .01). The same trend was displayed at 3 months (P < .05; not significant on the basis of Mann Whitney U test and after Holm-Bonferroni correction). The fraction in pseudoprogressing metastases was also higher compared with that of normal brain tissue (P < .01 at 3 months; P < .05 at 6 months). (d) No significant differences in the fraction of microvessel pruning were observed after SRS. Lines with transparent field (median ± interquartile range); P-values from Mann Whitney U test (between groups) and Wilcoxon Signed Rank test (relative to normal brain).