Cystic Brain Metastasis Outcomes After Gamma Knife Radiation Therapy.

Purpose: The response of cystic brain metastases (BMets) to radiation therapy is poorly understood, with conflicting results regarding local control, overall survival, and treatment-related toxicity. This study aims to examine the role of Gamma Knife (GK) in managing cystic BMets. Methods and Materials: Volumetric analysis was conducted to measure tumor and edema volume at the time of GK and follow-up magnetic resonance imaging studies. Survival was described using the Kaplan-Meier method, and the cumulative incidence of progression was described using the Aalen-Johansen estimator. We evaluated the association of 4 variables with survival using Cox regression analysis. Results: Between 2016 and 2021, 54 patients with 83 cystic BMets were treated with GK at our institution. Lung cancer was the most common pathology (51.9%), followed by breast cancer (13.0%). The mean target volume was 2.7 cm3 (range, 0.1-39.0 cm3), and the mean edema volume was 13.9 cm3 (range, 0-165.5 cm3). The median prescription dose of single-fraction and fractionated GK was 20 Gy (range, 14-27.5 Gy). With a median follow-up of 8.9 months, the median survival time (MST) was 11.1 months, and the 1-year local control rate was 75.9%. Gamma Knife was associated with decreased tumor and edema volumes over time, although 68.5% of patients required steroids after GK. Patients whose tumors grew beyond baseline after GK received significantly more whole-brain radiation therapy (WBRT) before GK than those whose tumors declined after GK. Higher age at diagnosis of BMets and pre-GK systemic therapy were associated with worse survival, with an MST of 7.8 months in patients who received it compared with 23.3 months in those who did not. Conclusions: Pre-GK WBRT may select for BMets with increased radioresistance. This study highlights the ability of GK to control cystic BMets with the cost of high posttreatment steroid use.

A Prospective Registry Study of 68Ga-DOTATATE PET/CT Incorporation Into Treatment Planning of Intracranial Meningiomas.

PURPOSE: The current standard for meningioma treatment planning involves magnetic resonance imaging-based guidance. Somatostatin receptor ligands such as 68Ga-DOTATATE are being explored for meningioma treatment planning due to near-universal expression of somatostatin receptors 1 and 2 in meningioma tissue. We hypothesized that 68Ga-DOTATATE positron emission tomography (PET)-guided treatment management for patients with meningiomas is safe and effective and can identify which patients benefit most from adjuvant radiation therapy. METHODS AND MATERIALS: A single-institution prospective registry study was created for inclusion of patients with intracranial meningiomas who received a 68Ga-DOTATATE PET/CT to assist with radiation oncologist decision making. Patients who received a PET scan from January 1, 2018, to February 25, 2022, were eligible for inclusion. RESULTS: Of the 60 patients included, 40%, 47%, and 5% had World Health Organization grades 1, 2, and 3 meningiomas, respectively, and 8% (5 patients) had no grade assigned. According to Radiation Therapy Oncology Group 0539 criteria, 22%, 72%, and 7% were categorized as high, intermediate, and low risk, respectively. After completing their PET scans, 48 patients, 11 patients, and 1 patient proceeded with radiation therapy, observation, and redo craniotomy, respectively. The median follow-up for the entire cohort was 19.5 months. Of the 3 patients (5%) who experienced local failure between 9.2 and 28.5 months after diagnosis, 2 had PET-avid disease in their postoperative cavity and elected for observation before recurrence, and 1 high-risk patient with multifocal disease experienced local failure 2 years after a second radiation course and multiple previous recurrences. Notably, 5 patients did not have any local PET uptake and were observed; none of these patients experienced recurrence. Only 1 grade 3 toxicity was attributed to PET-guided radiation. CONCLUSIONS: This study examined one of the largest known populations of patients with intracranial meningiomas followed by physicians who used 68Ga-DOTATATE PET-guided therapy. Incorporating 68Ga-DOTATATE PET into future trials may assist with clinician decision making and improve patient outcomes.

