Radiation Necrosis Research Articles

Abstract 6442: Role of TWEAK-Fn14 axis in driving immunosuppression in glioblastoma multiforme

Abstract Cellular heterogeneity within glioblastoma multiforme (GBM) is a key driver of resistance to standard-of-care therapeutic approaches such as DNA damage (temozolomide, TMZ), angiogenesis inhibition (Bevacizumab, BM), radiation necrosis, and surgical resection. As such, understanding and targeting heterogeneous tumor-associated populations is a critical aim of ongoing GBM research. Central nervous system (CNS) resident microglia constitute significant percentages of primary GBM samples, often up to 50% of bulk tumor. Additionally, glioblastoma-associated microglia have been implicated in intra-tumoral immunosuppression, and are thus a key barrier to successful implementation of immunotherapies that seek to enhance T-cell mediated anti-tumoral cytotoxicity. As such, insight into targetable pathways that upregulate immunosuppressive cytokines within GBM-associated microglia is necessary for overcoming immuno-therapeutic failure. Here, we identify expression of the cytokine TWEAK (TNFSF12) and its receptor Fn14 (TNFRSF12A) within the myeloid compartment of primary GBM samples via scRNA-seq. Furthermore, we demonstrate TWEAK-mediated reprogramming of GBM-associated microglia towards an immunosuppressive phenotype capable of inhibiting CD8+ T cell activation and proliferation. These findings unveil a potent, targetable axis of immunosuppression within GBM and are thus an exciting step towards enhancing efficacy of existing T-cell based anti-cancer strategies for GBM patients. Citation Format: Angad Beniwal, Ryan Eghlimi, Kenneth D. Alexander, Mylan R. Blomquist, Nhan Tran. Role of TWEAK-Fn14 axis in driving immunosuppression in glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6442.

Evaluation of the Diagnostic Performance of F18-Fluorodeoxyglucose-Positron Emission Tomography, Dynamic Susceptibility Contrast Perfusion, and Apparent Diffusion Coefficient in Differentiation between Recurrence of a High-grade Glioma and Radiation Necrosis.

Differentiation between recurrence of brain tumor and radiation necrosis remains a challenge in current neuro-oncology practice despite recent advances in both radiological and nuclear medicine techniques. The purpose of this study was to compare the diagnostic performance of dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging (MRI), apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging, and F18-fluorodeoxyglucose-positron emission tomography (F18-FDG-PET) in the differentiation between the recurrence of a high-grade glioma and radiation necrosis. Patients with a diagnosis of high-grade glioma (WHO Grades III and IV) who had undergone surgical resection of the tumor followed by radiotherapy with or without chemotherapy were included in the study. DSC perfusion, diffusion-weighted MRI, and PET scan were acquired on a hybrid PET/MRI scanner. For each lesion, early and delayed tumor-to-brain ratio (TBR), early and delayed maximum standardized uptake value (SUVmax), normalized ADC ratio, and normalized relative cerebral blood volume (rCBV) ratio were calculated and the pattern of lesional enhancement was noted. The diagnosis was finalized with either histopathological examination or the characteristics on follow-up imaging. The statistical analysis using the receiver operator characteristic curves was done to determine the diagnostic performance of DSC perfusion, 18-F FDG-PET, and ADC in differentiation between tumor recurrence and radiation necrosis. Fifty patients were included in the final analysis, 32 of them being men (64%). A cutoff value of early TBR >0.8 (sensitivity of 100% and specificity of 80%), delayed TBR >0.93 (sensitivity of 92.3% and specificity of 80%), early SUVmax >10.2 (sensitivity of 76.9% and specificity of 80%), delayed SUVmax >13.2 (sensitivity of 61.54% and specificity of 100%), normalized rCBV ratio >1.21 (sensitivity of 100% and specificity of 60%), normalized ADC ratio >1.66 (sensitivity of 38.5% and specificity of 80%), and Grade 3 enhancement (sensitivity of 100% and specificity of 60%) were found to differentiate recurrence from radiation necrosis. Early TBR had the highest accuracy (94.44%), while ADC ratio had the lowest accuracy (50%). A combination of early TBR (cutoff value of 0.8), late TBR (cutoff value of 0.93), and rCBV ratio (cutoff value of 1.21) showed a sensitivity of 100%, specificity of 92.3%, positive predictive value of 88.9%, negative predictive value of 93.7%, and an accuracy of 96.6% in discrimination between radiation necrosis and recurrence of tumor. F18-FDG-PET and DSC perfusion can reliably differentiate tumor recurrence from radiation necrosis, with early TBR showing the highest accuracy. ADC demonstrates a low sensitivity, specificity, and accuracy in differentiating radiation necrosis from recurrence. A combination of early TBR, delayed TBR, and rCBV may be more useful in discrimination between radiation necrosis and recurrence of glioma, with this combination showing a better diagnostic performance than individual parameters or any other combination of parameters.

