Hippocampal Avoidance Whole Brain Radiation Research Articles

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.

CLRM-12 TITLE: STEREOTACTIC RADIOSURGERY (ADJUVANT OR NEOADJUVANT) COMPARED TO HIPPOCAMPAL AVOIDANCE WHOLE BRAIN RADIATION THERAPY WITH SIMULTANEOUS INTEGRATED BOOST FOR LIMITED BRAIN METASTASES (SRS-CHART): PHASE III OPEN-LABEL PARALLEL-GROUP RANDOMIZED CONTROLLED TRIAL

BACKGROUNDSurgery is indicated for large or symptomatic lesions in patients with limited brain metastasis (BM), followed by adjuvant stereotactic radiosurgery (A-SRS) to the cavity. Emerging evidence suggests promising role of neoadjuvant SRS (NA-SRS) before surgery with potentially lesser risk of leptomeningeal disease (LMD) and radionecrosis (RN). Hippocampal avoidance whole brain radiotherapy (HA-WBRT) results in better neurocognitive outcomes than standard WBRT, and use of simultaneous integrated boost (SIB) to surgical cavity can improve the local control. Absence of high-quality evidence forms the basis of current study comparing these three treatment strategies. OBJECTIVESPrimary endpoint is 1-year event-free survival (EFS) a composite endpoint comprising any local failure, LMD, DBF, symptomatic RN, or death as events. Other endpoints include individual endpoints and longitudinal neuro-cognitive function and quality-of-life assessment. METHODSTarget population includes adults with newly diagnosed BM (≤3 lesions) with life expectancy >1 year and one target lesion needing surgery. Patients will be randomized (1:1:1) to A-SRS (control arm) or one of two test arms (NA-SRS or HA-WBRT-SIB). In A-SRS arm, patients will receive single fraction (16-20Gy) or hypofractionated-SRS (24-27Gy/3 fractions or 30-32.5Gy/5 fractions) based on volume and location of cavity and other intact BM. In the test arms, patients will be allocated to either NA-SRS group (single/multi-fraction) followed by surgery within 2 weeks or HA-WBRT (30Gy/10 fractions) with SIB to cavity plus other intact BM (40-50Gy/10 fractions) combined with memantine within 6 weeks of surgery. A sample size of 168 patients is required to prove the superiority of test arms individually compared to the control arm with assumption of 1-year EFS of 43% versus 25% with a hazard ratio of 0.6 (two-sided alpha=0.05, power=80%, and 15% attrition rate). DISCUSSIONThe study will generate level 1 evidence investigating the role of NA-SRS or HA-WBRT-SIB compared to A-SRS in limited brain metastases.

Hippocampal Metastasis Rate Based on Non-Small Lung Cancer TNM Stage and Molecular Markers.

Hippocampal-avoidance whole-brain radiation therapy (HA-WBRT) is justified because of low hippocampal brain metastases (BM) rate and its prevention of cognitive decline. However, we hypothesize that the risk of developing BM in the hippocampal-avoidance region (HAR) may differ depending on the lung-cancer stage and molecular status. We retrospectively reviewed 123 patients with non-small cell lung cancer (NSCLC) at the initial diagnosis of BM. The number of BMs within the HAR (5 mm expansion) was counted. The cohort was divided into patients with and without BMs in the HAR, and their clinical variables, TNM stage, and epidermal growth factor receptor (EGFR) status were compared. The most influential variable predicting BMs in the HAR was determined using multi-variable logistic regression, classification and regression tree (CART) analyses, and gradient boosting method (GBM). The feasibility of HAR expansion was tested using generalized estimating equation marginal model. Patients with BMs in the HAR were more frequently non-smokers, and more likely to have extra-cranial metastases and EGFR mutations (p<0.05). Multi-variable analysis revealed that extra-cranial metastases were independently associated with the presence of BM in the HAR (odds ratio=8.75, p=0.04). CART analysis and GBM revealed that the existence of extra-cranial metastasis was the most influential variable predicting BM occurrence in the HAR (variable importance: 23% and relative influence: 37.38). The estmated BM incidence of patients without extra-cranial metastases in th extended HAR (7.5-mm and 10-mm expansion) did not differ significantly from that in the conventional HAR. In conclusion, NSCLC patients with extra-cranial metastases were more likely to have BMs in the HAR than those without extra-cranial metastases.

Perihippocampal failure after hippocampal-avoidance whole-brain radiotherapy in cancer patients with brain metastases: Results of a retrospective analysis.

