Hippocampal Avoidance Whole Brain Radiation Research Articles

Hippocampal sparing in whole-brain radiotherapy for brain metastases: controversy, technology and the future.

Whole-brain radiotherapy (WBRT) plays an irreplaceable role in the treatment of brain metastases (BMs), but cognitive decline after WBRT seriously affects patients' quality of life. The development of cognitive dysfunction is closely related to hippocampal injury, but standardized criteria for predicting hippocampal injury and dose limits for hippocampal protection have not yet been developed. This review systematically reviews the clinical efficacy of hippocampal avoidance - WBRT (HA-WBRT), the controversy over dose limits, common methods and characteristics of hippocampal imaging and segmentation, differences in hippocampal protection by common radiotherapy (RT) techniques, and the application of artificial intelligence (AI) and radiomic techniques for hippocampal protection. In the future, the application of new techniques and methods can improve the consistency of hippocampal dose limit determination and the prediction of the occurrence of cognitive dysfunction in WBRT patients, avoiding the occurrence of cognitive dysfunction in patients and thus benefiting more patients with BMs.

Dosimetric comparison of helical tomotherapy and volumetric modulated arc therapy in hippocampal avoidance whole-brain radiotherapy.

This study aimed to discuss the dosimetric advantages of helical tomotherapy (HT) and volumetric modulated arc therapy (VMAT) technology in hippocampal avoidance whole-brain radiotherapy and provide references for clinical selection of ideal radiotherapy technology. A total of 20 patients with hippocampal avoidance whole-brain radiotherapy were chosen randomly. Computed tomography (CT) and MRI scanning images were input into the treatment planning system (TPS). After the CT and enhanced magnetic resonance T1 weighted images were fused and registered, the same radiation therapy physician was invited to outline the tumor target volume. PTV-HS refers to the whole brain subtracted by 5mm outward expansion of the hippocampus (HP). The prescribed dose was 30Gy/10 fractions. HT and VMAT plans were designed for each patient in accordance with PTV. Under the premise that the 95% isodose curve covers the PTV, dose-volume histogram was applied to evaluate the PTV, conformal index (CI), heterogeneity index (HI), maximum dose (Dmax), mean dose (Dmean), minimum dose (Dmin) and absorbed doses of organs at risk (OARs) in HT and VMAT plans. Paired t-test was performed to compare the differences between two radiation therapy plans, and p < 0.05 was considered statistically significant. These two plans had no significant difference in PTV-HS (max, min, and mean). However, the HI and CI of the HT plan were significantly better than those of the VMAT plan, showing statistically significant difference (p<0.05). The HT plan was significantly superior to the VMAT plan in terms of the Dmax, Dmin, and Dmean of HP, left and right eye lens, left and right eye, and spinal cord, showing statistically significant difference (p<0.05). The HT plan was also better than the VMAT plan in terms of the Dmax of the left optic nerve. However, the two plans showed no obvious differences in terms of the absorbed doses of the right optic nerve and brainstem, without statistical significance. Compared with the VMAT plan of hippocampal avoidance, HT technology has significant dosimetric advantages. HT plans significantly decreased the radiation dose and radiation volume of OARs surrounding the target area (e.g., surrounding eye lens and eye, especially hippocampal avoidance area) while increasing the CI and HI of PTV dose in whole brain radiotherapy (WBRT) greatly, thus enabling the decrease in the incidence rate of radioactive nerve function impairment.

Feasibility of flattening filter free beams for hippocampal avoidance whole-brain radiotherapy: a dosimetric and radiobiological analysis

Feasibility of flattening filter free beams for hippocampal avoidance whole-brain radiotherapy: a dosimetric and radiobiological analysis

RADT-03. A CASE OF PARTIAL HIPPOCAMPAL-AVOIDANCE WHOLE BRAIN RADIOTHERAPY IN A PATIENT WITH METASTATIC INFILTRATION OF THE LEFT HIPPOCAMPUS

Abstract In addition to surgical resection and systemic therapy, whole brain radiotherapy (WBRT) is a crucial modality in the treatment of cancers that have metastasized to the brain. It has been shown to improve intracranial disease control and overall survival. However, WBRT also increases the risk of radiation-associated damage to sensitive structures like the hippocampus, often resulting in neurocognitive dysfunction and decline. Hippocampal avoidance WBRT (HAWBRT) has been shown to reduce neurocognitive sequalae without worsening survival outcomes or increasing the risk of metastasis to the spared region compared to conventional WBRT. In cases where both hippocampi cannot be completely spared, the effectiveness of partial hippocampal avoidance on neurocognitive function and tumor control have been poorly described. We present the case of a patient diagnosed with triple negative invasive ductal carcinoma of the breast and disease metastatic to the brain, lung, bones, adrenal glands, and liver. Brain imaging revealed multiple brain metastases, two of which were noted near the left hippocampus. The patient underwent partial HAWBRT with complete avoidance of the right hippocampus and partial avoidance of the left. At 1-year follow-up, there was no evidence of metastasis in or near the partially spared left hippocampus. The patient’s neurocognitive functional status remained consistent with the findings of prospective randomized trials in which total bilateral hippocampal sparing was performed. To our knowledge, no such case has been presented in the literature. Further studies assessing the role of partial hippocampal avoidance in WBRT are needed.

