Hippocampal Sparing Research Articles

Treatment planning and 3D dose verification of whole brain radiation therapy with hippocampal avoidance in rats

Despite increasing use of stereotactic radiosurgery, whole brain radiotherapy (WBRT) continues to have a therapeutic role in a selected subset of patients. Selectively avoiding the hippocampus during such treatment (HA-WBRT) emerged as a strategy to reduce the cognitive morbidity associated with WBRT and gave rise to a recently published the phase II trial (RTOG 0933) and now multiple ongoing clinical trials. While conceptually hippocampal avoidance is supported by pre-clinical evidence showing that the hippocampus plays a vital role in memory, there is minimal pre-clinic data showing that selectively avoiding the hippocampus will reduce radiation-induced cognitive decline. Largely the lack of pre-clinical evidence can be attributed to the technical hurdles associated with delivering precise conformal treatment the rat brain. In this work we develop a novel conformal HA-WBRT technique for Wistar rats, utilizing a 225kVp micro-irradiator with precise 3D-printed radiation blocks designed to spare hippocampus while delivering whole brain dose. The technique was verified on rodent-morphic Presage® 3D dosimeters created from micro-CT scans of Wistar rats with Duke Large Field-of-View Optical Scanner (DLOS) at 1mm isotropic voxel resolution. A 4-field box with parallel opposed AP-PA and two lateral opposed fields was explored with conformal hippocampal sparing aided by 3D-printed radiation blocks. The measured DVH aligned reasonably well with that calculated from SmART Plan Monte Carlo simulations with simulated blocks for 4-field HA-WBRT with both demonstrating hippocampal sparing of 20% volume receiving less than 30% the prescription dose.

EP-1575: Automated VMAT planning for whole brain irradiation with hippocampus sparing

EP-1575: Automated VMAT planning for whole brain irradiation with hippocampus sparing

EP-1127: Dose to hippocampus in brain metastases radiosurgery: need for an hippocampal sparing approach

EP-1127: Dose to hippocampus in brain metastases radiosurgery: need for an hippocampal sparing approach

Subventricular zones: new key targets for glioblastoma treatment

BackgroundWe aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma.MethodsForty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS).ResultsMedian age was 59 years (range: 25–85). Median follow-up, OS and TTP were 22.7 months (range 7.5–69.7 months), 22.7 months (95% CI 14.5–26.2 months) and 6.4 months (95% CI 4.4–9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively).ConclusionOur results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.

P05.04 Dosimetrical consequences of unilateral (left) hippocampus sparing WBRT

P05.04 Dosimetrical consequences of unilateral (left) hippocampus sparing WBRT

Prospective Study of Hippocampal-Sparing Prophylactic Cranial Irradiation in Limited-Stage Small Cell Lung Cancer

Toprospectively evaluate cognitive function and intracranial failure patterns after hippocampal-sparing prophylactic cranial irradiation (PCI) for limited-stage small cell lung cancer (SCLC). Adults with limited-stage SCLC, achieving a complete response to chemoradiotherapy and no brain metastases, were eligible. Patients received PCI 25Gy/10 fractions, with a mean hippocampal dose limited to <8Gy and ≥90% of the brain receiving 90% of the prescription. A diverse battery of neuropsychological testing was performed at baseline and 6 and 12months after PCI. Brain MRI scans were performed at baseline and 6, 12, 18, and 24months. The primary endpoint was memory measured by the Hopkins Verbal Learning Test-Revised Delayed Recall at 6months after PCI. The 25-Gy arm of Radiation Therapy Oncology Group protocol 0212 was used as a reference of potential efficacy. Development of intracranial metastases was recorded. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Eight men and 12 women with a median age of 61years enrolled. Two-year overall survival was 88% (95% confidence interval 68%-100%). There was no significant decline in performance between baseline and 6 or 12months for any of the tests. The association between baseline intelligence quotient and change in performance on testing was not significant. Magnetic resonance imaging revealed asymptomatic brain metastases at a cumulative rate of 20%, with no concurrent extracranial progression. Two patients developed a metastasis in the under-dosed region. Neither involved the dentate gyrus, but 1 involved the avoidance region. Both patients concurrently developed additional metastasis in fully treated brain regions. There were 2 neurologic deaths. This prospective study suggests a potential benefit of hippocampal sparing in limiting the neuropsychological sequelae of brain radiation, but with a risk of failures in the spared region. These data strongly support continued enrollment on ongoing cooperative group randomized trials. Clinical Trials registration number: NCT01797159.