Perihippocampal failure is a rare clinical scenario in brain metastatic cancer patients following hippocampal-avoidance (HA) whole-brain radiotherapy (HA-WBRT). The clinical features have not been fully identified because clinical data on intracranial failure after HA-WBRT are limited. It is thus necessary to accumulate clinical data.We retrospectively analyzed cancer patients with brain metastases who were diagnosed between January 2014 and September 2020 at a regional referral hospital. The medical records of patients who underwent HA-WBRT were reviewed. The clinical features of intracranial recurrence were described. Dosimetry parameters were compared in terms of deviation from the recommended protocol of the Radiation Therapy Oncology Report 0933.Twenty-four eligible patients with brain metastases who underwent HA-WBRT were identified; 13 (54%) were male. Seventeen patients (71%) had lung cancer, 6 (25%) had breast cancer, and 1 (4%) had liver cancer. The median overall survival was 12 months. Three patients developed intracranial failure during clinical follow-up, and 2 relapsed with intracranial failure in the perihippocampal region at 13 and 22 months, respectively. The perihippocampal failure rate was about 8%. One patient with small cell lung cancer received HA-prophylactic cranial irradiation; the minimum and maximum doses to the hippocampi were 6.8 and 10.7 Gy, respectively. Another patient with brain metastases from lung adenocarcinoma received HA-WBRT; the minimum and maximum doses to the hippocampi were 5.4 and 10.6 Gy, respectively.We reported unusual cases of intracranial failure in the perihippocampal region following HA-WBRT. Perihippocampal failure could be attributed to an under-dose of radiation partially or be resulted from aggressiveness of cancer per se. Further research on this topic is encouraged.

Practice Patterns Related to Mitigation of Neurocognitive Decline in Patients Receiving Whole Brain Radiation Therapy

PurposeWhole brain radiation therapy (WBRT) is often used as an effective treatment for patients with brain metastasis, although it is also known to have deleterious cognitive effects. Multiple trials have identified strategies to help mitigate neurocognitive decline after WBRT, although there may be barriers to integrating these techniques into routine clinical practice. The aim of this study was to characterize national practice patterns related to neurocognitive preservation strategies used during WBRT. Methods and MaterialsWe conducted an online survey of all American Society for Radiation Oncology-registered radiation oncologists (ROs), excluding trainees, regarding their practice patterns and attitudes toward employing memantine and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Pearson χ2 tests for categorical variables or Student t tests for continuous variables were used to assess associations between provider characteristics and prescribing of either memantine or HA. All statistical tests were 2-sided and a P value <.05 was considered statistically significant. ResultsAmong 4408 ROs invited to participate, 417 (9.5%) completed the survey. Among respondents, 79.6% reported having offered memantine, 72.7% HA-WBRT, and 63.1% both for any of their patients undergoing WBRT. Common reasons for not offering memantine included limitations of current evidence (35.3%) and concerns about adverse effects (22.4%). Common reasons for not offering HA-WBRT included resource-intensive treatment planning and treatment delay (43.9%) and concern about obtaining prior authorization (38.6%). ROs with fewer years in practice (mean 15.7 vs 23.4 years) were more likely to prescribe memantine (P < .001), whereas HA was more likely prescribed by central nervous system specialists (P < .001) and ROs in academic settings (P = .04). ConclusionsOur survey suggests that the majority of respondents offer approaches for neurocognitive preservation during WBRT for their patients. Further efforts are needed to broaden education and reduce barriers among ROs to improve implementation of neurocognitive-sparing techniques in patients undergoing WBRT.

Effect of the simulated half leaf width of a multileaf collimator on volumetric modulated arc therapy plan quality in hippocampal avoidance whole-brain radiotherapy.