Treatment of Central Nervous System Tumors on Combination MR-Linear Accelerators: Review of Current Practice and Future Directions.

Magnetic resonance imaging (MRI) provides excellent visualization of central nervous system (CNS) tumors due to its superior soft tissue contrast. Magnetic resonance-guided radiotherapy (MRgRT) has historically been limited to use in the initial treatment planning stage due to cost and feasibility. MRI-guided linear accelerators (MRLs) allow clinicians to visualize tumors and organs at risk (OARs) directly before and during treatment, a process known as online MRgRT. This novel system permits adaptive treatment planning based on anatomical changes to ensure accurate dose delivery to the tumor while minimizing unnecessary toxicity to healthy tissue. These advancements are critical to treatment adaptation in the brain and spinal cord, where both preliminary MRI and daily CT guidance have typically had limited benefit. In this narrative review, we investigate the application of online MRgRT in the treatment of various CNS malignancies and any relevant ongoing clinical trials. Imaging of glioblastoma patients has shown significant changes in the gross tumor volume over a standard course of chemoradiotherapy. The use of adaptive online MRgRT in these patients demonstrated reduced target volumes with cavity shrinkage and a resulting reduction in radiation dose to uninvolved tissue. Dosimetric feasibility studies have shown MRL-guided stereotactic radiotherapy (SRT) for intracranial and spine tumors to have potential dosimetric advantages and reduced morbidity compared with conventional linear accelerators. Similarly, dosimetric feasibility studies have shown promise in hippocampal avoidance whole brain radiotherapy (HA-WBRT). Next, we explore the potential of MRL-based multiparametric MRI (mpMRI) and genomically informed radiotherapy to treat CNS disease with cutting-edge precision. Lastly, we explore the challenges of treating CNS malignancies and special limitations MRL systems face.

Hippocampal Avoidance Whole Brain Radiotherapy with Reduced Whole Brain Dose in Patients with Non-Small Cell Lung Cancer Brain Metastases

Hippocampal avoidance whole brain radiation (HA-WBRT) results in improved neurocognitive function (NCF) compared to standard WBRT, but > 50% of patients still experience NCF failure. We examined whether gentler fractionation of HA-WBRT with lower biologically effective dose (BED), typically delivering 30 Gy over 15 versus 10 fractions, may allow for better hippocampal sparing without impacting intracranial disease control in patients with non-small cell lung cancer (NSCLC). We conducted a retrospective study of patients with NSCLC receiving HA-WBRT between 2014-2022. Endpoints were distant brain failure free survival (DBFFS), local brain failure free survival (LBFFS), left and right hippocampal mean BED2 and BED21%. Kaplan-Meier survival analysis and Welch's t-test were performed. NCF outcomes were graded with CTCAEv5. The IRB approved this study. Sixty-nine consecutive patients treated with HA-WBRT were included, with median follow up of 51.2 weeks. Median age was 63 years and 29% had a targetable mutation. Thirty-six patients received standard HA-WBRT with median dose of 30 Gy (range 30-35 Gy) in 10 fractions (range 10-14). Thirty-three patients received reduced BED HA-WBRT, with median dose of 30 Gy (range 23-30) in 15 fractions (range 9-15) to the radiographically uninvolved brain. All patients in the reduced BED (RD) group had a simultaneous integrated boost (SIB) to gross disease (median 37.5 Gy (range 36-37.5 Gy)), while 18/36 in the standard dose (SD) group had an SIB (median 35 Gy (range 34-39 Gy)). There were no significant differences between SD and RD cohorts in age, systemic therapy use before WBRT or targetable mutations. There was no significant difference in median DBFFS of the SD [23.1 weeks (IQR 11.3-49.3)] and RD groups [40 weeks, (IQR 20.9-109.1)] (p = 0.27). There was also no difference in LBFFS of the SD (median 26.4 weeks, IQR 11.3-76.2) and RD groups (median 40 weeks, IQR (21-71.4) (p = 0.84). For the left and right hippocampi, both mean BED2 and D1% were significantly lower in the RD group (Table 1). Median cognitive disturbance was Grade (G) 0 (range 0-3) in both groups, with 4 G>2 events in the SD cohort vs. 3 in the RD cohort. In this single-institution cohort, HA-WBRT using a gentler fractionation with SIB was associated with improved hippocampal sparing without compromising intracranial control in patients with NSCLC. We suggest that further optimization of HA-WBRT dose and schedule may improve both intracranial control and NCF outcomes. This study is limited by its retrospective nature and potential selection bias. A phase II prospective study to test these concepts is ongoing.