Hippocampal dose from stereotactic radiosurgery for 4 to 10 brain metastases: Risk factors, feasibility of dose reduction via re-optimization, and patient outcomes

This study aimed to report hippocampal dose from single-fraction stereotactic radiosurgery (SRS) for 4 to 10 brain metastases and determine feasibility of hippocampal-sparing SRS. Patients with 4 to 10 brain metastases receiving single-isocenter, multi-target single-fraction SRS were identified. Hippocampi were contoured using the Radiation Therapy Oncology Group (RTOG) 0933 atlas. RTOG 0933 dose constraints were converted to a biologically effective dose using an alpha/beta of 2 (D100 421 cGy, Dmax 665 cGy). Number of metastases, total target volume, prescribed dose, and distance of nearest metastasis (dmin) were analyzed as risk factors for exceeding hippocampal constraints. If hippocampi exceeded constraints, the SRS plan was re-optimized. Key dosimetric parameters were compared between original and re-optimized plans. To determine if a single target can exceed constraints, all targets but the closest metastasis were removed from the plan, and dosimetry was compared. Forty plans were identified. Fifteen hippocampi (19%) exceeded constraints in 12 SRS plans. Hippocampal sparing was achieved in 10 of 12 replanned cases (83%). Risk factors associated with exceeding hippocampal constraints were decreasing dmin (24.0 vs 8.0 mm, p = 0.002; odds ratio [OR] 1.14, 95% confidence interval [CI] 1.04 to 1.26) and total target volume (5.46 cm3vs 1.98 cm3, p = 0.03; OR 1.14, 95% CI 1.00 to 1.32). There was no difference in exceeding constraints for 4 to 5 vs 6 to 10 metastases (27% vs 21%, p = 0.409) or prescribed dose (18 Gy, p = 0.58). For re-optimized plans, there were no significant differences in planning target volume (PTV) coverage (99.6% vs 99.0%, p = 0.17) or conformality index (1.47 vs 1.4, p = 0.78). Six (50%) plans exceeded constraints with a single target. A substantial minority of hippocampi receive high radiation dose from SRS for 4 to 10 brain metastases. Decreasing distance of the closest metastasis and total target volume are associated with exceeding hippocampal constraints. Re-optimizing these plans yielded hippocampal-sparing SRS plans with acceptable dosimetry. Prospective evaluation of the impact of hippocampal dose from SRS on neurocognition merits consideration.

Volumetric-modulated arc therapy (VMAT) for whole brain radiotherapy: not only for hippocampal sparing, but also for reduction of dose to organs at risk

