Multiple Brain Metastases Research Articles

Narrative review of neurocognitive and quality of life tools used in brain metastases trials.

Development of brain metastases are common in patients with advanced malignancies leading to significant morbidity and mortality. Although overall survival is an important endpoint in these patients, neurocognition and health related quality of life (HRQoL) more accurately highlights the impact of the disease and its treatment on patients. Whole brain radiotherapy (WBRT) has historically played a key role in the management of these patients, especially those with multiple brain metastases. Clinical trials have supported the use of stereotactic radiosurgery (SRS) alone in patients with limited brain metastases sparing neurocognitive function and HRQoL as compared to the combination of SRS plus WBRT. Furthermore, new systemic agents are increasingly being used in clinical practice and have shown promise in patients with brain metastases. The upcoming clinical trials are tasked with defining treatment guidelines that are more specific to patient and tumour factors incorporating radiation, surgery, and systemic therapy. The validity of findings in these trials rest on the rigor of the study methodology and the utilisation of validated assessment tools for neurocognition and HRQoL. This review aims to appraise and summarise the neurocognitive and HRQoL tools used in modern brain metastases trials.

A Dutch phase III randomized multicenter trial: whole brain radiotherapy versus stereotactic radiotherapy for 4-10 brain metastases.

BackgroundThe clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases.MethodsPatients with 4–10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at 3 months post-treatment.ResultsThe study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range: 4–9) and the median total treatment volume was 13.0 cc3 (range: 1.8–25.9 cc3). QOL at 3 months decreased in the SRS group by 0.1 (SD = 0.2), compared to 0.2 (SD = 0.2) in the WBRT group (P = .23). The actuarial 1-year survival rates were 57% (SRS) and 31% (WBRT) (P = .52). The actuarial 1-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (P = .22).ConclusionIn patients with 4–10 BM, SRS alone resulted in 1-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

Oral Presentation

Oral Presentation

Stereotactic Radiosurgery Helps Patients With Multiple Brain Metastases

Stereotactic Radiosurgery Helps Patients With Multiple Brain Metastases

Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients with Brain Metastases of Melanoma: A Multiplex Whole Slide Immunofluorescence Study.

Simple SummaryThe introduction of immune-checkpoint inhibitors improved the therapeutic landscape for patients with advanced malignant melanoma. However, many patients, including patients with melanoma brain metastases, do not derive benefit from immune-checkpoint blockade. Hence, biomarkers are needed to identify potential mechanisms of resistance and optimize patient selection. This study aimed to explore the role of hypoxia-mediated immunosuppression within the tumor microenvironment of patients with metastatic melanoma using multiplex immunofluorescence. We analyzed the prognostic relevance of the hypoxia surrogate marker GLUT-1, the adenosine-synthesizing ectoenzymes CD73/CD39, and the infiltration by CD8 positive lymphocytes, and evaluated their spatial interaction within the tumor microenvironment (TME). Finally, we outlined the role of the melanoma immune phenotype for the patient’s prognosis and discussed the importance of tumor hypoxia and the adenosine system in shaping the tumor immune phenotype.Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the overall survival has been achieved for many patients with multiple brain metastases from melanoma. However, heterogeneity between individual tumor responses is incompletely understood. In order to determine the impact of the individual tumor phenotype on the prognosis of melanoma patients, we examined surgical sections from 33 patients who were treated with radiotherapy (whole-brain radiotherapy, WBRT, stereotactic radiotherapy, STX, or both) and Ipilimumab. We analyzed multiplex staining of the hypoxia marker GLUT-1, the adenosine (ADO)-associated enzymes CD73 and CD39, and CD8, a marker of cytotoxic T lymphocytes (CTL) on a single-cell basis using QuPath. Additionally, the MOSAIC interaction analysis algorithm was used to explore the hypothesis that CTL systematically avoid GLUT-1high tumor areas. Our results revealed, that a strong GLUT-1 expression, low numbers of CTL, or exclusion of CTL from the tumor were correlated with significant prognostic detriment. Hypoxic tumors overall have smaller amounts of CTL, and spatial analysis revealed a repellent effect of hypoxia on CTL. In contrast to in vitro studies, specific upregulation of ADO-related enzymes CD73 and CD39 in GLUT-1high tumor regions was never observed. In this study, we could show direct in vivo evidence for hypoxia-mediated immunosuppression in melanoma. Moreover, this study suggests a significant prognostic relevance of the tumor immune phenotype, the strength of CD8 infiltration in the tumor, and the expression of hypoxia marker GLUT-1 on melanoma cells. Last, our results suggest a temporal stability of the microenvironment-mediated immunosuppressive phenotype in melanoma.

Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy.

Simple SummaryIn non-small cell lung cancer patients with brain metastases, combined Gamma Knife radiosurgery and immunotherapy or targeted therapy showed an increase in overall survival. The combination of Gamma Knife radiosurgery and immunotherapy or targeted therapy did not increase complications related to radiosurgery. Therefore, the combined treatment seems to be a safe and powerful treatment option for non-small cell lung cancer patients with brain metastases.The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3–11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT (p < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment.

Benefit of dosimetry distribution for patients with multiple brain metastases from non-small cell lung cancer by a Cyberknife stereotactic radiosurgery (SRS) system

BackgroundIn order to obtain a high dose conformal index of tumor and steep dose fall-off in healthy tissues for brain metastasis stereotactic radiosurgery (SRS), the aim of this study was to investigate SRS planning optimization by comparing one multiple-lesions plan (MLP) with multiple single-lesion plans (SLPs) for patients with multiple brain metastases using the Cyberknife (CK) system.MethodsFifty non-small cell lung cancer (NSCLC) patients (28 males and 22 females) with 2–4 brain metastases, inter-tumour distances less than 3 cm, were retrospectively replanned with the original prescription dose (12–32 Gy) in the original fractions (1–3). Two different clinical CK SRS plans (SLPs and MLP) were generated for the same patients with the same collimator and prescription isodose line (62–68%) by the CK Multiplan System. Both SLPs and MLP were able to achieve > 95% PTV volume covered prescription dose and met the Timmerman 2011 organs at risk (brainstem, optic nerve and pituitary) constraints.ResultsCompared with those in the SLPs, the maximum dose (Dmax) and mean dose (Dmean) of brainstem in the MLP were reduced 0.22–3.13% (2.62%) and 2.71–12.56% (5.57%), respectively, all P < 0.05. Meanwhile, the volumes of the whole brain minus the tumors that received a single dose equivalent of 8–16 Gy (V8Gy-V16Gy) were effectively reduced in the MLP. The treatment time parameters, the total number of beams and monitor units, of the MLP were reduced by 3.31 and 1.47% (P < 0.05), respectively. Although there were a few differences in the conformity index (CI) and homogeneity index (HI) between the two treatment plans, the differences were not statistically significant (P = 2.94 and 1.08 > 0.05).ConclusionOne multiple-lesions plan for brain metastases could achieve higher precision in the target and lower doses in healthy tissue while shortening the treatment time and improving the treatment efficiency over multiple single-lesion plans.

Management of melanoma brain metastases: Evidence-based clinical practice guidelines by Cancer Council Australia.

The brain is a common site of metastatic disease for patients with advanced melanoma. Brain metastasis portends a poor prognosis, often causing deterioration in neurological function and quality of life, and leading to neurological death. Treatment approaches including surgery, radiotherapy and systemic therapy can lead to better control of this problem. Therefore, appropriate guidelines for the management of melanoma brain metastases need to be established, with regular updating when new treatment options become available. A multidisciplinary working party established by Cancer Council Australia has produced up-to-date, evidence-based clinical practice guidelines for the management of melanoma. After selecting key clinical questions, a comprehensive literature search for relevant studies was conducted, followed by systematic review of those studies. Data were summarised and the evidence was assessed, leading to the development of recommendations. Symptomatic lesions are best treated with surgery, when possible; this provides safe and effective local control. For patients with single or a small number of asymptomatic brain metastases, stereotactic radiotherapy is recommended, but in asymptomatic patients who have not previously received systemic treatment, drug therapy can be considered as a first-line treatment option. Whole brain radiotherapy may provide palliative benefits in patients with multiple brain metastases. Whenever possible, melanoma patients with brain metastases should be managed by a multidisciplinary team of melanoma specialists that considers the optimal combination and sequencing of surgery, radiotherapy and systemic therapy.

