An incompletely understood pathogenesis and the mechanisms of treatment-related toxicity directly affect treatment-volume definitions, and the timing and sequencing of therapies. However, recent discoveries that new neurons and glia are produced throughout life from neural stem cells (NSCs) provide us with alternate explanations for the origin of CNS neoplasias, and challenge the stochastic model of carcinogenesis, which lies at the heart of conventional treatments. Furthermore, an increasing appreciation of NSCs as the source of neural plasticity and innate repair in developing and aged mammalian brains provides an important hypothesis that treatment-induced NSC dysfunction leads to the observed late toxicity associated with either radiotherapy (RT) or chemotherapy treatments.

Carefully crafted murine studies led to the prospective identification and isolation of NSCs in embryonic, mature, and diseased mammalian CNSs. The realization that neurogenesis persists into adulthood, predominantly in two well-defined neurogenic brain regions, challenges the traditional models of CNS repair, plasticity, and tumorigenesis. Neural stem cells are a heterogeneous population of mitotically active, self-renewing, and multipotent cells. Adult NSCs are relatively quiescent, with cell-cycle time of 28 days. This small population of cells, however, generates transiently dividing progenitor cells that are characterized by a cell-cycle time of 12 h. These early progenitor cells are also located in neurogenic centers, and retain a multipotency that is restricted to neuronal lineage cells. The resulting daughter cells then migrate throughout the brain parenchyma, and integrate as interneurons in the cortical layers. Neural stem cells show complex patterns of gene expression, and consequently phenotypic expression, that vary in space and time . The ganglionic eminence(s) in the embryo, and both the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus in adults, were consistently shown to represent major germinal niches, containing cells capable of driving neurogenesis and gliogenesis . These processes are thought to be central to nervous-system repair and the preservation or reconstitution of function. Despite accumulating evidence that NSCs have a prominent role in intrinsic brain-repair processes in CNS disease, it is also known that the endogenous stem-cell compartment is unable to promote full, long-lasting repair in the setting of chronic inflammation. Data suggest that cellular and humoral inflammatory mediators may be responsible for such dysfunction. It is in this context that the effects of ionizing radiation on NSC function were examined. Radiation studies demonstrated increased rates of hippocampal apoptosis, decreased rates of proliferation, and a decrease in adult neurogenesis after exposure to ionizing radiation . These radiation-induced alterations in neurogenesis were shown to correlate with treatment-related cognitive deficits in murine models. It appears that even therapeutic doses of radiation can result in rapid ablation of the NSC compartments and a consequent decrease in neuronal-fate differentiation among surviving cells. The implications of these processes in conventional CNS RT are significant. Nevertheless, the dose-dependence of radiation-induced NSC dysfunction, coupled with a growing knowledge of the spatial localization of NSC niches in the mammalian brain, provides an opportunity to design and execute NSC-preserving RT treatments. This study marks the first such attempt to maximize NSC preservation, using current RT techniques.

Methods and Materials: A single computed tomography (CT) dataset depicting a right periventricular lesion was used in this study as this location reflects the most problematic geometric arrangement with respect to NSC preservation. Conventional and NSC preserving radiotherapy (RT) plans were generated for the same lesion using two clinical scenarios: cerebral metastatic disease and primary high-grade glioma. Disease-specific target volumes were used. Metastatic disease was conventionally treated with whole-brain radiotherapy (WBRT) to 3,750 cGy (15 fractions) followed by a single stereotactic radiosurgery (SRS) boost of 1,800 cGy to gross disease only. High-grade glioma was treated with conventional opposed lateral and anterior superior oblique beams to 4,600 cGy (23 fractions) followed by a 1,400 cGy (7 fractions) boost. NSC preservation was achieved in both scenarios with inverse-planned intensity modulated radiotherapy (IMRT).

Conventional whole-brain radiotherapy (WBRT) was planned with opposed lateral 6-MV photon fields, prescribed to the midplane. The NSC-preserving whole-brain treatment was designed with inverse-planned, intensity-modulated radiotherapy (IMRT). The IMRT plan consisted of nine coplanar 6-MV photon beams prescribed to a whole-brain volume defined as all intracranial structures above the foramen magnum. The dose–volume constraints used for plan optimization are listed in Table 1. Because of the tendency of the inverse-IMRT planning algorithm to redistribute doses around avoidance structures, it was necessary to create a ventricular pseudostructure that contained both lateral ventricles and the intervening tissue. This pseudostructure was associated with a relatively high avoidance penalty, to maximize dose gradients abutting the NSC compartments. Both treatment plans were prescribed to 3,750 cGy in 15 fractions.
Table 1.

Dose–volume constraints used in inversely planned, intensity-modulated radiotherapy
       
    Structure                             Limiting dose (cGy)    Limiting volume (%)   
    Lens                                               750                                       0    
    Globe(s)                                       4,500                                  10    
    Optic nerve(s)                            4,500                                  10    
    Chiasm                                        4,500                                    10    
    Brainstem                                    4,500                                   10    
    Spinal cord                                 4,500                                     0    
    Cochlea                                      5,500                                  20    
    Subventricular zone                    0                                       0    
    Subgranular zone                        0                                        0    
       

Conventional and NSC-preserving stereotactic radiosurgical (SRS) boost plans were also generated, to deliver an additional 1,800 cGy in a single fraction. The planning target volume (PTVm) was defined as the contrast-enhancing volume on T1-weighted magnetic resonance (MR) images plus a 1.5-mm expansion. The conventional SRS boost plan used five noncoplanar dynamic arcs, with a uniform angular shift between adjacent arc planes. Treatment dose was equally distributed among the five arc beams, and delivered throughout the entire arc range. Five noncoplanar dynamic arcs were also used in the NSC-preserving SRS boost plan, but asymmetric interarc angles and limited arc ranges were used to minimize exit doses to the contralateral NSC compartments. Both SRS boost plans were prescribed to the 80% isodose line.

Results: Cumulative dose reductions of 65% (metastatic disease) and 25% (high-grade glioma) to the total volume of the intracranial NSC compartments were achieved with NSC-preserving IMRT plans. The reduction of entry and exit dose to NSC niches located contralateral to the target contributed most to NSC preservation.

Conclusions: Neural stem cells preservation with current external beam radiotherapy techniques is achievable in context of both metastatic brain disease and high-grade glioma, even when the target is located adjacent to a stem cell compartment. Further investigation with clinical trials is warranted to evaluate whether NSC preservation will result in reduced toxicity.