Symptomatic radionecrosis after postoperative but not preoperative stereotactic radiosurgery in a single patient: illustrative case.

BACKGROUND: Standard of care for brain metastases involves stereotactic radiosurgery (SRS). For cases that also require surgery because of lesion size, edema, or neurological symptoms, whether to provide pre- or postoperative SRS has become a prevalent debate. OBSERVATIONS: Herein, the unique case of a patient with brain metastases of the same pathology and similar size in two different brain locations at two different times is described. The patient underwent surgery with preoperative SRS for the first lesion and surgery with postoperative SRS for the second lesion. Although both treatments resulted in successful local control, the location that received postoperative SRS developed symptomatic and rapidly progressive radiation necrosis (RN) requiring a third craniotomy. LESSONS: Large randomized controlled trials are ongoing to compare pre- versus postoperative SRS for the treatment of symptomatic brain metastases (e.g., study NRG-BN012). Recent interest in preoperative SRS has emerged from its theoretical potential to decrease rates of postoperative RN and leptomeningeal disease. This valuable case in which both therapies were applied in a single patient with a single pathology and similar lesions provides evidence supportive of preoperative SRS.

Relevance of the Updated Recursive Partitioning Analysis (U-RPA) Classification in the Contemporary Care of Patients with Brain Metastases.

Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019. With survival as the primary endpoint, we calculated the U-RPA and generated estimates using Kaplan-Meier curves and hazard ratios. Of 862 eligible patients, 752 received BDT and 110 received best supportive care (BSC). Median overall survival with BDT and BSC was 9.3 and 1.3 months, respectively. Patients in RPA class 1, 2A, 2B and 3 who underwent BDT had median survival of 28.1, 14.7, 7.6 and 3.3 months, respectively. The median survival for patients in RPA 3 who received BDT (n = 147), WBRT (n = 79) and SRS (n = 54) was 3.3, 2.9 and 4.1 months, respectively. The U-RPA defines prognosis estimates, independent of tumor type and treatment modality, which can assist to make value-based care treatment decisions. The prognosis for patients in U-RPA class 2B and 3 remains poor, with consideration for early palliative care involvement in these cases.

Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001.

PURPOSE: Initial report of NRG Oncology CC001, a phase 3 trial of whole-brain radiation therapy plus memantine (WBRT + memantine) with or without hippocampal avoidance (HA), demonstrated neuroprotective effects of HA with a median follow-up of fewer than 8 months. Herein, we report the final results with complete cognition, patient-reported outcomes, and longer-term follow-up exceeding 1 year. METHODS AND MATERIALS: Adult patients with brain metastases were randomized to HA-WBRT + memantine or WBRT + memantine. The primary endpoint was time to cognitive function failure, defined as decline using the reliable change index on the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association, or the Trail Making Tests (TMT) A and B. Patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory with Brain Tumor Module and EQ-5D-5L. RESULTS: Between July 2015 and March 2018, 518 patients were randomized. The median follow-up for living patients was 12.1 months. The addition of HA to WBRT + memantine prevented cognitive failure (adjusted hazard ratio, 0.74, P = .016) and was associated with less deterioration in TMT-B at 4 months (P = .012) and HVLT-R recognition at 4 (P = .055) and 6 months (P = .011). Longitudinal modeling of imputed data showed better preservation of all HVLT-R domains (P < .005). Patients who received HA-WBRT + Memantine reported less symptom burden at 6 (P < .001 using imputed data) and 12 months (P = .026 using complete-case data; P < .001 using imputed data), less symptom interference at 6 (P = .003 using complete-case data; P = .0016 using imputed data) and 12 months (P = .0027 using complete-case data; P = .0014 using imputed data), and fewer cognitive symptoms over time (P = .043 using imputed data). Treatment arms did not differ significantly in overall survival, intracranial progression-free survival, or toxicity. CONCLUSIONS: With median follow-up exceeding 1 year, HA during WBRT + memantine for brain metastases leads to sustained preservation of cognitive function and continued prevention of patient-reported neurologic symptoms, symptom interference, and cognitive symptoms with no difference in survival or toxicity.

