Clinical Investigation
Hippocampal Dosimetry Predicts Neurocognitive Function Impairment After Fractionated Stereotactic Radiotherapy for Benign or Low-Grade Adult Brain Tumors

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Purpose

To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT).

Methods and Materials

Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test–retest interval. NCF impairment was defined as a z score ≤−1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose–volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD2) assuming an α/β ratio of 2 Gy were computed. Fisher’s exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose–response data were fit to a nonlinear model.

Results

Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD2 to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD2 to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068).

Conclusion

EQD2 to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.

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.

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