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      Hippocampal Dosimetry and the Necessity of Hippocampal-Sparing in Gamma Knife Stereotactic Radiosurgery for Extensive Brain Metastases

      research-article
      , BS a , , PhD b , , MD, PhD b ,
      Advances in Radiation Oncology
      Elsevier

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          Abstract

          Purpose

          To characterize hippocampal dosimetry in Gamma Knife stereotactic radiosurgery (GK-SRS) for extensive brain metastases and evaluate the need for hippocampal-sparing in GK-SRS treatment planning.

          Methods and Materials

          We reviewed 75 GK-SRS plans for the treatment of 4 to 30 brain metastases generated without consideration of the hippocampi. The mean dose, maximum dose to 100% of the volume (D 100), maximum dose to 40% of the volume (D 40), and maximum point dose (D max, 0.03 cm 3) were obtained for the unilateral and bilateral hippocampi and compared between plans with 4 to 9 and ≥10 lesions. The rate at which plans met hippocampal dose constraints (D 100 ≤ 4.21 Gy, D 40 ≤ 4.50 Gy, and D max ≤ 6.65 Gy) was compared between groups, and each was examined for risk factors associated with excessive hippocampal dosing. For plans that exceeded constraints, we attempted replanning to spare the hippocampi.

          Results

          Compared with those for the treatment of 4 to 9 brain metastases, GK-SRS plans with ≥10 lesions were associated with significantly greater median bilateral mean dose (1.0 vs 2.0, P = .001), D 100 (0.4 vs 0.8, P = .003), D 40 (0.9 vs 1.9, P = .001), and D max (2.0 vs 4.9, P = .0005). These plans also less frequently met hippocampal constraints, with this difference trending toward significance (80% vs 93%; P = .1382; odds ratio 0.29; 95% CI, 0.06-1.4). Risk factors for exceeding constraints included greater total disease volume and closer approach of the nearest metastasis to the hippocampi, both of which depended upon the number of metastases present. Seven plans failed to meet constraints and were successfully replanned to spare the hippocampi with minimal increases in treatment time and without compromise to target coverage or conformity.

          Conclusions

          Patients with extensive brain metastases treated with GK-SRS are at increased risk for excessive hippocampal dosing when ≥10 lesions are present or when lesions are in close proximity to the hippocampi and may benefit from hippocampal-avoidant treatment planning.

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          Most cited references19

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          Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial.

          Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, -4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series. © 2014 by American Society of Clinical Oncology.
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            Irradiation induces neural precursor-cell dysfunction.

            In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.
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              Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.

              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). 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 (EQD(2)) 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. Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) 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 EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). EQD(2) 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. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Adv Radiat Oncol
                Adv Radiat Oncol
                Advances in Radiation Oncology
                Elsevier
                2452-1094
                30 October 2019
                Mar-Apr 2020
                30 October 2019
                : 5
                : 2
                : 180-188
                Affiliations
                [a ]Tufts University School of Medicine, Boston, Massachusettes
                [b ]Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusettes
                Author notes
                []Corresponding author: Kathryn E. Huber, MD, PhD khuber@ 123456tuftsmedicalcenter.org
                Article
                S2452-1094(19)30159-9
                10.1016/j.adro.2019.10.003
                7136666
                22801cc1-3877-4e74-933a-984c6c9d8833

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 12 August 2019
                : 15 October 2019
                : 19 October 2019
                Categories
                Central Nervous System Tumor

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