465 Defining the Immune Profile of Radiation Necrosis Through Single-cell Analysis of Intracranial Lesions

INTRODUCTION: The incidence of radiation necrosis (RN), a common and morbid side effect of radiosurgical management of brain metastases, is growing as patient survival and use of immunotherapy increases. RN is thought to be immunologically driven; however, its pathophysiology remains poorly understood. Further, difficulty distinguishing it radiographically from recurrent metastatic disease often necessitates invasive brain biopsies for diagnosis. METHODS: Over 12 months, we collected intraoperative samples from patients undergoing craniotomy for RN and/or metastatic tumor. We created a bank of these 16 patient samples and processed them for scRNAseq analysis. Using fluorescence-activated cell sorting (FACS) and 10x Genomics single cell RNA sequencing, we analyzed the cellular immune profile of lesional tissue and time-matched blood from each patient. RESULTS: Compared to metastases, RN demonstrates decreased expression of FOXP3, NKG7, and GZMB, markers of regulatory and cytotoxic T cells, and natural killer (NK) cells, and increased expression of interleukin 7 receptor (IL7R), a marker of naÏve and memory T cells – profiles reflective of bystander transcriptional signatures. In contrast, metastases demonstrate an antigen-reactive profile, including commonly observed exhaustion signatures. Importantly, blood samples from patients reflect these differences as well. Interestingly, increased IL7R is implicated in autoimmune disorders, suggesting an iatrogenically-induced autoreactive process underlying RN. CONCLUSIONS: These findings demonstrate, firstly, the feasibility of extracting live cells from RN tissue, and, secondly, suggest RN and metastases have unique immune profiles that can be detected in patient blood. Therefore, in addition to beginning to define the immune landscape of this poorly understood pathology, this work has the potential to open new avenues for the development of improved diagnostic and therapeutic approaches to allow for earlier detection and more effective treatment of RN in metastatic brain tumors patients.

Brain injury after cranial radiotherapy combined with immunotherapy for brain metastases in lung cancer: a retrospective study.

Aim: To explore whether immune checkpoint inhibitors (ICIs) increase the incidence of radiation-induced brain injury in lung cancer patients with brain metastases. Methods: According to whether they received ICIs within 6months before and after cranial radiotherapy (CRT), all patients were divided into two groups: ICIs+CRT group and CRT+non-ICIs group. Results: The incidence of radiation necrosis (RN) in the CRT+ICIs group was 14.3%, while that in the CRT+non-ICIs group was 5.8% (p =0.090). If ICIs were used within 3 months of CRT, there was statistical significance. A maximum diameter of brain metastasis >3.3cm and cumulative radiation dose of metastatic lesions >75.7Gy were risk factors for RN. Conclusion: ICIs could increase the risk of RN, especially when used within 3 months of CRT.

