|Purpose: Recent discoveries have
implicated neural stem cells (NSC) as the source of plasticity and repair in the mature
mammalian brain. Treatment-induced NSC dysfunction may lead to observed toxicity. This
study evaluates the feasibility of NSC-preserving external beam radiotherapy.
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 dosevolume 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.
Dosevolume constraints used in inversely planned, intensity-modulated radiotherapy
dose (cGy) Limiting volume (%)
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.