Low-risk meningioma: Initial outcomes from NRG Oncology/RTOG 0539.

BACKGROUND: Three- and five-year progression-free survival (PFS) for low-risk meningioma managed with surgery and observation reportedly exceeds 90%. Herewith we summarize outcomes for low-risk meningioma patients enrolled on NRG/RTOG 0539. METHODS: This phase II trial allocated patients to one of three groups per World Health Organization grade, recurrence status, and resection extent. Low-risk patients had either gross total (GTR) or subtotal resection (STR) for a newly diagnosed grade 1 meningioma and were observed after surgery. The primary endpoint was 3-year PFS. Adverse events (AEs) were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 3. RESULTS: Among 60 evaluable patients, the median follow-up was 9.1 years. The 3-, 5-, and 10-year rates were 91.4% (95% CI, 84.2 to 98.6), 89.4% (95% CI, 81.3 to 97.5), 85.0% (95% CI, 75.3 to 94.7) for PFS and 98.3% (95% CI, 94.9 to 100), 98.3%, (95% CI, 94.9 to 100), 93.8% (95% CI, 87.0 to 100) for overall survival (OS), respectively. With centrally confirmed GTR, 3/5/10y PFS and OS rates were 94.3/94.3/87.6% and 97.1/97.1/90.4%. With STR, 3/5/10y PFS rates were 83.1/72.7/72.7% and 10y OS 100%. Five patients reported one grade 3, four grade 2, and five grade 1 AEs. There were no grade 4 or 5 AEs. CONCLUSIONS: These results prospectively validate high PFS and OS for low-risk meningioma managed surgically but raise questions regarding optimal management following STR, a subcohort that could potentially benefit from adjuvant therapy.

Case report: Fractional brain tumor burden magnetic resonance mapping to assess response to pulsed low-dose-rate radiotherapy in newly-diagnosed glioblastoma.

Background: Pulsed low-dose-rate radiotherapy (pLDR) is a commonly used reirradiation technique for recurrent glioma, but its upfront use with temozolomide (TMZ) following primary resection of glioblastoma is currently under investigation. Because standard magnetic resonance imaging (MRI) has limitations in differentiating treatment effect from tumor progression in such applications, perfusion-weighted MRI (PWI) can be used to create fractional tumor burden (FTB) maps to spatially distinguish active tumor from treatment-related effect. Methods: We performed PWI prior to re-resection in four patients with glioblastoma who had undergone upfront pLDR concurrent with TMZ who had radiographic suspicion for tumor progression at a median of 3 months (0-5 months or 0-143 days) post-pLDR. The pathologic diagnosis was compared to retrospectively-generated FTB maps. Results: The median patient age was 55.5 years (50-60 years). All were male with IDH-wild type (n=4) and O6-methylguanine-DNA methyltransferase (MGMT) hypermethylated (n=1) molecular markers. Pathologic diagnosis revealed treatment effect (n=2), a mixture of viable tumor and treatment effect (n=1), or viable tumor (n=1). In 3 of 4 cases, FTB maps were indicative of lesion volumes being comprised predominantly of treatment effect with enhancing tumor volumes comprised of a median of 6.8% vascular tumor (6.4-16.4%). Conclusion: This case series provides insight into the radiographic response to upfront pLDR and TMZ and the role for FTB mapping to distinguish tumor progression from treatment effect prior to redo-surgery and within 20 weeks post-radiation.

Association of Pretreatment Hippocampal Volume With Neurocognitive Function in Patients Treated With Hippocampal Avoidance Whole Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology/RTOG 0933.

