Imaging biomarker dynamics in an intracranial murine glioma study of radiation and antiangiogenic therapy

Abstract

Purpose: There is a growing need for noninvasive biomarkers to guide individualized spatiotemporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI).

Methods and materials: Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhanced T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K(trans), K(ep)).

Results: Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K(trans) reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K(ep) reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of -0.878 (P=.002) and -0.80 (P=.01), respectively.

Conclusions: Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future.

Fig. 1.

Timeline of the treatments and MRI imaging sessions. MRI on Day 0 confirmed and measured baseline tumor volume. Sunitinib (SU) was delivered for 7 weekdays. Radiation (RT) 8 Gy in 1 fraction was delivered on Day 1 of treatment, after the first dose of SU. Multiparametric MRI was on Days 3, 7, 10, 14, and 21.

Fig. 2.

(a) Representative intracranial tumors at baseline showing the variability in size and location. (b) Representative images of the radiation plan: (i) axial coregistered baseline T1-weighted gadolinium-enhanced MRI and treatment day CBCT; (ii) axial CBCT image with radiation isodoses (10% orange, 90% red, 95% teal), around the tumor and the isocenter at the center of the 2 axes, placed using visual estimation of the tumor location using baseline MRI.

Fig. 3.

(a) Survival curves showing median survival of 35 days for SURT mice, 30 days for both RT and SU mice, and 26 days for control mice. (b) Tumor growth curves show tumor volume change over time. Mixed effects model analysis showed that overall tumor growth rate increases per day was lower for the 2 RT arms compared with control (P=.003) and SU (P=.005) mice.

Fig. 4.

(a) Representative T1-weighted gadolinium-enhanced images and ADC maps at baseline and on treatment Day 3 (D3) for a mouse treated with SURT. (b) Mean normalized ADC (ie, normalized to contralateral brain to account for slice-to-slice variation from respiratory motion) over time (days) showing a significant rise in ADC for the 2 RT arms vs that in the non-RT arms (P=.00001) as early as Day 3.

Fig. 5.

(a) Mean percent change in K_trans from baseline showing a significant decrease in both SU arms at Day 3 (SU, P=.04; SURT, P=.04) and a sustained drop in K_trans in the SURT arm. (b) Mean percent change in K_ep showing a significant decrease in both SU arms at Day 3 (SU, P=.01; SURT, P=.02). (c) Mean percent change in precontrast tumor T1 from baseline. (d) Mean percent change in K_trans when population T1 and individual mouse T1 are used in the modified Tofts model for each treatment arm showing less variability with individual T1.

Fig. 6.

Relationship between estimated Ln (tumor growth rate) using linear effects modeling for individual mouse tumor volume data and individual MRI responses at Day 3 and Day 7. Square = RT; circle = no RT; gray = SU; black = no SU (a, b). ADC response shows high correlation (b, c). K_trans response was a weak association (c, d). K_ep response shows no correlation.