A prospective clinical trial, Radiation Therapy Oncology Group (RTOG) 0933, has demonstrated that whole brain radiotherapy (WBRT) using conformal radiation delivery technique with hippocampal avoidance is associated with less memory complications. Further sparing of other organs at risk (OARs) including the scalp, ear canals, cochleae, and parotid glands could be associated with reductions in additional toxicities for patients treated with WBRT. We investigated the feasibility of WBRT using volumetric-modulated arc therapy (VMAT) to spare the hippocampi and the aforementioned OARs. Ten patients previously treated with nonconformal WBRT (NC-WBRT) using opposed lateral beams were retrospectively re-planned using VMAT with hippocampal sparing according to the RTOG 0933 protocol. The OARs (scalp, auditory canals, cochleae, and parotid glands) were considered as dose-constrained structures. VMAT plans were generated for a prescription dose of 30 Gy in 10 fractions. Comparison of the dosimetric parameters achieved by VMAT and NC-WBRT plans was performed using paired t-tests using upper bound p-value of < 0.001. Average beam on time and monitor units (MUs) delivered to the patients on VMAT were compared with those obtained with NC-WBRT. All VMAT plans met RTOG 0933 dosimetric criteria including the dose to hippocampi of 100% of the volume (D100%) of 8.4 ± 0.3 Gy and maximum dose of 15.6 ± 0.4 Gy, respectively. A statistically significant dose reduction (p < 0.001) to all OARs was achieved. The mean and maximum scalp doses were reduced by an average of 9 Gy (32%) and 2 Gy (6%), respectively. The mean and maximum doses to the auditory canals were reduced from 29.5 ± 0.5 Gy and 31.0 ± 0.4 Gy with NC-WBRT, to 21.8 ± 1.6 Gy (26%) and 27.4 ± 1.4 Gy (12%) with VMAT. VMAT also reduced mean and maximum doses to the cochlea by an average of 4 Gy (13%) and 2 Gy (6%), respectively. The parotid glands mean and maximum doses with VMAT were 4.4 ± 1.9 Gy and 15.7 ± 5.0 Gy, compared to 12.8 ± 4.9 Gy and 30.6 ± 0.5 Gy with NC-WBRT, respectively. The average dose reduction of mean and maximum of parotid glands from VMAT were 65% and 50%, respectively. The average beam on time and MUs were 2.3minutes and 719 on VMAT, and 0.7 minutes and 350 on NC-WBRT. This study demonstrated the feasibility of WBRT using VMAT to not only spare the hippocampi, but also significantly reduce dose to OARs. These advantages of VMAT could potentially decrease the toxicities associated with NC-WBRT and improve patients' quality of life, especially for patients with favorable prognosis receiving WBRT or patients receiving prophylactic cranial irradiation (PCI).

Comparison of TomoTherapy and RapidArc in Hippocampus Sparing Brain Radiotherapy in Pediatrics

Background and Objectives: Both TomoTherapy and RapidArc have been examined in hippocampus sparing whole brain irradiation in adults. We aim to compare both techniques in pediatrics with relatively smaller brain volume. Patients and Methods: The hippocampus, the whole brain and the eyes were manually contoured in 3 pediatric patients. TomoTherapy plan was created aiming at adequate brain coverage and as low as possible hippocampus dose, RapidArc was challenged to achieve similar or better plan results. The prescription dose was 36 Gy in 20 treatment fractions to the whole brain. Results: TomoTherapy was able to achieve a mean hippocampus dose of 13.6 Gy with brain homogeneity index [HI] of 0.14 Using RapidArc [single arc], the same hippocampus dose was not achievable without compromising the brain HI significantly. By using 2 arcs, similar results to the TomoTherapy plan were achieved. The treatment time for TomoTherapy was 3.5 minutes while it was 1.2 minutes for single arc and 2.4 minutes for two arcs. Conclusions: TomoTherapy can achieve better target coverage with lower doses to the hippocampus compared to single arc RapidArc technique, while using 2 arcs RapidArc can achieve similar results with shorter treatment time.

PUB045 The Capability and Characteristic of Helical Tomotherapy at Sparing Hippocampus in Prophylactic Cranial Irradiation