Purpose: Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933. Methods and Materials: Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test-Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test. Results: Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cm3 (range, 1.9-7.4 cm3), 2.8 cm3 (range, 0.9-4.0 cm3), and 2.7 cm3 (range, 1.0-3.7 cm3), respectively. The median total brain volume was 1343 cm3 (range, 1120.5-1738.8 cm3). For all measures of corrected HV, increasing HV was associated with higher baseline HVLT-R TR and DR scores (ρ: range, 0.35-0.40; P-value range, .009-.024) and 4-month TR and DR scores (ρ: range, 0.29-0.40; P-value range, .009-.04), with the exception of right HV and 4-month DR scores (ρ: 0.29; P = .059). There was no significant association between HV and NCF change between baseline and 4 months. Fourteen patients (33.3%) developed NCF deterioration per the primary endpoint of RTOG 0933. There was no significant difference in HV between patients with deteriorated and nondeteriorated NCF, although in all instances, patients with deteriorated NCF had numerically lower HV. Conclusions: Larger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF.

Radiotherapy for elderly patients with glioblastoma: an assessment of hypofractionation and modern treatment techniques.

Glioblastoma (GBM) is a disease with a poor prognosis. For decades, radiotherapy has played a critical role in the management of GBM. The standard of care radiation prescription is 60 Gy in 30 fractions, but landmark trials have historically excluded patients older than 70 years. Currently, there is considerable variation in the management of elderly patients with GBM. Shortened radiation treatment (hypofractionated) regimens have been explored since conventional treatment schedules are lengthy and many elderly patients have functional, cognitive, and social limitations. Clinical trials have demonstrated the effectiveness of hypofractionated radiotherapy (40 Gy in 15 fractions) to treat elderly or frail patients with GBM. Although previous studies have suggested these unique hypofractionation prescriptions effectively treat these patients, there are many avenues for improvement in this patient population. Herein, we describe the unique tumor biology of glioblastoma, key hypofractionated radiotherapy studies, and health-related quality of life (HRQOL) studies for elderly patients with GBM. Hypofractionated radiation has emerged as a shortened alternative and retrospective studies have suggested survival outcomes are similar for elderly patients with GBM. Prospective studies comparing hypofractionation with conventional treatment regiments are warranted. In addition to evaluating survival outcomes, HRQOL endpoints should be incorporated into future studies.

Quality of Life and Cognitive Function Evaluations and Interventions for Patients with Brain Metastases in the Radiation Oncology Clinic.

Brain metastases (BMs) account for a disproportionately high percentage of cancer morbidity and mortality. Historically, studies have focused on improving survival outcomes, and recent radiation oncology clinical trials have incorporated HRQOL and cognitive assessments. We are now equipped with a battery of assessments in the radiation oncology clinic, but there is a lack of consensus regarding how to incorporate them in modern clinical practice. Herein, we present validated assessments for BM patients, current recommendations for future clinical studies, and treatment advances that have improved HRQOL and cognitive outcomes for BM patients.

Deep Learning-Based Automatic Detection of Brain Metastases in Heterogenous Multi-Institutional Magnetic Resonance Imaging Sets: An Exploratory Analysis of NRG-CC001.

