International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationHippocampal Dosimetry Predicts Neurocognitive Function Impairment After Fractionated Stereotactic Radiotherapy for Benign or Low-Grade Adult Brain Tumors
Introduction
Although memory impairment has been a well-documented toxicity of cranial irradiation, a pathophysiologic explanation remains ill defined. One plausible hypothesis, focused on the role of neurogenic stem cells located in the subgranular layer of the hippocampal dentate gyrus, has been proposed on the basis of preclinical data demonstrating that this stem cell compartment is exquisitely sensitive to therapeutic doses of cranial irradiation (1). Preclinical models have demonstrated loss of hippocampal-dependent functions of spatial learning and memory, as tested by water maze tests, as a consequence of hippocampal irradiation 2, 3. However, to date, there is a paucity of clinical data to suggest that radiation dose to the hippocampus leads to long-term memory effects. We sought to address this hypothesis by conducting a prospective observational study of adult patients with benign or low-grade brain tumors treated with fractionated stereotactic radiotherapy (FSRT) and correlating hippocampal dose–volume histogram (DVH) data with long-term neurocognitive function (NCF) impairment.
Section snippets
Patient population
Adult patients with diagnoses of pathologically confirmed or clinically suspected benign or low-grade intracranial neoplasms were enrolled in this prospective protocol, approved by the University of Wisconsin Health Sciences Institutional Review Board. Eligible patients were >18 years of age, with no history of prior chemotherapy or radiotherapy. If biopsy or therapeutic resection was performed, patients were enrolled at least 1 week after biopsy and at least 4 weeks after resection.
Fractionated stereotactic radiotherapy
All
Results
In this prospective study, 29 experimental patients and 12 healthy control individuals were enrolled and underwent baseline NCF testing. However, statistical analysis was limited to the 18 experimental patients and 6 healthy control individuals who also completed NCF testing at the 18-month follow-up. Comparison of patient characteristics between experimental patients and control individuals revealed no significant differences (Table 2). In addition, no significant differences were observed
Discussion
In all adult mammals, including humans, new hippocampal 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, 9. Preclinical evidence has associated neurogenesis within the dentate gyrus with normal cognitive function (10). Cranial irradiation in rat models has been observed to induce apoptosis of these precursor cells and to alter their differentiation toward a
Conclusion
Preclinical evidence suggests that the neurogenic stem cell compartment in the hippocampal dentate gyrus is central to radiation-induced cognitive impairment after cranial irradiation. In this prospective observational study of adult patients with benign or low-grade brain tumors treated with FSRT, we observed a dose relationship between EQD2 to the bilateral hippocampi and likelihood of long-term memory impairment. Specifically, we observed that a EQD2 to 40% of the bilateral hippocampi (D40%)
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Supported by grant R01-CA109656 (PI: W.A. Tomé) from the National Cancer Institute of the United States of America.
Conflict of interest: Minesh Mehta has or has had the following roles in the past 2 years (2010–2011): Consultant: Adnexus, Bayer, Merck, Roche, Tomotherapy; Stock options: Colby, Pharmacyclics, Procertus, Stemina Tomotherapy; Data Safety Monitoring Boards: Apogenix; Board of Directors: Pharmacyclics; Medical Advisory Boards: Colby, Stemina, Procertus; Speaker: Merck. The authors report no other conflict of interest.