PurposeWhole‐brain radiotherapy (WBRT) is commonly used in patients with multiple brain metastases. Compared with conventional WBRT, hippocampal avoidance WBRT (HA‐WBRT) more favorably preserves cognitive function and the quality of life. The hippocampal volume is considerably small (approximately 3.3 cm3). Therefore, downsizing the leaf width of a multileaf collimator (MLC) may provide higher spatial resolution and better plan quality. Volumetric modulated arc therapy (VMAT) could simulate the half MLC leaf width through couch shifting between arcs. This study investigated changes in VMAT quality for HA‐WBRT with a simulated fine MLC leaf width.MethodsWe included 18 patients with brain metastasis. All target and avoidance structures were contoured by an experienced radiation oncologist. The prescribed dose was 30 Gy in 10 fractions. For each patient, three different treatment plans were generated for comparison: VMAT with couch‐shift, VMAT without couch‐shift, and TomoTherapy. All treatment plans fulfilled Radiation Therapy Oncology Group (RTOG) 0933 criteria for HA‐WBRT. The Wilcoxon paired signed‐rank test was used to compare different treatment plans.ResultsVMAT with couch‐shift had the better average conformity index (0.823) with statistically significant difference compared to VMAT without couch‐shift (0.810). VMAT with couch‐shift (0.219) had a more favorable average homogeneity index (HI) than did VMAT without couch‐shift (0.230), although the difference was not significant. TomoTherapy had an optimal average HI of 0.070. In terms of the hippocampus, all three treatment plans met the RTOG 0933 criteria. VMAT with couch‐shift had a lower average D max (15.2 Gy) than did VMAT without couch‐shift (15.3 Gy, p = 0.071) and TomoTherapy (15.5 Gy, p = 0.133). The average D 100% of hippocampus was the same for both VMAT with and without couch‐shift (8.5 Gy); however, TomoTherapy had a lower average D 100% value of 7.9 Gy. The treatment delivery time was similar between VMAT with and without couch‐shift (average, 375.0 and 369.6 s, respectively). TomoTherapy required a long average delivery time of 1489.9 s.ConclusionThe plan quality of VMAT for HA‐WBRT was improved by using the couch‐shift technique to simulate the half MLC leaf width. However, the improvement was not statistically significant except conformity index. The downsizing effect decreased with the use of the sophisticated grade of VMAT. TomoTherapy offered superior plan quality but required the longest delivery time.

The Risk of Hippocampal Metastasis and the Associated High-Risk Factors in 411 Patients With Brain Metastases

Background and AimsTo retrospectively analyze the incidence of hippocampal metastasis and the associated high-risk factors in patients with brain metastases and evaluate the safety of hippocampal avoidance whole-brain radiation therapy (HA-WBRT).MethodsWe retrospectively analyzed the data of patients with brain metastases diagnosed by contrast-enhanced cranial Magnetic resonance imaging (MRI) at the First Hospital of Lanzhou University from 2017 to 2020. The boundaries of the hippocampus, hippocampus + 5 mm area, hippocampus + 10 mm area, and hippocampus + 20 mm area were delineated, and the distances from the brain metastases to the hippocampus were measured. Univariate and multivariate logistic regressions were adopted to analyze the high-risk factors of hippocampal metastasis.ResultsA total of 3,375 brain metastases in 411 patients were included in the analysis. The metastasis rates in the hippocampus and surrounding areas of the entire group were as follows: 7.3% (30/411) in the hippocampus, 16.5% (68/411) in the hippocampus + 5 mm area, 23.8% (98/411) in the hippocampus + 10 mm area, and 36.5% (150/411) in the hippocampus + 20 mm area. Univariate logistic regression showed that the pathological type, the number of metastases, the maximum diameter of metastases, and the volume of brain metastases were all correlated with hippocampal metastasis. Multivariate logistic regression showed that the pathological type, the number of metastases, and the total volume of metastases were correlated with hippocampal metastasis.ConclusionThe pathological type, the number of metastases, and the total volume of metastases are the high-risk factors associated with hippocampal metastasis. Small cell lung cancer (SCLC) has a significantly higher rate of hippocampal metastasis than other tumor types. The greater the number and total volume of metastases, the more likely the hippocampal metastasis. For patients with SCLC or a greater number and total volume of brain metastases, the implementation of HA-WBRT may bring a higher risk of tumor recurrence.

Automatic one-click planning for hippocampal-avoidance whole-brain irradiation in RayStation.