PURPOSE: Deep learning-based algorithms have been shown to be able to automatically detect and segment brain metastases (BMs) in magnetic resonance imaging, mostly based on single-institutional data sets. This work aimed to investigate the use of deep convolutional neural networks (DCNN) for BM detection and segmentation on a highly heterogeneous multi-institutional data set. METHODS AND MATERIALS: A total of 407 patients from 98 institutions were randomly split into 326 patients from 78 institutions for training/validation and 81 patients from 20 institutions for unbiased testing. The data set contained T1-weighted gadolinium and T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging acquired on diverse scanners using different pulse sequences and various acquisition parameters. Several variants of 3-dimensional U-Net based DCNN models were trained and tuned using 5-fold cross validation on the training set. Performances of different models were compared based on Dice similarity coefficient for segmentation and sensitivity and false positive rate (FPR) for detection. The best performing model was evaluated on the test set. RESULTS: A DCNN with an input size of 64 × 64 × 64 and an equal number of 128 kernels for all convolutional layers using instance normalization was identified as the best performing model (Dice similarity coefficient 0.73, sensitivity 0.86, and FPR 1.9) in the 5-fold cross validation experiments. The best performing model demonstrated consistent behavior on the test set (Dice similarity coefficient 0.73, sensitivity 0.91, and FPR 1.7) and successfully detected 7 BMs (out of 327) that were missed during manual delineation. For large BMs with diameters greater than 12 mm, the sensitivity and FPR improved to 0.98 and 0.3, respectively. CONCLUSIONS: The DCNN model developed can automatically detect and segment brain metastases with reasonable accuracy, high sensitivity, and low FPR on a multi-institutional data set with nonprespecified and highly variable magnetic resonance imaging sequences. For large BMs, the model achieved clinically relevant results. The model is robust and may be potentially used in real-world situations.

68Ga-DOTATATE PET-Based Radiation Contouring Creates More Precise Radiation Volumes for Patients With Meningioma.

PURPOSE: Radiation treatment planning for meningiomas traditionally involves magnetic resonance imaging (MRI) contrast enhanced images to define residual tumor. However, the gross tumor volume may be difficult to delineate for patients with a meningioma in the skull base sagittal sinus or after resection. Advanced positron emission tomography (PET) imaging using 68Ga-DOTATATE, which has been shown to be more sensitive and specific than MRI imaging, can be used for target volume delineation in these circumstances. We hypothesized that 68Ga-DOTATATE PET scan-based treatment planning would lead to smaller radiation volumes and would detect additional areas of disease compared with standard MRI alone. METHODS AND MATERIALS: Our data evaluated retrospective, deidentified, and blinded gross tumor volume contour delineation with 7 central nervous system (CNS) specialists (4 CNS radiation oncologists and 3 neuroradiologists) for 25 patients with a meningioma diagnosis who received both a 68Ga-DOTATATE PET and an MRI for radiation treatment planning. Both the MRI and the PET were nonsequentially contoured by each physician for each patient. RESULTS: The median MRI volume for each physician ranged from 16.94-25.53 cm3. The median PET volume for each physician ranged from 2.09 to 8.36 cm3. The median PET volume was smaller for each physician. In addition, 7 of the 25 patients (28%) had new nonadjacent areas contoured on PET by at least 6 of the 7 physicians that were not contoured by these physicians on the corresponding MRI. These new areas would not have been in the traditional MRI-based volumes. CONCLUSIONS: Our study supports that 68Ga-DOTATATE PET imaging may help radiation oncologists create more precise radiation treatment volumes through finding undetected areas of disease not seen on MRI. Treatment planning guided by 68Ga-DOTATATE PET should be studied prospectively.

Department-focused electronic health record thrive training.

A novel approach of department-focused electronic health record (EHR) training was implemented to improve efficiency and time management of EHR use. Based off baseline log data, 5 in-person training sessions were designed, focusing on the common inefficiencies of 6 chosen participants. Log data of 4 key metrics and 2 efficiency scores were analyzed 4 months post-training. A survey was conducted to assess self-reported EHR competence. Individually, several participants had improved efficiency scores. There was a reduced average time spent in the inbox per day, in notes per dictation, and in notes per day. This translated to an average of 8.9 min saved per day (range 0-29.1 min/day) and 37.1 hours saved per year (range 0-116.2 hours/year). From the post-training surveys, all participants felt more efficient in their use of the EHR. This study demonstrates an example of department-focused EHR training and log-based analysis improving time management and efficiency.

Dose Escalated Radiation Therapy for Glioblastoma Multiforme: An International Systematic Review and Meta-Analysis of 22 Prospective Trials.