NIMG-03. DEEP LEARNING SURVIVAL ANALYSIS FOR MULTIPLE BRAIN METASTASES

Abstract PURPOSE Deep learning survival models show promise for outcome prediction by leveraging the ability to model non-linear relationships between pixel-level imaging predictors and survival data. We hypothesized that a deep learning survival model derived from quantitative imaging predictors would be more effective than traditional models of survival in patients with brain metastases. METHODS We analyzed 831 patients with 3596 total brain metastases treated with primary stereotactic radiosurgery at our institution between 2000-2018. The primary outcome of interest was overall survival following treatment. 851 3D radiomic features were extracted from T1 post contrast MRI images of each brain metastasis and aggregated per patient. Minimum redundancy maximum relevance was used for dimensionality reduction. Relevant features were trained on DeepSurv (Cox proportional hazard neural network architecture) to model overall survival. The disease-specific Graded Prognostic Assessment which uses age, Karnofsky performance status, presence of extracranial metastases, number of brain metastases, and disease-specific molecular characteristics was used as our traditional model. Discriminatory ability between models was assessed with concordance indices (c-index) using 100 bootstrapped samples of 415 patients and evaluated for statistical significance in difference with the 2-sample t-test. RESULTS Median overall survival was 13 months, median age was 63 years, and the most common primary sites were NSCLC (38.5%), melanoma (18.9%), breast (14.9%), SCLC (7.2%), renal (5.3%), and GI (4.7%). The deep learning model using radiomic imaging features (c-index: 0.848, 95% CI [0.811, 0.877]) had superior discriminatory ability compared to the GPA (c-index: 0.380, 95% CI [0.356, 0.403]). Performance was significantly improved with p&amp;lt; 0.001 on the 2-sample t-test. CONCLUSIONS A deep learning model using quantitative radiomic imaging features performed better than a traditional linear model using clinical predictors at modeling survival in patients with multiple brain metastases. This represents a promising method to improve prognostication for patients diagnosed with brain metastases.

Whole-Brain Radiotherapy Can Improve the Survival of Patients with Multiple Brain Metastases from Non-Small Cell Lung Cancer Treated by Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors.

ObjectiveTo observe whether whole-brain radiotherapy (WBRT) can bring survival benefits to patients with multiple brain metastases (BM) from non-small cell lung cancer (NSCLC) treated by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and determine the best time for WBRT intervention.MethodsA retrospective analysis was performed on 148 patients diagnosed with EGFR gene-mutated NSCLC. All patients had multiple BM and received EGFR-TKI targeted therapy, which was performed to observe whether WBRT can bring survival benefits, and whether the choice of WBRT timing affects the survival of patients.ResultsAmong the 148 patients with NSCLC treated with EGFR-TKI, 76 received WBRT; 72 were without WBRT. WBRT can reduce the intracranial progression rate in the patients (19.7% vs 33.3%, P=0.040), thus improving the intracranial progression-free survival (iPFS) (median iPFS: 11.9 months versus 10.2 months, P=0.039) and overall survival (OS) (median OS: 21.0 months versus 16.7 months, P=0.043). Multivariate analysis showed that WBRT (HR=0.606; 95% CI: 0.403–0.912, P=0.016) and the low Eastern Cooperative Oncology Group performance status (HR=1.884; 95% CI: 1.120–3.170, P=0.017) are independent prognostic factors in all patients. Further subgroup analysis showed that the choice of WBRT time had no effect on patient survival.ConclusionWBRT can improve the survival of patients with multiple BM from NSCLC receiving EGFR-TKI targeted therapy and is an independent prognostic factor. The choice of RT time has no effect on patient survival.