Comparison of Hippocampal Volume Change after Whole-Brain Radiotherapy with and without Hippocampal Avoidance: A Post-Hoc Analysis of a Phase II Randomized Trial

Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) preserves verbal memory compared to conformal WBRT in the previously reported randomized phase II clinical trial. In the present study, we analyzed the changes in hippocampus volume between groups at longitudinal follow-up time points. We hypothesize better preservation of hippocampus volumes with time in the HA-WBRT group. In this post-hoc analysis of a single institution, single-blind, randomized phase II trial, patients with brain metastases were randomized to receive either HA-WBRT or conformal WBRT with 30 Gy in 10 fractions. Patients received gadolinium contrast-enhanced MRI every three months or when clinically indicated after WBRT until progression. Only patients with at least one follow-up MRI were included. The MRI was used to assess baseline intracranial volume, hippocampal volume, the ratio of the total hippocampus to total intracranial volume (HT%), and the ratio of the left (HL%) or right (HR%) hippocampus to total intracranial volume. The volumes were automatically calculated by volBrain, an online MRI brain volumetry system. We used linear mixed models with fixed and random effects to compare the changes of repeated measures of the hippocampus volumes over time between the two groups. Among 70 randomized patients, 51 (25 in the HA-WBRT group and 26 in the WBRT group) were included in the present analysis. There were no significant differences between the two groups in the baseline demographics, HT%, HR%, and HL%. The median follow-up time was 13.9 months (range 2.1-31.8 months), and more than 60% of patients had at least one year of follow-up. Linear mixed model analyses showed a more significant decrease of HT% over time in the WBRT arm (regression coefficient β = -0.002, p = 0.001) compared to the HA-WBRT arm (regression coefficient, β = -0.001, p = 0.254), with a significant group by time interaction (F-value = 4.27, p = 0.050). The HL% was stable over time in the HA-WBRT arm (β = 0.0001, p = 0.769) while it decreased in the WBRT arm (β = -0.001, p = 0.003), with a significant group by time interaction (F-value = 6.51, p = 0.015). In contrast, the HR% decreased over time in both groups (HA-WBRT: regression coefficient β = -0.001, p = 0.006; WBRT: regression coefficient β = -0.001, p < 0.001) without significant group by time interaction (F-value = 0.20, p = 0.662). HA-WBRT better preserves total hippocampus volume with time compared to WBRT, with the main effect contributed by preserving the left hippocampus volume. Further research is warranted to establish the relationship between hippocampus volume perpetuation and cognitive function preservation. The future goal is to investigate whether left-side unilateral HA-WBRT provides similar neurocognitive function preservation compared to standard bilateral HA-WBRT.

A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiotherapy Using Diagnostic MR-Based and Online Adaptive Planning

We aimed to demonstrate the clinical feasibility and safety of a simulation-free hippocampal avoidance whole brain radiotherapy (HA-WBRT) workflow in a Phase I clinical trial (NCT05096286). Feasibility was defined as successful completion of the simulation-free HA-WBRT workflow through treatment delivery in at last 70% of treated patients. Ten candidates for HA-WBRT were enrolled for treatment on a ring gantry CT-guided Linac with online adaptive capabilities. Structures were contoured on the diagnostic brain MRI, which was then registered to a separate head computed tomography (CT) of similar head shape, obtained from an atlas-based database. A HA-WBRT "pre-plan" was generated using the atlas-based CT (AB-CT) and the NRG-CC001 constraints. At first fraction, the AB-CT was used as the primary dataset and deformed to the patient's cone-beam CT (CBCT) for dose calculation. The brain, ventricles, and brainstem contours were matched through rigid translation and rotation to the corresponding anatomy on the CBCT to aid in alignment, given the differences in rotational head positioning from diagnostic MRI to CBCT setup. Lastly, the lens, optic nerves, and brain contours were manually edited based on CBCT visualization. Plans were then optimized, and the adaptive plan was chosen for treatment if the plan met all objectives. Workflow tasks were timed. In addition, conventional plans using patients' sim CTs were created for each patient for the purpose of prospective dosimetric comparison. The dosimetric parameters were compared for each patient between the delivered sim-free plan and the conventional sim CT plan using the sign test via statistical software, with p<.05 indicating significance. Median time from approved sim order to first fraction was 4 days (range: 2-7); median time in room (door-to-door) was 49 minutes (range: 35-70). All patients successfully completed all ten fractions and 90% of the simulation-free radiation plans met all NRG-CC001 constraints. For one patient, the sim-free plan at fraction one failed the planning target volume (PTV) coverage objective (coverage of 89%); this was deemed acceptable for delivery by the treating radiation oncologist. An offline replan was then performed to meet NRG-CC001 constraints and used for the subsequent nine fractions. There was no clinically meaningful difference in dosimetric constraints between the sim-free plan (calculated on AB-CT) and conventional CT sim plan. Statistically, the sim-free plans provided improved PTV coverage to higher doses compared to the conventional plans (Table). At a median follow-up of 43 days (range: 9 -280), the intracranial progression-free survival rate was 90%. Simulation-free HA-WBRT is feasible, results in plans that are dosimetrically comparable to conventional CT sim workflows and succeeds in decreasing time to initiation of HA-WBRT by at least 50%. Further studies with a larger cohort are warranted to optimize the workflow.