This study aimed to verify the accuracy of auto-contouring and auto-dose optimization for hippocampal-avoidance whole-brain radiation therapy (HA-WBRT). Head computed tomography (CT) images of 15 patients were selected. The regions of interest, containing the brain, hippocampus, eyes, and lacrimal glands, were contoured manually and automatically on CT images. They were compared and evaluated for concordance rates using the Simpson coefficient. To verify the performance of dose optimization, auto-dose planning was compared with manual planning for 15 cases. All optimization plans were performed using the volumetric modulated arc therapy technique. The automatically contoured brain showed a very high concordance rate with the manually contoured brain; the Simpson coefficient was 0.990 ± 0.01. Contrastingly, the concordance rate of the hippocampal contour was low at 0.642 ± 0.15 (right) and 0.500 ± 0.16 (left); however, the rate improved to 0.871 ± 0.09 (right) and 0.852 ± 0.11 (left) with an additional 3-mm margin. For 2% of each planning target volume with the prescribed dose (D2%) and Dmean, there was no significant difference between the automatic and manual plans (35.50 Gy vs 35.23 Gy; p = 0.233 and 33.09 Gy vs 32.84 Gy; p = 0.073, respectively). The D98% was significantly better for the manual plan than for the automatic plan (25.49 Gy vs 26.11 Gy; p < 0.01). Dmax and D100% for the hippocampus did not show any significant difference between the automatic and manual plans (15.65, 16.09 Gy (right, left) vs 15.51, 15.80 Gy; p = 0.804, 0.233 and 8.08, 8.03 Gy vs 8.13, 8.01 Gy; p = 0.495, 1 respectively). The accuracy of auto-contouring for HA-WBRT can be guaranteed by providing an appropriate margin, and the precision of the auto-dose optimization was comparable to that of the manual plan.

Clinical evaluation of RTOG-atlas based contouring, MRI-atlas auto-contouring, and neuroradiologist contouring of the hippocampi for hippocampal avoidance whole-brain radiotherapy

Helen Lo, Patrick Estoesta, Elizabeth Claridge Mackonis, Regina Tse, Georgia Harris, Louise Van Camp, Ee Siang Choong

Erratum to: Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial

Erratum to: Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial

Innovations in radiotherapy and advances in immunotherapy for the treatment of brain metastases.

Radiotherapy for brain metastases has evolved tremendously over the past four decades, allowing for improved intracranial control of disease with reduced neurotoxicity. The main technological advance was provided by volumetric modulated arc therapy (VMAT), a computer-controlled delivery method that has opened the door for single-isocenter multi-metastases stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Other notable advances have occurred in the combination of immune checkpoint inhibitors (ICI) and radiosurgery. When these two modalities are combined in the proper sequence (within 30days from each other), it provides promising results in the treatment of intracranial metastases from melanoma. There is emerging evidence of a synergistic interaction between ICI and SRS, providing better intracranial tumor control and lengthening the survival of patients afflicted by this common complication of cancer.

The Effect of Hippocampal Avoidance Whole Brain Radiotherapy on the Preservation of Long-Term Neurocognitive Function in Non-Small Cell Lung Cancer Patients With Brain Metastasis.

Whole-brain radiotherapy (WBRT) is the mainstay of therapy in treating cancer patients with brain metastases, but unfortunately, it might also lead to decline in neurocognitive function. This study aims to investigate the preservation of long-term neurocognitive function in patients after hippocampal avoidance whole-brain radiotherapy (HA-WBRT). Retrospectively, 47 patients diagnosed with brain metastases of non-small cell lung cancer (NSCLC) between 2015-01-01 and 2017-12-31 at the Department of Oncology, XXX Hospital were selected and divided into 2 groups. Group A (n = 27) received HA-WBRT, whereas group B (n = 20) received WBRT. Neurocognitive function was analyzed at baseline and at 3, 6, 9, 12 and 24 months after radiotherapy, using Mine-Mental State Examination (MMSE) scales and Montreal Cognitive Assessment (MoCA) scales. The OS, PFS and tumor recurrence sites were also analyzed. When evaluated at 12 and 24 months after radiotherapy, the cognitive function scores of the hippocampal avoidance group were significantly higher than those of the non-hippocampal avoidance group (P < 0.001). In terms of patient survival, there was no significant difference in OS (P = 0.2) and PFS (P = 0.18) between these 2 groups. Fourteen patients in group A and 12 patients in group B had brain tumor recurrence after radiation, only one patient in group A occurred within 5 mm from the edge of the hippocampus (P > 0.05). In conclusion, HA-WBRT might have a protective effect on long-term neurocognitive function and did not affect patient survival.

Complete response of leptomeningeal carcinomatosis secondary to breast cancer

Leptomeningeal carcinomatosis (LC) is an unmet medical need associated with death in 4–6 weeks without treatment, delayed by 4 months in some patients with favorable prognosis and aggressive multimodal therapy. Unfortunately, most clinical trials excluded patients with LC, and the best management remains unknown.Here we present the first report of a LC secondary to HR positive breast cancer with a complete response to CDK4/6 inhibitors abemaciclib, letrozole and hippocampal-avoidance whole-brain radiotherapy.