OC-0475: Cranial SRS dosimetry audits of complex treatments of multiple brain metastases

OC-0475: Cranial SRS dosimetry audits of complex treatments of multiple brain metastases

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol

BackgroundRecent evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT) as the recommended treatment option in patients with good prognosis and multiple brain metastases as this results in better neurocognitive preservation compared to whole brain radiotherapy. However, there is often poor tumour control with this technique due to the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is given to patients who have a limited number of brain metastases, delivers a higher radiation dose to the metastases resulting in better target lesion control. With improvements in radiation technology, advanced dose-painting techniques now allow a simultaneous integrated boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve brain tumour control and preserve cognitive outcomes. This technique is abbreviated to HA-SIB-WBRT or HA-WBRT+SIB.MethodsWe hypothesise that the SIB in HA-SIB-WBRT (experimental arm) will result in better tumour control compared to HA-WBRT (control arm). This may also lead to better intracranial disease control as well as functional and survival outcomes. We aim to conduct a prospective randomised phase II trial in patients who have good performance status, multiple brain metastases (4–25 lesions) and a reasonable life expectancy (> 6 months). These patients will be stratified according to the number of brain metastases and randomised between the 2 arms. We aim for a recruitment of 100 patients from a single centre over a period of 2 years. Our primary endpoint is target lesion control. These patients will be followed up over the following year and data on imaging, toxicity, quality of life, activities of daily living and cognitive measurements will be collected at set time points. The results will then be compared across the 2 arms and analysed.DiscussionPatients with brain metastases are living longer. Maintaining functional independence and intracranial disease control is thus increasingly important. Improving radiotherapy treatment techniques could provide better control and survival outcomes whilst maintaining quality of life, cognition and functional capacity. This trial will assess the benefits and possible toxicities of giving a SIB to HA-WBRT.Trial registrationClinicaltrials.gov identifier: NCT04452084. Date of registration 30th June 2020.

Automatic Detection and Segmentation of Multiple Brain Metastases on MR Images Using Simultaneous Optimized Double-UNET Architecture

Brain metastases (BM) develops in approximately one third of patients throughout their disease course and can be a major cause of morbidity and mortality if not caught and treated early. BM is commonly detected using MRI. Once diagnosed, stereotactic radiation surgery (SRS) can offer effective local control. However, BM tends to be multifocal; 80% of the diagnosed patients have more than one BM and 50% have three or more. Moreover, the size and radiological appearance of BM can be highly heterogeneous. Detecting and segmenting multiple BM thus is challenging and dependent on clinicians’ experience. Here, we aim to develop an automated BM detection and segmentation method using a novel simultaneous optimized double-UNET architecture. With an IRB approval, contrast-enhanced T1 MR images from 195 patients with multiple BM were solicited from our institutional SRS database. The BM segmentations were verified by radiation oncologists with >5 years of experience. Of all 195 patients, 1034 BMs had been manually contoured for SRS planning. The patient cohort was split into training (160 patients, 809 lesions), validation (20 patients, 136 lesions) and testing (15 patients, 89 lesions) datasets. A double 3D-UNET architecture, each with a down-sampling and an up-sampling arm, was constructed to capture the spatial information. The inputs include channel (T1 MR) and 3D volumetric image size. The double 3D-UNET was trained using two different kernels (3x3x3 and 1x1x3 respectively). The weightings of the two UNETs were optimized to achieve the best detection sensitivity on the validation set. Dice similarity coefficient [defined as DSC(S, T) = 2|S∩T| / (|S| + |T|); S and T are automatic and manual segmentation respectively] and detection sensitivity [defined as TT/(TT+TN); TT and TN are number of correctly detected and undetected BM] were used as quantitative assessment metrics. The lesions in the testing set were further divided into 3 sub-groups based on the lesion sizes (A = 1-4mm, B = 5-8mm and C = 9-26mm) for performance reporting. As a comparison, a traditional single 3D-UNET was trained and evaluated using the same datasets. In the testing dataset, there were 47, 21 and 21 BM in the A, B and C sub-groups, respectively. The numbers of undetected BM using single 3D-UNET were 28, 2 and 0 for A, B and C. The single 3D-UNET achieved sensitivity of 0.40 and 0.90, and DSC of 0.44 and 0.69 for A and B respectively. The numbers of undetected BM using our double 3D-UNET are 24, 1 and 0 for A, B and C. Our double 3D-UNET improved sensitivity to 0.49 and 0.95, and DSC to 0.49 and 0.70 for A and B. For the C sub-group with relatively larger lesions, both models achieved 100% detection sensitivity and DSC of 0.82. A double-UNET architecture was successfully constructed for automated detection and segmentation of the multiple BM on contrast enhanced T1 MR images. Preliminary results showed more pronounced improvement in hard-to-detect small BMs comparing to single 3D-UNET.