Application of a Novel Methodology for Efficient Optimization of Hippocampal Avoidance Whole-Brain Radiotherapy

A growing awareness of the long-term neurocognitive toxicity associated with whole-brain radiotherapy (WBRT) has led to the development of newer delivery methods to achieve relative hippocampal sparing. In order to accomplish the required target coverage and dose constraints, however, hippocampal-avoidance WBRT (HA-WBRT) can prove labor intensive and time-consuming. We therefore developed a simplified and efficient planning model for generating optimized HA-WBRT treatment. Target volumes and organs at risk (OARs) were contoured per the NRG-CC001 protocol, including the whole-brain parenchyma, bilateral hippocampi, and optic apparatus. Treatment was planned using Eclipse 16.1 for a TrueBeam STx 2.7 LINAC, applying customizable optimization and clinical goals templates to rapidly generate uniform plans. An isocenter was placed at the point corresponding to the center of mass between the bilateral contoured 3-dimensional hippocampi. Volumetric modulated arc therapy (VMAT) using 6MV photons was designed using two sets of bi-directional full arcs, with collimator rotations of 85° and 95°. The two paired sets independently covered the superior and inferior portions of the treatment volume, respectively. Arcs shared a total 2cm overlap in the superior-inferior (X Jaws) direction. A total of 10 consecutive cases of HA-WBRT were retrospectively re-optimized using the described planning model. All plans were normalized to cover 95% of the treatment volume with prescription dose (V30Gy = 95%). The model achieved favorable dosimetry relative to NRG-CC001 per protocol constraints. Average maximal dose to the hottest 2% and minimal dose to 98% of the volume were 32.22 ± 0.26 Gy and 29.82 ± 1.46 Gy, well within protocol limits of 37.5 Gy and 25 Gy, respectively. The average maximal dose to 100% of the hippocampi (D100%) and to its hottest 0.03cc (Dmax) were 8.50 ± 0.34 Gy and 12.85 ± 0.70 Gy, compared to protocol limits of 9Gy and 16Gy, respectively. Mean Dmax to the total optic apparatus was 29.67 ± 0.52 Gy, with a maximum value within the cohort of 30 Gy, matching protocol constraints. The above presented methodology for optimizing HA-WBRT can consistently and efficiently generate plans with excellent target coverage and strict hippocampal avoidance per current collaborative group constraints. This method can be broadly applied to decrease the burden and heterogeneity across HA-WBRT planning.

Advancing beyond the Hippocampus to Preserve Cognition for Patients with Brain Metastases: Dosimetric Results from a Phase 2 Trial of Memory-Avoidance Whole Brain Radiotherapy

Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery (SRS), hippocampal avoidance whole brain radiation therapy (HA-WBRT), and memantine administration. However, 23% of patients receiving HA-WBRT and memantine on NRG-CC001 still experienced executive function deterioration at 4 months, with 12% experiencing total recall and delayed recognition deterioration at 6 months. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using an advanced "memory-avoidance" WBRT (MA-WBRT) approach sparing these substructures for patients with multiple (>15) brain metastases. Ten consecutive patients treated with MA-WBRT on a phase 2 clinical trial (OSU-21074) were reviewed. In each patient, the hippocampi, amygdalae, corpus callosa, and fornix were contoured. Patients were not eligible for MA-WBRT if they had metastases in these substructures. A memory- avoidance region created using a 5mm volumetric expansion around these substructures. Hotspots were avoided in the hypothalamus and pituitary gland. Dose constraints for these avoidance structures were modeled after NRG CC-001 and include a D100% ≤ 9 Gy and a D0.03 cc ≤ 16 (acceptable to 20 Gy). Coverage of brain metastases was prioritized over memory avoidance dose constraints. Linac-based volumetric modulated arc therapy (VMAT) plans were generated for a prescription dose of 30 Gy in 10 fractions. On average, the memory avoidance structure volume was 37.1 ccs (Range: 25.2-44.6 ccs), occupying 2.5% of the entire whole brain target volume. All treatment plans met the D100% dose constraint, and 8/10 plans met the D0.03cc constraint, with priority given to tumor coverage for the remaining 2 cases. VMAT spared the memory avoidance structures with a median dose range of 10.8-14.2 Gy and a maximum dose (D0.03cc) range of 15.6-22.7 Gy. The mean dose to the memory avoidance structures was 12.7 Gy (Range: 11.5-13.8 Gy). Target coverage (D98% > 25 Gy) and homogeneity (D2% ≤ 37.5 Gy) were achieved for all plans. Modern VMAT techniques allow for sparing of the hippocampus, amygdala, corpus callosum, and fornix with good target coverage and homogeneity. Prospective quality of life and cognitive data including are being collected and include the Functional Assessment of Cancer Therapy - Brain (Fact-Br), Hopkins Verbal Learning Test (HLVT-R), Trail Making Test A/B (TMT-A/B) and Controlled Oral Word Association Test (COWAT). After enrollment is completed, these data will be evaluated to assess the efficacy of MA-WBRT to mitigate declines in quality of life and cognition after whole brain radiation.