Prophylactic cranial irradiation (PCI) is efficient at avoiding lung cancer intra-cranial metastasis. However, PCI may cause neurocognitive impairment because of the hippocampal toxicities. It is reported that hippocampus V7.3Gy > 40% is associated with long-term impairment. Considering helical tomotherapy (HT) has higher modulation capabilities, we investigated the capability and characteristic of HT at sparing hippocampus in PCI. Six anonymous patients previously treated with whole-brain radiotherapy with hippocampal sparing were reviewed. Under T1-weighted MRI, the hippocampus was contoured, and hippocampal avoidance regions (HAR) were created using a 5-mm volumetric expansion around the hippocampus. The prescription dose 3.0Gy * 10 fractions was assigned on planning target volume (PTV) which was defined as whole-brain minus HAR and bilateral hippocampus. During the HT plan optimization process, evaluation factors of PTV and other dosimetry factors were recorded whenever the mean dose of hippocampus decreased by every 2Gy. The average of six HT plans without hippocampus sparing constraints are as follow: hippo_Dmean 27.33±2.22Gy, HAR_Dmean 28.62±1.84Gy, PTV_Dmean 30.77±0.74Gy, PTV_D2% 30.93±0.61Gy, PTV_D98% 29.86±0.34Gy, PTV_V30Gy 0.97±0.02% and conformal index (CI) 0.85±0.03, homogeneity index (HI) 0.04±0.01, plan delivery duration 13.70±1.92min. When V7.3Gy of bilateral hippocampus achieved 40%, the average dosimetry factors are as follow: hippo_Dmean 8.26±0.24Gy, HAR_Dmean 12.88±1.27Gy, PTV_Dmean 31.00±0.47Gy, PTV_D2% 31.97±0.63Gy, PTV_D98% 21.74±5.44Gy, PTV_V30Gy 0.93±0.02%, CI 0.77±0.08, HI 0.35±0.20, plan delivery duration 21.30±4.97min. During the process of hippocampus sparing, HAR_Dmean decreased linearly as well. However, dosimetry variation of PTV presented three steps: plateau region (> 20Gy), gradient region (∼20 to ∼10Gy) and falling region (<10Gy). There’s almost no significant impact on the PTV dosimetry factors when hippo_Dmean was not lower than 15Gy. With the hippocampus dose decreasing, CI decreased linearly and slightly, however, HI was impaired severely in the falling region. Plan delivery duration time was significantly prolonged process (from 13min to 23 min).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Clinical Features of Brain Metastases in Small Cell Lung Cancer: an Implication for Hippocampal Sparing Whole Brain Radiation Therapy

PURPOSE: To assess the clinical features and distribution of brain metastases (BMs) of small cell lung cancer (SCLC) in the hippocampal and perihippocampal region, with the purpose of exploring the viability of hippocampal-sparing whole-brain radiation therapy (HS-WBRT) on reducing neurocognitive deficits. METHODS: This was a retrospective analysis of the clinical characteristics and patterns of BMs in patients with SCLC. Associations between the clinical characteristics and hippocampal metastases (HMs)/perihippocampal metastases (PHMs) were evaluated in univariate and multivariate regression analyses. RESULTS: A total of 1594 brain metastatic lesions were identified in 180 patients. Thirty-two (17.8%) patients were diagnosed with BMs at the time of primary SCLC diagnosis. The median interval between diagnosis of primary SCLC and BMs was 9.3 months. There were 9 (5.0%) and 22 (12.2%) patients with HMs and PHMs (patients with BMs located in or within 5 mm around the hippocampus), respectively. In the univariate and multivariate analysis, the number of BMs was the risk factor for HMs and PHMs. Patients with BMs≥5 had significantly higher risk of HMs (odds ratio [OR] 7.892, 95% confidence interval [CI] 1.469-42.404, P=.016), and patients with BMs≥7 had significantly higher risk of PHMs (OR 5.162, 95% CI 2.017-13.213, P=.001). Patients with extracranial metastases are also associated with HMs. CONCLUSIONS: Our results indicate that patients with nonoligometastatic disease are significantly associated with HMs and PHMs. The incidence of PHMs may be acceptably low enough to perform HS-WBRT for SCLC. Our findings provide valuable clinical data to assess the benefit of HS-WBRT in SCLC patients with BMs.