Optimal Timing And Technique Of Local Therapy For Brain Metastases From Non-Small Cell Lung Cancer With Driver Mutations

Brain metastases (BM) are frequent in non-small cell lung cancer patients with driver mutations (dm-NSCLC). Since the availability of brain-penetrating tyrosine kinase inhibitors (TKI), the role of local therapy (LT) for BM from dm-NSCLC is frequently discussed. This analysis examines prognostic factors, particularly the effect of LT timing and technique, in patients with BM from dm-NSCLC. Between 2009 and 2019, 179 patients from one institution were diagnosed with BM from dm-NSCLC and subsequently received TKI-therapy. 78.8% (n = 141) were TKI-naive and selected for analysis. 108 patients (76.6%) had Epidermal Growth Factor Receptor (EGFR) mutations with exon19 deletion most prevalent (n = 61, 56.5%); 33 (23.4%) showed translocation of the Anaplastic Lymphoma Kinase (ALK) gene. 75 patients (41.9%) presented with ≥5 BM. 87 patients (61.7%) received early LT, whereas 54 (38.3%) received delayed LT upon progression (n = 34; 24.1%) or none (n = 20; 14.2%). LT consisted of stereotactic radiosurgery (SRS) (n = 40; 34.2%) or whole brain radiotherapy (WBRT) (n = 77; 65.8%); neurosurgical resection was performed with (n = 15; 10.6%) or without (n = 4; 2.8%) post-operative radiotherapy (RT) in 19 cases. TKI treatment comprised first (n = 93; 66.0%), second (n = 31; 22.0%) or third generation substances (n = 17; 12.1%). A univariate and multivariate Cox proportional hazards model was fitted for overall survival (OS) and intracranial progression-free survival (icPFS). Median OS was 23.0 [IQR 14.6-54.5] months for all patients, 49.1 [IQR 22.7-NA] months for the ALK subgroup and 19.5 [IQR 12.8-46.3] months for the EGFR subgroup (HR 2.6, 95%CI: [1.5-4.7], p = 0.001). Median icPFS was 15.7 [8.9-26.2] months for all patients, 15.7 [10.3-26.2] months and 14.0 [7.9-22.0] months for the subgroups, respectively (HR 1.1, 95%CI: [0.6-1.8], p = 0.814). On multivariate analysis, early LT improved icPFS (HR 0.5, 95%CI: [0.3-0.9], p = 0.009) but not OS (HR 1.4, 95%CI: [0.9-2.3], p = 0.140). This effect was reproduced in independent analysis of the ALK subgroup, but not in the EGFR subgroup. Here, exon 19 deletion (HR 0.4, 95%CI: [0.2-0.8], p = 0.009) and singular BM (HR 0.4, 95%CI: [0.2-0.7], p = 0.002) were independently prognostic of longer icPFS. In the combined cohort, RT technique (SRS vs. WBRT) and number of BM did not influence icPFS or OS. In this analysis, early LT improved icPFS but not OS in TKI-naive patients with BM from dm-NSCLC, compared to upfront TKI treatment. No benefit was shown for WBRT over SRS regarding either icPFS or OS. In light of the toxicities of WBRT, the choice of RT technique should be considered carefully in the context of overall prognosis and quality of life. Especially patients presenting initially with multiple BM may benefit from delaying RT or from individualized approaches like the SRS of multiple or only selected BM instead of WBRT.