Hippocampal avoidance whole brain radiotherapy in brain metastasis using volumetric modulated arc therapy: experience from a Regional Cancer Centre of Eastern India.

Whole-brain radiotherapy is associated with neurocognitive decline and decreased quality-of-life (QOL) among survivors of brain metastasis. Hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) has shown advantage in delaying or preventing the neurocognitive decline while maintaining disease control. This study was done to assess the benefits and feasibility of HA-WBRT in patients with cerebral metastasis in terms of preservation of neurocognitive function and quality of life. 27 patients with brain metastasis treated by HA-WBRT and having the records of detailed neurocognitive-assessments were analysed from the database of our hospital. The patients were treated with HA-WBRT to a total dose of 30 Gy in 10 fractions with LINAC based IMRT using the VMAT technique. Cognitive function assessment was carried out using "Examination of the Cognitive Functions" scale provided by Bangur-Institute-of-Neurosciences, Kolkata, 2 weeks prior to radiotherapy and post-treatment two-monthly up to 6 months followed by every 3 months till the last follow up. QOL was assessed at the same interval using the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR). Follow-up was done till the date of death. Mean relative cognitive decline percentage decreased over subsequent follow-up visits and was 13% (SD ± 6%), 5% (SD ± 5%), 5% (SD ± 9%) and 2% (SD ± 12%) at 2 months, 6 months, 9 months and 12 months, respectively (p ≤ 0.05). Statistically significant improvement was seen in the mean social-wellbeing (SWB) parameter of QOL (8%. ± 13%, 12%. ± 16%, 7%. ± 20%, no change at 2 months, 4 months, 6 months and 9 months, respectively) (p ≤ 0.05). Mean relative decline in the Emotional-Well Being (EWB) parameter was significant only at 12 months and was 20% (SD ± 35%) (p = 0.04). Mean FACT-BR total Score showed a slight decrease till 9 months from baseline, and then showed a slight improvement up to 12 months. HA-WBRT is feasible with LINAC-based IMRT using the VMAT technique and beneficial to the patients in preserving neurocognitive function and quality of life without compromising disease control.

TIPS-06 ADVANCING BEYOND THE HIPPOCAMPUS TO PRESERVE COGNITION FOR PATIENTS WITH BRAIN METASTASES: DOSIMETRIC RESULTS FROM A PHASE 2 TRIAL OF MEMORY-AVOIDANCE WHOLE BRAIN RADIOTHERAPY

Abstract Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery (SRS), hippocampal avoidance whole brain radiation therapy (HA-WBRT), and memantine administration. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using a “memory-avoidance” WBRT (MA-WBRT) approach that spares these substructures for patients with &amp;gt;15 brain metastases. Ten consecutive patients treated with MA-WBRT on a phase 2 clinical trial were reviewed. In each patient, the hippocampi, amygdalae, corpus callosum, and fornix were contoured. Patients were not eligible for MA-WBRT if they had metastases in these substructures. A memory- avoidance region created using a 5mm volumetric expansion around these substructures. Hotspots were avoided in the hypothalamus and pituitary gland. Coverage of brain metastases was prioritized over memory avoidance dose constraints. Dose constraints for these avoidance structures included a D100% ≤ 9Gy and D0.03cc ≤ 16Gy (variation acceptable to 20Gy). LINAC-based volumetric modulated arc therapy (VMAT) plans were generated for a prescription dose of 30 Gy in 10 fractions. On average, the memory avoidance structure volume was 37.1 ccs (Range: 25.2-44.6 ccs), occupying 2.5% of the entire whole brain target volume. All treatment plans met the D100% dose constraint, and 8/10 plans met the D0.03cc constraint, with priority given to tumor coverage for the remaining 2 cases. Target coverage (D98% &amp;gt;25Gy) and homogeneity (D2% ≤ 37.5Gy) were achieved for all plans. Modern VMAT techniques allow for sparing of the hippocampus, amygdala, corpus callosum, and fornix with good target coverage and homogeneity. After enrollment is completed, quality of life and cognitive data will be evaluated to assess the efficacy of MA-WBRT to mitigate declines in quality of life and cognition after whole brain radiation.