Steep Dose-response Relationship between Maximum Hippocampal Dose and Memory Deficits following Hippocampal Avoidance Whole Brain Radiation Therapy (HA-WBRT) for Brain Metastases: A Secondary Analysis of NRG/RTOG 0933

NRG/RTOG 0933 was a phase II study suggesting that HA-WBRT for brain metastases may help to preserve cognitive function. However, hippocampal dose constraints in clinical trials conducted to date have been driven predominantly by feasibility of sparing while maintaining adequate coverage of the at-risk areas, as the radiation tolerance of the hippocampus remains uncertain. The purpose of this study was to perform an analysis of hippocampal radiation dose-volume effects and memory decline following HA-WBRT using a prospectively collected multi-institutional dataset. 113 patients received HA-WBRT on RTOG 0933. All patients received 30 Gy in 10 fractions. Memory was measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) and Total Recall (TR) at baseline and 6 months after radiation. Dose–volume histograms (DVH) were generated for the composite bilateral hippocampi. Dose–response data were fitted to a nonlinear model for D100%, D50%, and Dmax to the bilateral hippocampi. The primary endpoint was memory decline, measured by HVLT-R DR and TR at baseline and 6 months after completion of radiation therapy. The Reliable Change Index (RCI) was used to measure a clinically meaningful decline between baseline and 6 months for HVLT-R DR and TR, defined as a raw score change greater than or equal to 3. Models were also repeated using an RCI threshold raw change score of greater than or equal to 5. Evaluations of statistical significance used the Fisher Exact Test. 27 patients had complete DVH data available in addition to both baseline and 6-month cognitive testing. D100% was per protocol (≤9 Gy) in all cases. Dmax was per protocol (≤16 Gy) in 23 cases, had an acceptable variation (≤17 Gy) in 3 cases and an unacceptable deviation (20 Gy) in 1 case. There was a steep dose-response relationship between higher maximum dose to the bilateral hippocampi and deterioration in short-term memory using a raw score change greater than or equal to 3. For example, a Dmax = 14Gy was associated with a 10% risk and Dmax = 16Gy was associated with a 25% risk (underpowered, p = 0.139). When evaluating for a raw score change of greater than or equal to 5, there was a steep dose-response for Dmax and deterioration in short term memory according to both HVLT-DR and TR, and a significant relationship between maximum dose to the bilateral hippocampi and performance on HVLT-TR (p = 0.028). These data demonstrate a steep dose relationship between maximum dose to the bilateral hippocampi and deterioration in short term memory, even amongst patients who met hippocampal constraints according to the protocol, suggesting that tighter constraints may be beneficial. Future investigations with larger sample sizes will be important to confirm these findings.

Semi-Automated Hippocampal Sparing Avoidance Whole-Brain Radiotherapy Using a Commercially Available Artificial Intelligence Toolkit

Hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) plus memantine has been proven to better preserve cognitive function in brain metastasis patients receiving WBRT. Recent results from the phase III trial NRG Oncology CC001 have shown HA-WBRT plus memantine can reduce cognitive deterioration without affecting intracranial progression free survival (PFS) or overall survival (OS), and should be considered standard of care for patients without metastases in the hippocampi. However, treatment planning techniques that are capable of reducing dose to the hippocampi typically involve inverse planning techniques (IMRT/VMAT) that require an extended planning timeline when compared to the prior standard of care using 2D planning. This timeline could be significantly reduced by leveraging available semi-automated planning algorithms. The purpose of this work was to evaluate the feasibility of using an artificial intelligence (AI)-assisted, commercially available, semi-automated planning algorithm for HA-WBRT. Six de-identified patients previously treated at our institution with HA-WBRT using VMAT were re-planned using a commercial, semi-automated treatment planning system workflow. Treatment plans were generated to deliver 30 Gy in 10 fractions, using target coverage and normal tissue constraints from NRG Oncology CC001. The clinical goals template was first iteratively optimized to generate plans that were comparable to the clinical VMAT plan and compliant with NRG CC001 using a single patient dataset. This same template was then used to automatically generate plans for the remaining 5 datasets. The semi-automated system generates five different plans for comparison that include a 5, 9 and 12-field IMRT plan, as well as a 2 and 3-arc VMAT plan. The automatically generated treatment plans were reviewed and compared with the previously delivered clinical VMAT plans. The automatically generated 9-field IMRT field consistently respected all NRG CC001 constraints and was chosen as the best plan for all six datasets. All constraints (or their acceptable variations) were met for all six datasets without any intervention. PTV_3000 coverage was comparable or slightly improved compared to clinical plans. On average, V30Gy for PTV_3000 was 0.7% higher (93.8% vs 93.1%) and D98% was 0.9 Gy higher (25.9 Gy vs 25.0 Gy), while D2% was reduced by 1.2 Gy (33.0 Gy vs 34.2 Gy). The dose to the hippocampi was increased but still within NRG CC001 constraints, with D0.03cc 1.6 Gy higher (14.6 Gy vs 12.9 Gy) and D100% 0.4 Gy higher (8.5 Gy vs 8.1 Gy). Dose to the optic nerves and optic chiasm was consistently reduced by an average of 2.5 Gy (31.9 Gy vs 29.3 Gy). A commercially available, semi-automated workflow aided by AI can generate comparable HA-WBRT plans as traditional inverse planning techniques while reducing the planning time. Further optimization can improve plan quality and reduce planning time to aid the widespread adoption of HA-WBRT.