Brain Metastases Resection Cavity Radiosurgery Based Primarily on T2-weighted MRI: Technique Assessment

Stereotactic radiosurgery (SRS) is commonly performed after surgical resection of brain metastases to reduce the chance of local tumor recurrence while maintaining cognitive function. Target delineation in these cases is typically based on T1-weighted post-gadolinium MRI (T1Gd). In this study, we report outcomes for patients having postoperative SRS in which the planning target volume (PTV) was based primarily on T2-weighted MRI (T2W). Sixty-two consecutive patients having single-fraction SRS after brain metastases resection were retrospectively reviewed. Patients with prior whole brain radiation therapy, multiple resection cavities, and small cell pathologies were excluded. Local control (LC), leptomeningeal disease (LMD), distant brain recurrence (DBR), and radiation necrosis (RN) were estimated by the Kaplan-Meier method. Cox proportional hazards model was performed on tumor and treatment factors (histology, number of metastases, preoperative tumor characteristics, time from surgery to SRS, extent of resection, PTV, and margin dose) against LC, LMD, and DBR. PTV based on T1Gd was independently contoured according to consensus guidelines and classified as decreased (<90% of the T2W PTV), unchanged (90%-110% of the T2W PTV), or increased (>110% of the T2W PTV). The median preoperative tumor size was 3.3 cm (range, 1.4-5.3); the median preoperative tumor volume was 12.9 cm3 (range, 1.4-62.6). The median PTV was 8.0 cm3; the median margin dose was 18 Gy. The median time from surgery to SRS was 11 days (range, 1-49); 26 patients (42%) had SRS ≤ 7 days. The median follow-up time after SRS was 15.1 months (range, 3-57). The 1-year LC, LMD, DBR, and RN rates were 88%, 25%, 36%, and 0%, respectively. No factor was associated with LC. Sub-total tumor resection was a risk factor for LMD (Hazard ratio [HR] 5.11, 95% Confidence interval [CI] 1.52-17.22, P = 0.003), whereas patients with multiple brain metastases had a greater risk of DBR (HR 2.88, 95% CI 1.24-6.67, = 0.01). Overall, the median PTV based on T2W was smaller compared to median PTV based on the consensus guidelines utilizing T1Gd (8.0 cm3 versus 9.1 cm3, P = 0.004). PTV based on T1Gd compared to T2W was decreased in 11 patients (18%; median volume decrease, -27%), unchanged in 14 patients (23%), and increased in 37 patients (60%; median volume increase, 29%). T2W MRI could provide accurate resection cavity delineation guidance even in the early postoperative period and was associated with decreased PTV compared to T1Gd MRI in the majority of cases.

Timeline Of Hippocampal Atrophy Following Whole-Brain Radiation Therapy With And Without Hippocampus Avoidance