P29. Proposal of technique for whole-brain radiotherapy with hippocampal sparing

Introduction Irradiation of the hippocampi is responsible for neurocognitive deficits, whereas metastasis incidence in this part of brain is low [1] . In this study, the objective is to develop a treatment technique with acceptable dosimetric coverage of the brain while minimizing the dose to hippocampi. Materials and methods Treatment planning of 10 patients was performed. Volumes were delineated according to the RTOG 0933 protocol. The prescribed dose was 30 Gy in 10 fractions and plans were normalized to the average of the PTV, minus the hippocampi’s PRV. For each dosimetry, goal was minimize the value of D40% and the maximum dose at hippocampi without unacceptable degradation of PTV’s coverage. VMAT technique is proposed with 5 non coplanar arcs. Isocenter is positioned at the gravity center of the two hippocampi. The first pair of arcs consist of two whole arcs with 10° couch rotation and 30° collimator rotation. The second pair of arc is identical but with an opposite rotation of table and collimator. Each arc of one pair has an asymmetric collimation so that one of the jaws, having a direction of movement identical to MLC leaves, is closed about 1 cm from the axis of the beam. The sum of two arcs of one pair covers the PTV. The fifth arc with table rotation and collimator rotation at 90° is an half-arc. It is adjusted so that the edges of jaws with MLC intersect the hippocampal volumes. For each patient, this technique was compared with an usually VMAT technique, based on 2 coplanar wholes arcs in clockwise and counterclockwise directions and collimator rotation at 30° and 330° respectively [2] . For each optimization, we used a dummy structure, between hippocampi, to control the dose. Results The average gain on the D40% of the hippocampus is 1.5 Gy and 3.2 Gy on the maximum dose. There is also an increase on the D98% of the PTV of 0.7 Gy and a diminution of 0.35 Gy to the D2%. The V95% is improved by 2%. Conclusions This technique with 5 arcs, although time-consuming during the treatment, seems to show a superiority in the hippocampal avoidance, but also in the covering of whole brain.

37. Hippocampal sparing whole brain radiotherapy with volumetric modulated arc therapy

Introduction Hippocampal Avoidance whole brain radiotherapy (HA-WBRT) is a strategy that aims to mitigate the neuro-cognitive side effects of whole brain radiotherapy treatment. The purpose of this study was to investigate the feasibility and efficiency of using volumetric modulated arc therapy (VMAT) to spare the hippocampi while delivering the prescribed dose to the rest of the brain. Methods A total of four patients were replanned for hippocampal sparing for a prescription dose of 30 Gy in 10 fractions. A cranial mask system with a 25° angle, inclined board was utilized for patient positioning. The hippocampi were contoured and hippocampal avoidance regions were created using a 5 mm volumetric expansion around the hippocampi. The whole brain planning target volume was defined as the whole brain tissue minus hippocampal avoidance region. The VMAT plans were generated in Eclipse treatment planning system version 11 for a Varian True Beam STx linear accelerator equipped with a high definition multileaf collimator. Different beam arrangements were studied.The treatment plans were evaluated on target coverage, homogeneity of the PTV, and minimum, maximum, mean dose, D40% to the hippocampi and maximum and mean dose to the lens. The goal was to generate treatment plans that met the RTOG 0933 [1] criteria for HAWBRT treatment. Results The choice of beam arrangements consisted in six arcs with two non-coplanar arcs and different collimator rotation. All the VMAT plans achieved target coverage of the brain while maintaining hippocampal doses conform to the RTOG 0933 protocol. Concerning the PTV, the mean D98%, D95% and D2% were 27.3 ± 0.3 Gy, 29.0 ± 0.1 Gy and 30.8 ± 0.1 Gy, respectively. The mean values of homogeneity index and conformity index were 0.11 ± 0.01 and 0.94 ± 0.01, respectively. The D100%, mean and maximum doses to hippocampi were 7.9 ± 0.4 Gy, 10.1 ± 0.8 Gy and 14.6 ± 1.0 Gy, on average, respectively. On average, the mean and maximum doses to lenses were 4.5 ± 0.4 Gy and 5.2 ± 0.2 Gy respectively. Conclusion An inclined head board at 25° combined to six VMAT arcs with two non-coplanar arcs provided highly conformal plans that spared hippocampi and met the RTOG 0933 criteria. In the future, we plan to evaluate dose escalation on multiple brain metastases and assess the minimum distance from the metastases to the hippocampi to satisfy hippocampal avoidance.