A simplified non-coplanar volumetric modulated arc therapy for the whole brain radiotherapy with hippocampus avoidance.

To evaluate the feasibility of using a simplified non-coplanar volumetric modulated arc therapy (NC-VMAT) and investigate its dosimetric advantages compared with intensity modulated radiation therapy (IMRT) and coplanar volumetric modulated arc therapy (C-VMAT) for hippocampal-avoidance whole brain radiation therapy (HA-WBRT). Ten patients with brain metastase (BM) were included for HA-WBRT. Three treatment plans were generated for each case using IMRT, C-VMAT, and NC-VMAT, respectively. The dosimetric results of the three techniques complied roughly with the RTOG 0933 criteria. After dose normalization, the V30Gy of whole brain planned target volume (WB-PTV) in all the plans was controlled at 95%. Homogeneity index (HI) of WB-PTV was significantly reduced in NC-VMAT (0.249 ± 0.017) over IMRT (0.265 ± 0.020, p=0.005) and C-VMAT (0.261 ± 0.014, p=0.020). In terms of conformity index (CI), NC-VMAT could provide a value of 0.821 ± 0.010, which was significantly superior to IMRT (0.788 ± 0.019, p<0.001). According to D2% of WB-PTV, NC-VMAT could provide a value of 35.62 ± 0.37Gy, significantly superior to IMRT (36.43 ± 0.65Gy, p<0.001). According to D50% of WB-PTV, NC-VMAT can achieve the lowest value of 33.18 ± 0.29Gy, significantly different from IMRT (33.47 ± 0.43, p=0.034) and C-VMAT (33.58 ± 0.37, p=0.006). Regarding D2%, D98%, and Dmean of hippocampus, NC-VMAT could control them at 15.57 ± 0.18Gy, 8.37 ± 0.26Gy and 11.71 ± 0.48Gy, respectively. D2% and Dmean of hippocampus for NC-VMAT was significantly lower than IMRT (D2%: 16.07 ± 0.29Gy, p=0.001 Dmean: 12.18 ± 0.33Gy, p<0.001) and C-VMAT (D2%: 15.92 ± 0.37Gy, p=0.009 Dmean: 12.21 ± 0.54Gy, p<0.001). For other organs-at-risk (OARs), according to D2% of the right optic nerves and the right lenses, NC-VMAT had the lowest values of 31.86 ± 1.11Gy and 7.15 ± 0.31Gy, respectively, which were statistically different from the other two techniques. For other organs including eyes and optic chiasm, NC-VMAT could achieve the lowest doses, different from IMRT statistically. The dosimetry of the three techniques for HA-WBRT could roughly comply with the proposals from RTOG 0933. After dose normalization (D95%=30Gy), NC-VMAT could significantly improve dose homogeneity and reduce the D50% in the brain. Besides, it can reduce the D2% of the hippocampus, optic nerves, and lens. With this approach, an efficient and straightforward plan was accomplished.

Precision Radiation for Brain Metastases With a Focus on Hypofractionated Stereotactic Radiosurgery

There are multiple published randomized controlled trials supporting single-fraction stereotactic radiosurgery (SF-SRS) for patients presenting with 1 to 4 brain metastases, with the benefit of minimizing radiation-induced neurocognitive sequelae as compared to whole brain radiotherapy . More recently, the dogma of SF-SRS as the only means of delivering an SRS treatment has been challenged by hypofractionated SRS (HF-SRS). The ability to deliver 25-35 Gy in 3-5 HF-SRS fractions is a direct consequence of the evolution of radiation technologies to allow image guidance, specialized treatment planning, robotic delivery and/or patient positioning corrections in all 6 degrees-of-freedom, and frameless head immobilization. The intent is to mitigate the potentially devastating complication of radiation necrosis and improve rates of local control for larger metastases. This narrative review provides an overview of outcomes specific to HF-SRS in addition to the more recent developments of staged SRS, preoperative SRS, and hippocampal avoidance-whole brain radiotherapy with simultaneous integrated boost.

Retrospective analysis of dosimetry on hippocampal-avoidance whole-brain radiotherapy in a regional hospital

Retrospective analysis of dosimetry on hippocampal-avoidance whole-brain radiotherapy in a regional hospital

Evaluating Pareto optimal tradeoffs for hippocampal avoidance whole brain radiotherapy with knowledge-based multicriteria optimization.

