A radiotherapy technique to limit dose to neural progenitor cell niches without compromising tumor coverage

Abstract

Radiation therapy (RT) for brain tumors is associated with neurocognitive toxicity which may be a result of damage to neural progenitor cells (NPCs). We present a novel technique to limit the radiation dose to NPC without compromising tumor coverage. A study was performed in mice to examine the rationale and another was conducted in humans to determine its feasibility. C57BL/6 mice received localized radiation using a dedicated animal irradiation system with on-board CT imaging with either: (1) Radiation which spared NPC containing regions; (2) Radiation which did not spare these niches; or (3) Sham irradiation. Mice were sacrificed 24 h later and the brains were processed for immunohistochemical Ki-67 staining. For the human component of the study, 33 patients with primary brain tumors were evaluated. Two intensity modulated radiotherapy (IMRT) plans were retrospectively compared: a standard clinical plan and a plan which spares NPC regions while maintaining the same dose coverage of the tumor. The change in radiation dose to the contralateral NPC-containing regions was recorded. In the mouse model, non-NPC-sparing radiation treatment resulted in a significant decrease in the number of Ki67(+) cells in dentate gyrus (DG) (P = 0.008) and subventricular zone (SVZ) (P = 0.005) compared to NPC-sparing radiation treatment. In NPC-sparing clinical plans, NPC regions received significantly lower radiation dose with no clinically relevant changes in tumor coverage. This novel radiation technique should significantly reduce radiation doses to NPC containing regions of the brain which may reduce neurocognitive deficits following RT for brain tumors.

Fig. 1

Mouse radiation treatment plans (left) and microscopy images (right) for the non-NPC-sparing (top) and NPC-sparing (bottom) radiotherapy plans. Left side MRI and CT images from the mouse radiation treatment plans showing the radiation dose distribution for the non-NPC sparing (top; a–c) and NPC-sparing radiation treatment plans (bottom; f–h). Note that for the non-NPC sparing plan, the region of the SVZ of the ipsilateral lateral ventricle receives a high radiation dose, whereas this region is effectively spared in the NPC Scans are: coronal MRI (a, f), coronal CT (b, g), and axial MRI (c, h). Dose values are shown in the legend. Right side Coronal sections showing Ki-67 stains (green) in the SVZ of the lateral ventricles following non-NPC sparing RT (d, e) and NPC-sparing RT (i, j). Co-staining is with DAPI (blue). Images d and i were taken with a 10× objective and the images e and j with 40× objective. LV left ventricle. (Color figure online)

Fig. 2

Ki67+ cell counts for three irradiation schemes: sham irradiation (white), non-NPC sparing radiation (black), and NPC-sparing radiation (gray) in the ipsilateral SVZ (a) and DG (b). There is no significant difference between the sham irradiation and NPC-sparing radiation groups

Fig. 3

Example radiotherapy plan from a patient with GBM showing the tumor (red) and solid lines delineating the isodose distribution (region of brain receiving a given dose of radiation). The left image is an axial slice from the non-NPC-sparing plan and the right image is from an NPC-sparing plan showing that a portion of the contralateral SVZ (blue) is limited to <5 Gy (light green isodose line) and the majority is limited to <10 Gy (yellow isodose line). Isodose lines are as follows: green 60 Gy, orange 40 Gy, red 20 Gy, yellow 10 Gy, light green 5 Gy. (Color figure online) contralateral SVZ region compared to the standard plan (left) without compromising tumor coverage.

Fig. 4

Example DVH for patient with GBM, showing the volume of the region (Y-axis) receiving less than or equal to a given dose of radiation (X-axis). Dashed lines represent the non-NPC-sparing plan. The solid lines represent the NPC-sparing radiation plan. Blue Contralateral SVZ. Red planning target volume (PTV = tumor plus margin). Note that close to 100% of the PTV is receiving the prescription radiation dose of 60 Gy in both the NPC-sparing and non-NPC-sparing RT plans, but that there is a substantial reduction in the radiation dose to the contralateral SVZ in the NPC-sparing RT plan compared with the non-NPC sparing RT plan. (Color figure online)