In the past decade, the overall survival rates of patients with cerebral metastases have significantly improved. Quality of life and, more specifically, the preservation of neurocognitive functions have thus gained increasing importance. Cognitive decline has been specifically correlated with hippocampal atrophy. The aim of this study was to depict and compare the time course of hippocampal atrophy following conventional whole-brain radiation therapy (WBRT) and hippocampus avoidance WBRT (HA-WBRT). 168 patients with cerebral metastases of solid tumors without meningeal spread, who had received WBRT or HA-WBRT between December 2003 and December 2016 were identified. Forty-six HA-WBRT and 92 WBRT patients were included, who underwent at least one three-dimensional (3D) contrast-enhanced T1-weighted magnetic resonance imaging sequence (Gd-T1MRI) before and after irradiation. HA-WBRT patients were treated analogously to the ongoing HIPPORAD-trial (DRKS00004598) protocol: HA-WBRT (30 Gy in 12 fractions, D98% to hippocampus ≤9 Gy, D2% ≤ 17 Gy) with simultaneous integrated boost (51/42 Gy in 12 fractions) on metastases/resection cavities. WBRT was mainly performed with 35 Gy in 14 fractions (43.9%) and 30 Gy in 10 fractions (30.8%). The bilateral hippocampal volume was segmented and quantified using the Computational Anatomy Toolbox (CAT12), based on 3D Gd-T1MRI sequences within 24 months before and 48 months after therapy. Surgical resections, pre- and post-irradiations were taken into account. The statistical analysis of the non-linear time course of hippocampal atrophy was performed with R (Version 3.4.4) using a Generalized Additive Mixed Model (GAMM), with “time” and “irradiation group” (WBRT versus HA-WBRT) as variables of interest and by modelling patients and scanners as random effects. Variability arising from interindividual differences such as age, sex and total brain volume was statistically controlled for. A total of 922 Gd-T1MRI sequences were analyzed. By evaluating the time course of hippocampal atrophy in the interval between 24 months before and 48 months after radiation therapy, the results revealed a significant hippocampal volume decrease across time after both WBRT and HA-WBRT (p < 10-16). However, the atrophy across time was significantly lower in the HA-WBRT group compared to the WBRT group as indicated by a significant interaction of irradiation group by time (p < .006). HA-WBRT is a therapeutic option for patients with multiple brain metastases, which can effectively and durably minimize the extent of irradiation-induced hippocampal atrophy compared to conventional WBRT. Considering this effect, HA-WBRT with simultaneous integrated boost has the potential to prevent neurocognitive adverse effects, which will be further evaluated in the multicentric phase II HIPPORAD-trial.

Institutional Outcomes of Whole Brain Radiotherapy for Metastatic Melanoma Brain Metastases

e14504Background: The management of melanoma with multiple brain metastases (MBM) is complex given improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (W...

Preserving Neurocognition Without Compromising Tumor Control During Whole-Brain Radiotherapy Therapy In Patients With Numerous Brain Metastases Via A Novel Superoxide Dismutase Mimetic: Initial Safety Lead-In And Design Of A Clinical Trial

Patients with a large number of brain metastases (BM) present a clinical challenge. While stereotactic radiosurgery (SRS) has extended the number of BM that can be effectively treated, SRS does not treat occult disease and distant brain failure (DBF) post-SRS remains high. In contrast, whole-brain radiotherapy (WBRT) provides high rates of local control and, compared to SRS, reduces the risk of distant brain failure. Unfortunately, WBRT is also associated with substantial neurocognitive deficits, even with hippocampal avoidance, altered fractionation and neuroprotectants. BMX-001, a novel Mn-porphyrin superoxide dismutase mimetic, has been shown to protect normal tissues from ionizing radiation in preclinical trials, reducing neurocognitive adverse effects, as well as enhancing tumor response. We hypothesized that this agent would reduce neurocognitive decline while possibly improving tumor control in patients with numerous brain metastases undergoing WBRT. This protocol is composed of a lead-in safety study of 5 patients followed by a randomized Phase 2 clinical trial of BMX-001, in 64 patients with multiple brain metastases (MBM) undergoing WBRT. Eligible patients are adults with more than 10 brain metastases, a KPS of >60 and a life expectancy >3 months. All patients will undergo WBRT to a total dose of 30 Gy in 3 Gy daily fractions. Patients in the safety lead-in study and the BMX-001 cohort of the randomized trial will receive a loading dose of this agent immediately prior to starting WBRT, then a maintenance dose twice weekly during WBRT and once within 4 days of completing WBRT. Primary endpoint is change in neurocognition, as measured by Trailmaking, Hopkins Verbal Learning and Controlled Oral Word Association tests pre and post WBRT. Secondary endpoints include overall survival, quality of life, toxicity, local recurrence, distant brain failure, neurologic death and radionecrosis. The safety lead-in portion of this trial was completed in August 2019. All 5 patients completed WBRT and BMX-001 per protocol. The majority of subjects experienced Grade 1 non-hematologic AEs, primarily injection site reactions (including erythema, itching, welts, bruising around injection sites); 1 patient experienced a Grade 2 QT prolongation. No severe toxicities (Grade 3), life-threatening toxicities (Grade 4), or treatment related deaths (Grade 5) were reported. Initial post-WBRT brain MR imaging showed at least a partial tumor response. The randomized clinical trial is now open at multiple institutions. It appears reasonable to proceed with the randomized clinical trial of WBRT +/- BMX-001 in patients with numerous brain metastases. Enrollment on this trial is essential to test the hypothesis that this agent is an effective neuroprotectant.

