The relative cerebral blood volume in normal-appearing white and grey matter remains almost constant following radio(chemo)therapy

Introduction:

Adjuvant radio(chemo)therapy (RT) is part of the treatment of primary brain tumor patients. In order to capture microscopic tumor extension and to compensate for random and systematic positioning uncertainties, it is inevitable that tumor-surrounding normal brain tissue is irradiated. The aim of this study was to determine relative cerebral blood volume (rCBV) changes in glioma patients before and after RT in normal appearing white matter (WM) and grey matter (GM).

Methods:

As part of an ongoing study, anatomical and functional MRI data of glioma patients undergoing gross tumor resection followed by RT is being collected. The analysis of a subset of this cohort, 17 glioma patients (3 grade II, 11 grade III, 3 grade IV, average age 46.9y ± 13.2y) is presented here. Two patients were treated with photon therapy, 14 patients with proton therapy and one patient received treatment modalities. MRI scans acquired prior to RT and at least one follow-up MRI obtained 3, 6 and 9 months after RT was evaluated. All MRI data were collected on a 3T Philips Ingenuity PET/MR scanner (Philips, Eindhoven, The Netherlands) using an 8 channel head coil and included anatomical T1w-images (3D-GRE, TR/TE=10/3.7ms, FA=20°, voxel size 1×1×1mm3) and dynamic susceptibility contrast (DSC) imaging using a PRESTO sequence (TR/TE=15/21ms, 60 dynamics, dynamic scantime=1.7s, voxel size 3.6×3.6×3.5mm3) with intravenous gadolinium contrast agent (0.1mol/kg, 4ml/s, 7s delay) followed by a saline flush (20ml, 4ml/s). The CBV-map (fig. 1D) was calculated as the area under curve (AUC) of the voxelwise time course of the 4D PRESTO image.
Computed tomographies (CTs) used for planning, radiation dose (fig.1C) and clinical target volume (CTV) contours were registered to the T1w images using ANTs1 . T1w-images were segmented into GM and WM using SPM122 and the corresponding 95% tissue probability maps were rigidly registered with ANTs1 to the CBV-map. B1 inhomogeneities as well as voxels with strong signal loss due to susceptibility artefacts were excluded. Only voxels outside the CTV and without any abnormalities appearing on the FLAIR image were considered.
Symmetrical GM and WM ROIs in supraventricular contralateral and ipsilateral hemisphere (fig.1A,B) were evaluated. The relative CBV (rCBV) was calculated as the ratio of the mean ipsilateral and contralateral CBV:
rCBV=(CBV_ipsi)/(CBV_contra )
The radiation dose in the ROI was determined as the dose difference of ipsilateral to contralateral side.
In a second analysis, the ROI was divided into bins of relative dose differences (ΔRD): low (0-20Gy), medium (20-40Gy) and high (>40Gy). Time-dependent alteration of rCBV was determined by the normalized difference between follow-up (v0x) and baseline measurement:
ΔrCBV=(rCBV_v0x–rCBV_baseline)/(rCBV_baseline )
Dose- and time-dependent ΔrCBV distributions were compared with the paired Wilcoxon signed-rank test.

Results:

The entire ROIs (fig. 2G,H) as well as the dose-separated regions (fig. 2A-F) of GM and WM rCBV did not show significant changes between baseline and follow-up, neither over time nor with increasing dose. One exception was the statistically significantly reduced mean ΔrCBV of -7.6% (p<0.008) after 6 months in WM volumes receiving a ΔRD of 0-20Gy (fig. 2A). In volumes receiving a ΔRD of <40Gy a trend towards increasing rCBV was detected 9 months after RT [mean WM +22,4% (p=0.063) and mean GM +3.1% (p=0.098); fig. 2C and 2F]. Patient-dependent fluctuations were higher in WM-regions than in GM-regions, however, the deviations remained below 20%.

Discussion:

The evaluation of radiation-induced rCBV changes in normal-appearing tissue resulted mainly in constant perfusion without continuous changes after RT, while the majority of the previous studies reported a perfusion reduction prominently appearing in high radiation dose regions3–7. Significant rCBV reduction 6-9 months after RT with a recovery after 18 month in low-dose areas was reported in combined grey and white matter region7, which is in line with our results of WM perfusion decrease in low- ΔRD volumes. However, the authors7 also reported similar behavior for high-dose regions not consistent with our results. An early radiation response of decreasing rCBV followed by a recovery 3 months after RT has also been measured8, which agrees with our observation of constant rCBV 3, 6 and 9 months after radiation. One study reported increasing rCBV in the low-dose region9, while our results indicated a trend for increasing rCBV in the high ΔRD area. It is possible, that the trend to perfusion increase did not reach significance due to the low number of patients especially for the WM evaluation.