Radiation Dose–Dependent Hippocampal Atrophy Detected With Longitudinal Volumetric Magnetic Resonance Imaging

After radiation therapy (RT) to the brain, patients often experience memory impairment, which may be partially mediated by damage to the hippocampus. Hippocampal sparing in RT planning is the subject of recent and ongoing clinical trials. Calculating appropriate hippocampal dose constraints would be improved byefficient invivo measurements of hippocampal damage. In this study we sought to determine whether brain RT was associated with dose-dependent hippocampal atrophy. Hippocampal volume was measured with magnetic resonance imaging (MRI) in 52 patients who underwent fractionated, partial brain RT for primary brain tumors. Study patients had high-resolution, 3-dimensional volumetric MRI before and 1year after RT. Images were processed using software with clearance from the US Food and Drug Administration and Conformité Européene marking for automated measurement of hippocampal volume. Automated results were inspected visually for accuracy. Tumor and surgical changes were censored. Mean hippocampal dose was tested for correlation with hippocampal atrophy 1year after RT. Average hippocampal volume change was also calculated for hippocampi receiving high (>40Gy) or low (<10Gy) mean RT dose. A multivariate analysis was conducted with linear mixed-effects modeling to evaluate other potential predictors of hippocampal volume change, including patient (random effect), age, hemisphere, sex, seizure history, and baseline volume. Statistical significance was evaluated at α=0.05. Mean hippocampal dose was significantly correlated with hippocampal volume loss (r=-0.24, P=.03). Mean hippocampal volume was significantly reduced 1year after high-dose RT (mean -6%, P=.009) but not after low-dose RT. In multivariate analysis, both RT dose and patient age were significant predictors of hippocampal atrophy (P<.01). The hippocampus demonstrates radiation dose-dependent atrophy after treatment for brain tumors. Quantitative MRI is a noninvasive imaging technique capable of measuring radiation effects on intracranial structures. This technique could be investigated as a potential biomarker for development of reliable dose constraints for improved cognitive outcomes.

Atrophy in Alzheimer's Disease andSemantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies.

Alzheimer's disease (AD) and semantic dementia (SD) have distinct episodic memory profiles despite the hippocampal atrophy that characterizes both diseases. The aim of this study was to delineate the pattern of gray matter (GM) atrophy associated with AD and SD as well as any differences in these patterns by pooling together the results of previous voxel-based morphometry (VBM) studies.Methods/Overview: We conducted a meta-analysis of VBM studies that investigated GM atrophy in AD patients versus controls (CTRLs) and in SD patients versus CTRLs using the activation likelihood estimation (ALE) approach. Our systematic review allowed us to identify 63 VBM studies. The results confirmed that in addition to the classical cortical pattern of atrophy involving posterior medial and lateral regions in AD and the anterior lateral temporal lobes in SD, both AD and SD patients are characterized by bilateral atrophy of the hippocampus. Furthermore, in SD, the hippocampal atrophy was limited to the anterior portion of the hippocampus, while in AD, both the anterior and posterior parts of the hippocampus exhibited atrophy. When we compared the foci identified in the studies that compared AD patients versus CTRLs with those identified in the studies that compared SD patients versus CTRLs, we observed that the atrophy in the posterior hippocampus and precuneus was more severe in AD. These results support theories that propose that the deficits observed in AD result from damage to the episodic memory network, which involves the posterior hippocampus and posterior medial brain regions. However, sparing of the posterior hippocampus in SD could explain the absence of episodic memory deficits in this population.

Hippocampal sparing whole brain irradiation: Experience in our department

Introduction Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Hippocampal sparing whole brain radiotherapy (HS-WBRT) may delay or reduce the frequency and severity of neurocognitive decline in these patients. Purpose In this work we present initial data on the first 20 patients treated in our institution with HA-WBRT. Materials and Methods 20 patients have been treated in our institution with HS-WBRT, nine prophylactic cranial irradiation for small lung cancer and two for brain metastases, to a dose of 30 Gy (10-15 fractions). RTOG 0933 recommendations were applied for treatment planning. Magnetic resonance imaging (MRI) and computerized tomography (CT) sets were registered for each patient prior to delineation of the hippocampus. Intensity-modulated radiotherapy (IMRT) treatment plans for the Varian 2100CD linear accelerator were generated using the DMPO algorithm of Pinnacle TPS for optimizing a 12 beams solution class. Results The value of the maximum dose mean in the hippocampus was 15.63 Gy and the value of mean dose in the whole brain was 30.95 Gy, with a dose range of 36.4–40.2 Gy. The maximum dose to optic nerves and chiasma did not exceed 37.5 Gy. Mean number of segments and monitor units was 100 and 994 respectively. Conformation index mean value was 0.85. Conclusion The results obtained in this series of patients of our institution with HS-WBRT are comparable with the published series, fulfilling the recommendations of the RTOG 0933. Disclosure Authors disclose any relationship that may bias this work.