Whole Brain Radiotherapy vs. Stereotactic Radiotherapy for 4-10 Brain Metastases: A Prematurely Closed Dutch Phase III Randomized Multicenter Trial

Background: Since publication of the QUARTZ trial, the clinical value of whole brain radiotherapy (WBRT) for brain metastases is a matter of debate due to significant side effects. In order to avoid these side effects and to improve local tumor control, stereotactic radiosurgery (SRS) is an attractive treatment option. We have initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS alone than after WBRT in patients with newly diagnosed multiple brain metastases. Methods: Patients with 4 up to 10 brain metastases (BM) were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). Primary endpoint was difference in quality of life (QOL) at three months after radiotherapy compared to baseline (EQ5D5L EUROQOL score). Findings: The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized between July 2016 and May 2018, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions per patient was 6 (range, 4-9) and the median total treatment volume was 13.0 cc 3 (range, 1.8-25.9 cc 3 ). QOL at three months decreased in the SRS group with 0.1 (SD=0.2), compared to 0.2 (SD=0.2) in the WBRT group (p=0.23).The actuarial one year survival was 57% (SRS) and 31% (WBRT) (p=0.52). The actuarial one year brain salvage free survival was 50% (SRS) and 78% (WBRT) (p=0.22). Interpretation: In patients with 4 up to 10 BM, SRS alone resulted in one-year survival in 57% of patients while maintaining quality of life. Due to premature closure of the trial, no statistical significant differences could be determined between SRS alone and WBRT in the investigated endpoints. Trial Registration: NCT02353000 Funding Statement: Varian Medical Systems, the Dutch technology Foundation STW, and Kankeronderzoekfonds Limburg. Declaration of Interests: No competing interests to declare. Ethics Approval Statement: All patients willing to participate gave written informed consent. The study protocol was approved by the medical ethical committee of the Maastricht University Medical Center, The Netherlands.

Concurrent Apatinib and Brain Radiotherapy in Patients With Brain Metastases From Driver Mutation-negative Non–small-cell Lung Cancer: Study Protocol for an Open-label Randomized Controlled Trial

Brain radiotherapy (BR) is a well-recognized approach for multiple brain metastases (BMs) from non–small-cell lung cancer (NSCLC). However, the prognosis for these patients remains poor. Apatinib, an antiangiogenic agent targeting vascular endothelial growth factor receptor-2, has shown excellent efficacy in multiple solid tumors. This phase II (WWW. ClinicalTrials.gov Identifier: VEGFR-2 NCT03801200) randomized trial aims to evaluate the efficacy and safety of this combined modality paradigm in patients with BMs from driver mutation-negative NSCLC. This is a multicenter, open-label, randomized controlled clinical trial. A total of 90 eligible patients will be allocated in a 1:1 ratio, to either the experimental group (concurrent apatinib and BR) or the control group (BR alone). The primary endpoint is intracranial progression-free survival. The secondary endpoints include intracranial objective response rate, intracranial disease control rate, intracranial time to progression, overall survival, and occurrence of peritumoral brain edema using standardized measurement. Quality of life and adverse events will also be evaluated. Assessments will be carried out before enrollment (baseline) along with 4 and 12 weeks after radiotherapy, followed by every 12 weeks thereafter and up to 24 months. In summary, the aim of this trial is to demonstrate the clinical efficacy and safety of concurrent BR and apatinib in patients with driver mutation-negative NSCLC with multiple BMs, in efforts to expand management options for this population with poor prognosis.