The goal of this study is to investigate the Pareto optimal tradeoffs between target coverage and hippocampal sparing using knowledge-based multicriteria optimization (MCO). Ten prior clinical cases were selected that were treated with hippocampal avoidance whole brain radiotherapy (HA-WBRT) using VMAT. A new, balanced plan was generated for each case using an in-house RapidPlan model in the Eclipse V16.1 treatment planning system. The MCO decision support tool was used to create 4 Pareto optimal plans. The Pareto optimal plans were created using PTV Dmin and hippocampus Dmax as tradeoff criteria. The tradeoff plans were generated for each patient by adjusting PTV Dmin from the value achieved by the corresponding balanced plan in fixed intervals as follows: -4 Gy, -2 Gy, +2 Gy, and +4Gy. All plans were normalized so that 95% of the PTV was covered by the prescription dose. A 1-way ANOVA, with Geisser-Greenhouse correction, was used for statistical analysis. When evaluating the achieved PTV Dmin and D98%, the results showed the dose to the hippocampus decreased as coverage lowered and in comparison, D98% was higher when the PTV coverage was increased. When comparing multiple tradeoffs, the p-value for PTV D98% was 0.0026, and the p-values for PTV D2%, PTV Dmin, Hippocampus Dmax, Dmin, and Dmean were all less than 0.0001, indicating that the tradeoff plans achieved statistically significant differences. The results also showed that Pareto optimal plans failed to reduce hippocampal dose beyond a certain point, indicating more limited achievability of the MCO-navigated plans than the interface suggested. This study presents valuable data for planning results for HA-WBRT using MCO. MCO has shown to be mostly effective in adjusting the tradeoff between PTV coverage and hippocampal dose.

Hippocampal avoidance whole brain radiotherapy: developing a RapidPlan model

Background: Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) has emerged as an approach to retain intracranial tumour control while minimizing cognitive decline. However, the contouring and planning requirements are more complex and time consuming compared to standard WBRT. RapidPlan is an automated treatment planning software that is designed to increase planning efficiency whilst maintaining plan quality. Our group developed an automated HA-WBRT RapidPlan model (Auto) and compared it to a manually optimised standard template (Manual) to assess plan quality and planning efficiency.

Cost-effectiveness analysis of 3 radiation treatment strategies for patients with multiple brain metastases.

Patients diagnosed with multiple brain metastases often survive for less than 2 years, and clinicians must carefully evaluate the impact of interventions on quality of life. Three types of radiation treatment are widely accepted for patients with multiple brain metastases: Whole brain radiation therapy (WBRT), hippocampal avoidance whole-brain radiation therapy (HA-WBRT), and stereotactic radiosurgery (SRS). WBRT, the standard option, is less costly than its newer alternatives but causes more severe adverse effects such as memory loss. To determine whether the cost-effectiveness ratio of HA-WBRT and SRS are superior to WBRT, we used published data to simulate cases of multiple brain metastases. We designed a Markov model using data from previously published studies to simulate the disease course of patients with 5 to 15 brain metastases and determine the cost-effectiveness of HA-WBRT and SRS relative to WBRT. Incremental cost-effectiveness ratios (ICERs) were calculated and compared against a willingness-to-pay threshold of $100 000 per quality-adjusted life year. SRS met the threshold for cost-effectiveness, with ICERs ranging $41 198-$54 852 for patients with 5 to 15 brain metastases; however, HA-WBRT was not cost-effective, with an ICER of $163 915 for all simulated patients. Model results were robust to sensitivity analyses. We propose that SRS, but not HA-WBRT, should be offered to patients with multiple brain metastases as a treatment alternative to standard WBRT. Incorporating these findings into clinical practice will help promote patient-centered care and decrease national healthcare expenditures, thereby addressing issues around health equity and access to care.

In-Silico Trial of Simulation-Free Hippocampal-Avoidance Whole Brain Radiotherapy Using Diagnostic MRI-Based and Online Adaptive Planning