PURPOSE: Limited evidence is available on the utility of dose-escalated radiation therapy (DE-RT) with or without temozolomide (TMZ) versus standard-of-care radiation therapy (SoC-RT) for patients with newly diagnosed glioblastoma multiforme. We performed a systematic review/meta-analysis to compare overall survival (OS) and progression-free survival (PFS) between DE-RT and SoC-RT. METHODS AND MATERIALS: We used a Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses/Meta-analysis of Observational Studies in Epidemiology selection criterion to identify studies. The primary and secondary outcomes were 1-year OS and 1-year PFS, respectively. Outcomes and comparisons were subdivided based on receipt of TMZ and MGMT status. DE-RT was defined based on equivalent dose calculations. Random effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted. Meta-regression was used to compare therapeutic (eg, DE-RT or TMZ) and pathologic characteristics (eg, MGMT methylation status) using the Wald-type test. RESULTS: Across 22 published studies, 2198 patients with glioblastoma multiforme were included; 507 received DE-RT. One-year OS after DE-RT alone was higher than SoC-RT alone (46.3% vs 23.4%; P = .02) as was 1-year PFS (17.9% vs 5.3%; P = .02). No significant difference in 1-year OS (73.2% vs 64.4%; P = .23) or 1-year PFS (44.5% vs 44.3%; P = .33) between DE-RT + TMZ and SoC-RT + TMZ was noted. No difference in 1-year OS was noted between DE-RT + TMZ and SoC-RT + TMZ in either MGMT methylated (83.2% vs 73.2%; P = .23) or MGMT unmethylated (72.6% vs 50.6%; P = .16) patients. CONCLUSIONS: DE-RT alone resulted in superior PFS and OS versus SoC-RT alone. DE-RT + TMZ did not lead to improved outcomes versus SoC-RT + TMZ. No differential benefit based on MGMT status was found. Future studies are warranted to define which subgroups benefit most from DE-RT.

MR-Guided Radiotherapy for Brain and Spine Tumors.

MRI is the standard modality to assess anatomy and response to treatment in brain and spine tumors given its superb anatomic soft tissue contrast (e.g., T1 and T2) and numerous additional intrinsic contrast mechanisms that can be used to investigate physiology (e.g., diffusion, perfusion, spectroscopy). As such, hybrid MRI and radiotherapy (RT) devices hold unique promise for Magnetic Resonance guided Radiation Therapy (MRgRT). In the brain, MRgRT provides daily visualizations of evolving tumors that are not seen with cone beam CT guidance and cannot be fully characterized with occasional standalone MRI scans. Significant evolving anatomic changes during radiotherapy can be observed in patients with glioblastoma during the 6-week fractionated MRIgRT course. In this review, a case of rapidly changing symptomatic tumor is demonstrated for possible therapy adaptation. For stereotactic body RT of the spine, MRgRT acquires clear isotropic images of tumor in relation to spinal cord, cerebral spinal fluid, and nearby moving organs at risk such as bowel. This visualization allows for setup reassurance and the possibility of adaptive radiotherapy based on anatomy in difficult cases. A review of the literature for MR relaxometry, diffusion, perfusion, and spectroscopy during RT is also presented. These techniques are known to correlate with physiologic changes in the tumor such as cellularity, necrosis, and metabolism, and serve as early biomarkers of chemotherapy and RT response correlating with patient survival. While physiologic tumor investigations during RT have been limited by the feasibility and cost of obtaining frequent standalone MRIs, MRIgRT systems have enabled daily and widespread physiologic measurements. We demonstrate an example case of a poorly responding tumor on the 0.35 T MRIgRT system with relaxometry and diffusion measured several times per week. Future studies must elucidate which changes in MR-based physiologic metrics and at which timepoints best predict patient outcomes. This will lead to early treatment intensification for tumors identified to have the worst physiologic responses during RT in efforts to improve glioblastoma survival.