MRI as a central component of clinical trials analysis in brainstem glioma: a report from the Pediatric Brain Tumor Consortium (PBTC)

Abstract

We report MRI findings from 2 pediatric clinical trials of diffuse intrinsic brainstem glioma (BSG) incorporating concurrent radiation therapy (RT) with molecularly targeted agents (gefitinib and tipifarnib). We determined associations of MRI variables with progression-free survival and overall survival and investigated effects of treatment on these variables. MRI (including diffusion and perfusion) was done before treatment, every 8 weeks (first year), every 12 weeks (thereafter), and at the end of treatment or disease progression. Reduced tumor volume (P < .0001) and tumor diffusion values (P <.0001) were apparent on the first post-RT/drug studies. Decreases in tumor volume correlated with pre-RT volume (P < .0001) and pre-RT diffusion values (P < .0001); larger decreases were noted for tumors with higher volumes and diffusion values. Patients with larger pre-RT tumors had longer progression-free survival (P < .0001). Patients with ≥ 25% decrease in tumor volume and diffusion values after RT had longer progression-free survival (P = .028) and overall survival (P = .0009). Enhancement at baseline and over time was significantly associated with shorter survival. Tumor diffusion values with baseline enhancement were significantly lower than those without (P = .0002). RT of BSG is associated with decreased tumor volume and intralesional diffusion values; patients with ≥ 25% decrease in values post-RT had relatively longer survival intervals, apparently providing an early imaging-based surrogate for relative outcomes. Patients with larger tumors and greater decreases in tumor volume and diffusion values had longer survival intervals. Tumor enhancement was associated with shorter survival, lower tumor diffusion values (increased cellularity), and a smaller drop in diffusion values after RT (P = .006). These associations justify continued investigation in other large clinical trials of brainstem glioma patients.

Figures

Fig. 1.

Region of interest (ROI) measurements for diffusion and perfusion MR images in brainstem glioma. (A), Axial T1-weighted post-contrast image of a child with brainstem glioma demonstrates expansion of the pons and a region of tumoral enhancement (red arrow) anterior to the fourth ventricle. (B), Cerebral blood volume perfusion map demonstrates a ROI (green circle) chosen on the basis of the highest perfusion value within the tumor. (C), Apparent diffusion coefficient map with the ROI (green circle) placed in an anatomical location closest to that used for perfusion, while avoiding the ventricle.

Fig. 2.

Progression-free survival for PBTC-007 (dashed line) and PBTC-014 (solid line).

Fig. 3.

Decline in tumor volume (A) and diffusion values (B) after radiation therapy (RT). DR, diffusion ratio; TVF, tumor volume flair.

Fig. 4.

Radiation effect on tumor volume and diffusion values. Patients with a larger decrease in tumor volume also had larger drops in diffusion values after radiation and drug (Spearman's rank correlation, 0.39, P = .001). RT, radiation therapy.

Fig. 5.

Kaplan-Meier estimate of progression-free survival (A) and overall survival (B) by percentage decrease in tumor volume or diffusion ratio values during radiation therapy for the 2 subgroups of patients with brainstem glioma: one group with a ≥25% decrease in tumor volume or in diffusion ratio (dashed line) versus those without this change (solid line). The progression-free survival is better for patients with a ≥25% decrease in tumor volume after radiation.

Fig. 6.

Axial FLAIR images from a 17-year-old girl with diffuse intrinsic brainstem glioma obtained before (top) and after (bottom) radiation therapy, demonstrating an 86% decrease in tumor volume from 37.96 cc to 5.22 cc, with progression-free survival duration of 317 days.

Fig. 7.

Axial T2 images from an 8-year-old girl with diffuse intrinsic brainstem glioma before (top) and after (bottom) radiation therapy, demonstrating a 5% increase in tumor volume, with a short progression-free survival duration of 38 days.

Fig. 8.

Apparent diffusion coefficient maps before (top) and after (bottom) radiation therapy for a 4-year-old girl with brainstem glioma. The ratio of the diffusion value within the tumor normalized with frontal white matter demonstrates a 41% decrease in values, with a longer progression-free survival duration of 602 days.

Fig. 9.

Apparent diffusion coefficient maps before (top) and after (bottom) radiation therapy for a 6-year-old girl with brainstem glioma. The ratio of the diffusion value within the tumor normalized with frontal white matter demonstrates a 0.8% decrease in values, with a short progression-free survival duration of 104 days.