New considerations in radiation treatment planning for brain tumors: neural progenitor cell-containing niches

Abstract

The purpose of this critical review is to explore the controversy regarding the relationship between radiation dose to the neural progenitor cell (NPC) niches and patient outcomes, in terms of both toxicity and tumor control. NPCs in the subventricular zone (SVZ) and hippocampus are paradoxically associated with long-term neurocognitive sequelae of brain irradiation, as well as resistance to therapy and tumor recurrence. The reconciliation of these somewhat opposing functions is challenging. Current literature suggests that radiation and other treatments against the NPC in the hippocampus and the SVZ may influence patient outcome. As a result, both the SVZ and the hippocampus could have important implications on radiation treatment planning strategies, and future laboratory and clinical evaluations will be critical in designing studies to optimize treatment outcome, effectiveness, and safety.

Figure 1

Germinal regions of the adult human brain. The subventricular zone (SVZ) is the largest germinal region in the adult mammalian brain, located in the lateral wall of the lateral ventricle. The subgranular zone (SGZ) is located within the dentate gyrus of the hippocampus. The CA1, CA2, and CA3 represent Cornu Annulis fields of hippocampus proper and, along with dentate gyrus, constitute the hippocampal formation, the primary memory center in the brain. (Color version of figure is available online.) © 2006 MediVisuals Inc. Reprinted with permission from Barani IJ, Benedict SH, Lin PS, “Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies,” Int J Radiat Oncol Biol Phys 68(2):324-333, 2007.

Figure 2

Full-scale IQ distribution in patients with medulloblastoma from Grill et al. Long-term neurocognitive deficits are observed with radiation therapies in a dose-dependent manner. In this study, patients treated with 35 Gy of craniospinal (CSI) radiation demonstrated significantly poorer performance on the full-scale IQ testing than patients treated with 25 Gy of CSI. Number of patients in group CSI = 25 Gy is 11. Number of patients in group CSI = 35 Gy is 8. FSIQ, full-scale IQ.

Figure 3

Performance on neuropsychological testing is worse with increasing radiation dose to the hippocampus from Redmond et al. The performance on the Purdue Pegboard both hands test (Z-scores), a measure of motor dexterity and speed, at 6 months following completion of RT relative to (A) mean left hippocampal radiation dose, P = 0.049, and (B) mean right hippocampal radiation dose, P = 0.032 is shown. Standardized scores were used in this analysis to account for the effect of age on test performance.

Figure 4

An example hippocampal-sparing prophylactic cranial irradiation (PCI) treatment plan. The prescription dose is 25 Gy in 10 fractions. The mean dose to the hippocampal avoidance region is <8 Gy with >90% of prescription dose covering >90% of whole brain.

Figure 5

Mouse radiation treatment plans (left) and microscopy images (right) for the non–NPC-sparing (top) and NPC-sparing (bottom) radiotherapy plans from Redmond et al. Left side MR and CT images from the mouse radiation treatment plans showing the radiation dose distribution for the non–NPC-sparing (A–C) and NPC-sparing radiation treatment plans (F–H). It can be noted 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-sparing plan. Scans taken are as follows: coronal MRI (A and F), coronal CT (B and G), and axial MRI (C and 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 and E) and NPC-sparing RT (I and J). Ki-67 is a marker of cellular proliferation and is used in this model as a potential indicator of NPCs. Costaining is performed using DAPI (blue). Images (D and I) were taken with a 109 objective lens and the images (E and J) with 409 objective lens. CT, computed tomography; DAPI, 4′,6-diamidino-2-phenylindole; MRI, magnetic resonance imaging; LV, left ventricle.

Figure 6

Progression-free survival (PFS) and overall survival (OS) improve in the subgroup of patients that underwent gross total resection and received increased dose to SVZ in Chen et al. (A) PFS by ipsilateral subventricular dose in gross total resection patients (n = 41). PFS in patients whose ipsilateral subventricular zone (SVZ) received less than 40 Gy was significantly different from that in those who received a dose of 40 Gy or greater as measured by median PFS of 10.3 vs 15.1 months (95% CI: 7.4–13.2 months) and log-rank test (PZ.023), as well as adjusted hazard ratio for PFS (2.60) (PZ.028). (B) Overall survival (OS) by ipsilateral subventricular dose in gross total resection patients (n = 41). OS in patients whose ipsilateral subventricular zone (SVZ) received less than 40 Gy was significantly different from those who received a dose of 40 Gy or greater as measured by median overall survival of 15.6 vs 17.5 months (95% CI: 11.3–19.9 months) and adjusted hazard ratio for progression-free survival (2.60) (PZ.027).