<h3>Purpose/Objective(s)</h3> Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) has been shown to better preserve cognitive function with no difference in intracranial progression-free and overall survival. One limiting factor for its wider implementation is the plan complexity and considerably longer planning time required. We hypothesized that, <i>in silico,</i> a simulation-free workflow using diagnostic magnetic resonance (MR)-based radiation planning and online adaptation to account for differences in head position would expedite time to HA-WBRT delivery without compromising plan quality. <h3>Materials/Methods</h3> Seven patients treated for brain tumors who had cone beam computed tomography (CBCT) imaging available that sufficiently visualized the brainstem and ventricles were selected for this <i>in silico</i> study. Structures were contoured on the diagnostic brain MR, and a baseline HA-WBRT plan was generated. Then, to mimic simulation-free first fraction treatment, contours were transferred onto a daily setup CBCT for each patient. Within a commercially available, CT-based adaptive platform, contours were manually adjusted for anatomical differences; differences in head tilt between the diagnostic brain MR and CBCT were accounted for by triangulating with the brainstem, ventricles, and cranium and by online adaptation. Constraints were based on CC-001 protocol. Workflow tasks were timed, and baseline and adapted plans were compared using paired t-test on statistical software. <h3>Results</h3> All plans required adaptation at first fraction to account for head tilt differences and to meet constraints. An adaptive hippocampal avoidance planning template was applied to each patient with no modifications resulting in all objectives being met in the initial plan and adaptive plan. Structures that benefitted the most from first-fraction adaptation included hippocampi and optic chiasm; 71% and 57% of cases, respectively, required adaptation to meet constraints at first fraction. On pairwise comparison, there was a significant improvement in all dosimetric parameters for target coverage and with limiting hotspots in the hippocampal avoidance zone after adaptation (<i>p≤</i> .02); planning target volume (PTV) coverage increased by a median of 5% (IQR: 4%). Median duration of tasks was as follows: structure propagation and alignment on CBCT (8.5 min); contour adjustment (22.4 min); dose calculation (12.4 min); plan evaluation (0.9 min); total process time was 44.2 min. <h3>Conclusion</h3> Simulation-free HA-WBRT plans were successfully created using diagnostic brain MR imaging and first-fraction online adaptation to account for positional differences between diagnostic and on-table imaging. A Phase I clinical trial (NCT05096286) evaluating the feasibility and safety of simulation-free HA-WBRT using this methodology is underway.

Predictors of Radiation Necrosis and Dose/Volume Tolerance of the Brain after Three-Fraction Radiosurgery for Brain Metastases: A Large Single-Institutional Analysis

<h3>Purpose/Objective(s)</h3> Stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) is the current standard of care in patients with brain metastases and controlled extracranial disease. Radiation necrosis (RN) is the dose-limiting side-effect of SRS but the dose constraints are poorly defined. FSRT can decrease risk of RN over SRS while maintaining or improving high rates of overall survival (OS). We assessed the survival and risk of RN after FSRT with a goal to identify specific dose/volume constraints associated with grade 3 or higher RN using NTCP modeling. <h3>Materials/Methods</h3> A single-institutional retrospective review of patients treated with 3-fraction FSRT from 2015 to 2020 was performed. Tissue volume (brain + target) around each target lesion was contoured in a consistent manner and volumetric doses per lesion were recorded. RN was defined using biopsy or MRI with perfusion as available and graded using CTCAE version 5.0. Our primary endpoint was grade 3 or higher RN. All statistical analyses were performed using statistical software. <h3>Results</h3> From 2015 to 2020, a total of 439 patients underwent 509 courses of 3-fraction Linac-based FSRT, treating a total of 2394 metastatic lesions (range 1-71, mean = 4.7 and median = 3 lesions per course). 61 patients had ≥10 and 31 patients had ≥15 lesions treated per course. Median RT dose per fraction was 8 Gy (range 5-9 Gy). 11.8% patients received prior whole brain radiation (WBRT). Median follow-up after RT was 8 months (IQR 3-18m). A total of 64 patients (78 lesions) developed RN with 17, 17, 29 and 1 patients developing grade 1, 2, 3 and 4 RN respectively. Grade 3 or higher RN was observed in 5.9% patients. On per lesion analysis, rate of any RN and grade 3 RN was 3.2% and 1.5% respectively. Median time to RN was 11.3m (range 0.7 – 38.4). Of 30 patients with grade 3 or higher RN, 7 (23%) received prior WBRT, 19 (63%) received post-op FSRT to the cavity and 1 (3%) received pre-op FSRT. Most of these patients were managed by steroids, while 25 underwent resection and 6 received bevacizumab. Tissue volume receiving 20 Gy (V20) of <20cc or >20 cc was associated with 2.5% and 10.2% risk of RN respectively, while a V23 of <20 cc or >20 cc was associated with 2.3% vs 12.1% risk of grade 3 or higher RN. Mean V20 in patients who developed Grade 3 or higher RN was statistically higher than the entire cohort (36.9cc vs 14.1cc, p=0.002). Median OS after RT was 10m (1yr and 2yr OS of 45.8% and 30.4%, respectively) while patients who developed RN survived longer compared to rest of the cohort (32m vs 8m, p <0.001). Patients with 15 or more lesions treated per course had similar survival compared to rest of the cohort (8m vs 10m, p = 0.136), after excluding those who received prior WBRT. <h3>Conclusion</h3> In patients receiving 3 fraction FSRT, grade 3 or higher RN was seen in 5.9% patients and 1.5% lesions treated. Risk of RN was significantly lower in patients with V23 of <20 cc. Further studies evaluating the outcomes and RN in patients treated with FSRT compared to SRS or hippocampal avoidance WBRT are warranted.