Dose-dependent short- and long-term effects of ionizing irradiation on neural stem cells in murine hippocampal tissue cultures: neuroprotective potential of resveratrol.

IntroductionRadiation therapy plays an essential role in the treatment of brain tumors, but neurocognitive deficits remain a significant risk, especially in pediatric patients. In recent trials, hippocampal sparing techniques are applied to reduce these adverse effects. Here, we investigate dose‐dependent effects of ionizing radiation (IR) on juvenile hippocampal neurogenesis. Additionally, we evaluate the radioprotective potential of resveratrol, a plant polyphenol recognized for its bifunctional tumor‐preventive and anticancer effects.MethodsOrganotypic entorhinal–hippocampal slice cultures from transgenic nestin‐CFPnuc C57BL/J6 mice, postnatal days 3–6, were irradiated on a X‐ray machine (4.5, 8, 12, and 16 Gy, single doses) after about 2 weeks. Nestin‐positive neural stem cells were counted at a confocal live imaging microscope 0, 2, 4, 14, 25, and 42 days after IR. Resveratrol (15 μmol/L) was added 2 hr before and 24 hr after IR. Proliferation and cell death were assessed by BrdU pulse label, 48 hr after and by propidium iodide staining 96 hr after IR. GFAP‐ and NeuN‐positive cells were counted 42 days after IR in cryosectioned immunofluorescence‐stained slices.ResultsThe observed age‐related changes of nestin‐positive stem cells in the organotypic slice culture model resembled the reduction of neural stem cells in vivo. IR (4.5–16 Gy) led to a dose‐dependent damage of the neural stem cell pool in the dentate gyrus. No recovery was seen within 42 days after doses from 4.5 Gy onward. The decline of nestin‐positive cells was paralleled by increased cell death and decreased proliferation. The number of GFAP‐positive cells was significantly enhanced. No significant change was detected in the overall NeuN‐positive cell population, whereas the number of newborn, NeuN/BrdU double‐positive neurons was reduced. Resveratrol treatment reversed the irradiation‐induced decline of neural stem cells.ConclusionThe neuroprotective action of resveratrol on irradiated hippocampal tissue warrants further investigation as a possible supplement to hippocampal sparing procedures.

Estimating the probability of underdosing microscopic brain metastases with hippocampal-sparing whole-brain radiation

Purpose/objectivesWhole-brain radiation for brain metastases can result in cognitive side effects. Hippocampal-sparing techniques have been developed to decrease morbidity, but they carry the risk of underdosing lesions near the hippocampus due to the unavoidable dose gradient from the hippocampal surface to the prescription isodose surface. This study examines the impact of variable levels of hippocampal sparing on the underdosing of potential brain metastases. Materials/methodsHelical intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were developed for hippocampal-sparing whole-brain treatment. For all plans, 30Gy was prescribed in 10 fractions to result in mean hippocampal doses of 6–12Gy. From a series of expanded shells, we determined the distance from the hippocampus at which the parenchyma would receive less than specified doses. Then, using published data, a mathematical model was constructed to predict the incident probability of potential brain metastases receiving different doses for different levels of hippocampal sparing. ResultsWhole-brain radiation plans were able to spare the hippocampi to mean doses of 7–12Gy under our planning constraints; more stringent constraints compromised brain coverage. The dose gradients were ∼4% per mm, regardless of the hippocampal constraint, and they decreased sharply by a factor of almost 4 at approximately 15mm from the hippocampi. A mathematical model was constructed and combined the plan information with published data on the distribution of brain metastases, to determine the percentage of potential brain metastases receiving specified doses, as a function of technique and level of hippocampal sparing. ConclusionsOur results describe the characteristics of an array of hippocampal-sparing whole-brain radiation dose distributions. These can be used as a decision-making guideline for weighing the benefit of decreased dose to the hippocampi against the cost of decreased dose to potential brain metastases when deciding on a hippocampal-sparing whole-brain irradiation treatment approach.