Feasibility of hippocampal avoidance whole brain radiation in patients with hippocampal involvement: Data from a prospective study

PurposeAmong patients with brain metastases, hippocampal avoidance whole brain radiation (HA-WBRT) preserves neurocognitive function relative to conventional WBRT but the feasibility of hippocampal sparing in patients with metastases in/near the hippocampus is unknown. We identified the incidence of hippocampal/perihippocampal metastases and evaluated the feasibility of HA-WBRT in such patients. Materials/MethodsDosimetric data from 34 patients randomized to HA-WBRT (30 Gy/10 fractions) in a phase III trial (NCT03075072) comparing HA-WBRT to stereotactic radiation in patients with 5 to 20 brain metastases were analyzed. Patients with metastases in/near the hippocampi received HA-WBRT with prioritization of tumor coverage over hippocampal avoidance. Target coverage and hippocampal sparing metrics were compared between patients with targets in/near the hippocampus versus not. ResultsIn total, 9 of 34 (26%) patients had targets in the hippocampus and an additional 5 of 34 (15%) patients had targets in the hippocampal avoidance zone (HAZ, hippocampus plus 5 mm expansion) but outside the hippocampus. Patients with targets within the hippocampus and those with targets in the HAZ but outside the hippocampus were spared 34% and 73% of the ipsilateral mean biologically equivalent prescription dose, respectively. Of the latter cohort, 88% and 25% met conventional hippocampal sparing metrics of Dmin ≤ 9 Gy and Dmax ≤ 16 Gy, respectively. Among 11 patients with unilateral hippocampal/perihippocampal involvement, the uninvolved/contralateral hippocampus was limited to Dmin ≤ 9 Gy and Dmax ≤ 17 Gy in all cases. ConclusionsIn this study, a substantial percentage of patients with 5 to 20 brain metastases harbored metastases in/near the hippocampus. In such cases, minimizing hippocampal dose while providing tumor coverage was feasible and may translate to neurocognitive protection.

Preservation of long-term neurocognitive function by hippocampal avoidance whole-brain radiotherapy in patients with brain metastases.

124 Background: To investigate the preservation of long-term neurocognitive function in patients after hippocampal avoidance whole-brain radiotherapy (HA-WBRT). Methods: For the retrospective analysis, 50 patients diagnosed with brain metastases were selected and divided into two groups from 2015-01-01 to 2017-12-31 at the Department of Oncology, Jiangsu Subei People's Hospital. Group A (n=27) was hippocampal avoidance whole-brain radiotherapy group; group B (n=23) was whole brain radiation therapy (WBRT) group. Neurocognitive function was statistically analyzed at 3, 6, 9, 12, and 24 months after radiotherapy, as scored by the MMSE (Mine-Mental State Examination) scales and the MoCA (Montreal Cognitive Assessment) scales. The OS, PFS and tumor recurrence sites of the two groups was also analyzed. Results: After 12, 24 months after radiotherapy, there was a significant difference between the two groups. The cognitive function of the hippocampal protection group was significantly higher than that of the non-hippocampal protection group (P&lt;0.05). There was no significant difference in OS (P=0.2) and PFS (P=0.18) between the two groups. 14 patents in group A and 12 patents in group B had brain tumor recurrence after radiation, only one patient in group A occurred 5 mm within the edge of the hippocampus (P&gt;0.05). Conclusions: First, HA-WBRT has a protective effect on long-term neurocognitive function. Second, there was no statistically significant different on OS and PFS in patients who underwent HA-WBRT or WBRT. Third, HA-WBRT didn’t increase the risk of brain tumor recurrence within the edge of the hippocampus.