Preclinical evidence suggests that the neural stem cell compartment within the dentate gyrus plays a critical role in hippocampal neurogenesis (8
), and damage to it during cranial irradiation contributes significantly to the development of neurocognitive decline, most notably in memory-related domains (1
). Conformal avoidance of the hippocampus using intensity-modulated radiotherapy (IMRT) may spare patients some of the neurocognitive sequelae of cranial irradiation without significantly altering the therapeutic benefit. Clinical implementation of hippocampal sparing, however, poses a number of important challenges: 1) accurate delineation of the hippocampus is critical to deriving the postulated neurocognitive benefit and to avoiding excess risk of intracranial disease progression; and, 2) the central location of the hippocampus within the brain necessitates the use of IMRT technology to spare the hippocampus of a clinically significant radiation dose, without compromising target coverage and homogeneity.
The hippocampus consists of two U-shaped interlocking laminae: the cornu ammonus and the dentate gyrus. It is a component of the entire limbic circuit, which includes white matter tracts such as the fimbriae and fornices (the primary efferent system of the hippocampus) and gray matter structures such as the amygdala and parahippocampal gyrus. Memory function has been associated with the pyramidal and granule cells located in the dentate gyrus of the hippocampus (12
). In all adult mammals, including humans, new granule cells are generated from mitotically active neural stem cells, which are located in the subgranular zone of the dentate gyrus and which migrate into the granular cell layer (8
). Preclinical evidence has associated neurogenesis within the dentate gyrus with normal cognitive function (19
). Cranial irradiation in rat models has been observed to induce apoptosis of these precursor cells and alter their differentiation towards a gliogenic fate, resulting in a significant reduction in hippocampal neurogenesis (1
) and associated cognitive impairment (3
). In contrast, neural progenitor cells within the subventricular zone of the lateral ventricles differentiate into olfactory bulb neurons and play a role in olfactory discrimination (22
Since the primary avoidance region is postulated to be the subgranular stem cell compartment, we have adopted a targeted approach to contouring the hippocampus, focusing on the dentate gyrus and cornu ammonus, rather than comprehensively contouring the entire limbic circuit or the subventricular zones. Minimizing the avoidance volume is critical to avoiding a clinically unacceptable risk of intracranial disease progression. In this study, the mean hippocampal avoidance volume was 27.5 cm3
, representing, on average, 2.1% of the whole brain. We used the contouring technique described in this paper to review 371 patients who presented with 1133 metastases (23
). In this comprehensive multi-institution analysis, we observed a metastasis within the hippocampal avoidance region (hippocampus plus 5mm margin) in 8.6% of patients, with 11.5% as the upper limit of the 95% confidence interval, and 3.0% of brain metastases. None of the metastases lay within the hippocampus. Assuming that the risk of developing subsequent brain metastasis within the hippocampal avoidance region scales in the same proportion as that at presentation, we estimated that a patient treated with hippocampal sparing during whole-brain radiotherapy (WBRT) will derive 91.4% of the relative benefit of WBRT in terms of preventing the emergence of radiographically visible intracranial lesions, with a lower 95% confidence limit of 88.5%.
Using helical tomotherapy and LINAC-based intensity-modulated radiotherapy (IMRT), we have been successfully able to spare the hippocampus. For a prescription dose of 30 Gy in 10 fractions, the median and maximum dose received by the hippocampus is 5.5 Gy and 12.8 Gy, respectively, for helical tomotherapy and 7.8 and 15.3, respectively, for LINAC-based IMRT. In addition, mean dose to the hippocampus, normalized to 2-Gy fractions (NTDmean), is reduced by 87% from 37.5 Gy2
(30 Gy in 10 fractions) to 4.9 Gy2
using helical tomotherapy, and by 81% to 7.3 Gy2
using LINAC-based IMRT. That helical tomotherapy offered better hippocampal sparing as compared to LINAC-based IMRT, is not surprising. In similar clinical applications of IMRT for sparing of deep anatomic structures, such as parotid sparing in head and neck irradiation, helical tomotherapy has demonstrated improved sparing capability compared to step-and-shoot IMRT (24
). However, we postulate that using either helical tomotherapy or LINAC-based IMRT will sufficiently spare the hippocampus to yield a clinically significant neurocognitive benefit. Using a rat model, Michelle Monje and colleagues have observed a radiation dose-dependent effect on neurogenesis, with a single fraction of 10 Gy inducing a 62% reduction in neural stem cell proliferation and a 97% reduction in hippocampal neurogenesis (1
). On a per-fraction basis, sparing of the hippocampus in this study reduced NTDmean to the hippocampus from 3.75 Gy2
to 0.49 Gy2
and 0.73 Gy2
using helical tomotherapy and LINAC-based IMRT, respectively.
In this study, hippocampal sparing was achieved with acceptable target coverage and homogeneity. Helical tomotherapy achieved improved whole brain target coverage and homogeneity. However, a large component of this difference can be attributed to the more rapid dose fall-off offered by helical tomotherapy. When the whole brain planned target volume was re-defined (but not re-planned) to exclude the hippocampal avoidance region plus 2mm (that is, the hippocampus plus 7mm), the differences in target coverage and homogeneity between helical tomotherapy and LINAC-based IMRT were no longer apparent. This difference in dose fall-off can be visualized spatially in . Given the ability of helical tomotherapy and LINAC-based IMRT to spare the hippocampus with acceptable whole brain target coverage and homogeneity, we conclude that hippocampal avoidance during whole-brain radiotherapy is feasible and safe for clinical testing using both IMRT modalities.
The postulated neurocognitive benefit of hippocampal sparing during cranial irradiation remains to be tested clinically. Through the RTOG (RTOG 0933), we have developed a multi-institutional phase II clinical trial of HA-WBRT in patients with brain metastases (). This trial has been approved by the Division of Cancer Prevention at the National Cancer Institute and is scheduled to open in 2010. The trial consists of a pilot training component followed by a phase II feasibility component. For the pilot component, attending physicians and institutions planning on treating patients on the phase II component will receive fused Stealth MRI and head CT simulation images in DICOM format for one sample patient. Using the technique described in this paper, they will be asked to 1) manually generate hippocampal contours, 2) expand these three-dimensionally into hippocampal avoidance zones, and 3) develop a treatment plan with hippocampal avoidance. Hippocampal contours and treatment plans will be reviewed centrally by our research group, and instructive feedback will be provided electronically to each site and attending physician. Once an institution’s attending physician demonstrates sufficient competence in hippocampal contouring and treatment planning, that institution will be certified to accrue patients to the phase II component. At this point, hippocampal sparing during cranial irradiation should not be used outside this clinical trial.
Study schema for RTOG 0933, a multi-institution phase II trial of hippocampal sparing during WBRT for brain metastases.