SU-F-T-339: Comparison Between Coplanar and Non-Coplanar RapidArc Approach of Hippocampal-Sparing Whole Brain Radiotherapy

Purpose: To compare the dosimetry of coplanar and non-coplanar RapidArc whole brain plans for hippocampal sparing Methods: We studied the RapidArc plans of patient with brain metastases, with the prescription of 3750 cGy in 15 fractions. The coplanar approach used a full clockwise (CW) arc and a full counterclockwise (CCW) arc, with the couch angle to be 0°. The non-coplanar approach used a full arc with a couch angle of 0°, and a partial arc with a couch angle of 90°. Treatment planning system is Eclipse Ver. 11. Constraints for eyes, lens, brainstem, optical nerves and chiasm are employed in the optimization so that these OARs’ dose are below tolerance. Constraints for hippocampus are employed so that they receive dose as low as possible while maintain good coverage to whole brain. The beam delivery machine is Varian 21 IX. T1-weighted MRI images were used for hippocampus contouring. Results: The target coverage index for coplanar and non-coplanar RapidArc plans are 94.9% and 95.4%, respectively, with homogeneity index of 0.223 vs 0.226, which is defined as (D2% – D98%)/Dmean of target volume. V95 and V100 are 99.0% and 94.8% for coplanar plan, vs 99.1% and 95.4% for non-coplanar plan, while the mean dose of hippocampus are 1244.5 cGy for coplanar plan vs 1212.3 cGy for non-coplanar plan. Dose for eyes, lens, optical nerves, optical chiasm and brainstem are all below tolerance. Conclusion: Coplanar RapidArc plan provides good target coverage while achieves good hippocampal sparing, and there is no benefit to use non-coplanar approach.

SU‐F‐T‐539: Dosimetric Comparison of Volumetric Modulated Arc Therapy and Intensity Modulated Radiation Therapy for Whole Brain Hippocampal Sparing Radiation Therapy Treatments

Purpose:To compare the treatment plan quality and dose gradient near the hippocampus between VMAT (RapidArc) and IMRT delivery techniques for whole brain radiation therapy.Methods:Fifteen patients were evaluated in this retrospective study. All treatments were planned on Varian Eclipse TPS, using 3‐Arc VMAT and 9‐Field IMRT, following NRG Oncology protocol NRG‐CC001 guidelines evaluated by a single radiation oncologist. Prescribed doses in all plans were 30 Gy delivered over 10 fractions normalized to a minimum of 100% of the dose covering 95% of the target volume. Identical contour sets and dose‐volume constraints following protocol guidelines were also applied in all plans. A paired t‐test analysis was used to compare VMAT and IMRT plans.Results:NRG‐CC001 protocol dose‐volume constraints were met for all VMAT and IMRT plans. For the planning target volume (PTV), the average values for D2% and D98% were 6% lower and 4% higher in VMAT than in IMRT, respectively. The average mean and maximum hippocampus doses in Gy for VMAT vs IMRT plans were (11.85±0.81 vs. 12.24±0.56, p=0.10) and (16.27±0.78 vs. 16.59±0.71, p=0.24), respectively. In VMAT, the average mean and maximum chiasm doses were 3% and 1% higher than in IMRT plans, respectively. For the left optic nerve, the average mean and maximum doses were 10% and 5% higher in VMAT than in IMRT plans, respectively. These values were 12% and 3% for the right optic nerve. The average percentage of dose gradient around the hippocampus in the 0–5mm and 5–10mm abutted regions for VMAT vs. IMRT were (4.42%±2.22% /mm vs. 3.95%±2.61% /mm, p=0.43) and (4.54%±1.50% /mm vs. 4.39%±1.28% /mm, p=0.73), respectively.Conclusion:VMAT plans can achieve higher hippocampus sparing with a faster dose fall‐off than IMRT plans. Though statistically insignificant, VMAT offers better PTV coverage with slightly higher doses to OARs.