109 A Small RNA Signature from Extracellular Vesicles in Patient Plasma Correlates With Recurrence or Progression of High-Grade Gliomas

INTRODUCTION: Glial cell-derived tumors of the central nervous system make up the largest group of brain tumors. Most are high-grade gliomas (HGG) and are universally fatal despite multimodal therapy. In managing patients with HGG, predicting recurrence, or differentiating between pseudoprogression (radiation necrosis) and true tumor progression would be invaluable in improving overall prognosis. Characterizing small RNA (sRNA) expression profiles from plasma-derived extracellular vesicles (EVs) over the course of a patient’s treatments, may allow for patient-specific treatment modifications and improve outcomes. METHODS: Plasma EVs were isolated using Vn96 capture from HGG patients perioperatively and with routine, follow-up surveillance imaging. Small RNA sequencing was conducted and unsupervised hierarchal clustering of sRNA signatures were completed. Expression profiles were grouped longitudinally with the clinical status of patients. RESULTS: Cluster analysis of nine HGG patients, has revealed a sRNA signature that is able to distinguish between tumors showing evidence of progression and those remaining stable over time. Those samples obtained from patients where a clinical diagnosis of tumor progression or pseudoprogression were uncertain, were found to cluster into progression vs. stable signatures. Annotation of differentially expressed small RNAs identified from stable vs. clinically progressed patient include small nuclear RNA, ribosomal RNA, and micro RNA among others. MiRNA species we have identified correspond to previously identified miRNA, which have been ascribed functional significance to HGG aggressiveness and progression. CONCLUSIONS: These preliminary findings demonstrate the potential utility of sRNA profiling of plasma-derived EVs obtained from patients with high-grade gliomas as non-invasive biomarkers for recurrent/progressive disease or stability/pseudoprogression.

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

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

Stereotactic Radiation Therapy for Brain Metastases: Factors Affecting Outcomes and Radiation Necrosis

Stereotactic radiation therapy (SRT) is a proven effective treatment for brain metastases (BM); however, symptomatic radiation necrosis (RN) is a late effect that may impact on patient's quality of life. The aim of our study was to retrospectively evaluate survival outcomes and characterize the occurrence of RN in a cohort of BM patients treated with ablative SRT at Federico II University Hospital. Clinical and dosimetric factors of 87 patients bearing a total of 220 BMs treated with SRT from 2016 to 2022 were analyzed. Among them, 46 patients with 127 BMs having clinical and MRI follow-up (FUP) ≥ 6 months were selected for RN evaluation. Dosimetric parameters of the uninvolved brain (brain without GTV) were extracted. The crude local control was 91% with neither clinical factors nor prescription dose correlating with local failure (LF). At a median FUP of 9 (1-68) months, the estimated median overall survival (OS), progression-free survival (PFS), and brain progression-free survival (bPFS) were 16, 6, and 9 months, respectively. The estimated OS rates at 1 and 3 years were 59.8% and 18.3%, respectively; bPFS at 1 and 3 years was 29.9% and 13.5%, respectively; PFS at 1 and 3 years was 15.7% and 0%, respectively; and local failure-free survival (LFFS) at 1 and 3 years was 87.2% and 83.8%, respectively. Extracranial disease status was an independent factor related to OS. Fourteen (30%) patients manifested RN. At multivariate analysis, adenocarcinoma histology, left location, and absence of chemotherapy were confirmed as independent risk factors for any-grade RN. Nine (20%) patients developed symptomatic (G2) RN, which improved or stabilized after 1-16 months of steroid therapy. With prompt recognition and, when necessary, medical therapy, RN radiological and clinical amelioration can be obtained.

Hypofractionated stereotactic radiosurgery (HSRS) as a salvage treatment for brain metastases failing prior stereotactic radiosurgery (SRS)

Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5cc and 37.5Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). Salvage HSRS results in high local control rates and toxicity rates that compare favorably to thosesingle fraction SRS re-irradiationexperiences reported in the literature.

Role of Boswellia Serrata in Management of CNS Radiation Necrosis After Radiosurgery for Brain Metastases

Role of Boswellia Serrata in Management of CNS Radiation Necrosis After Radiosurgery for Brain Metastases

Proton Radiosurgery: Current Concepts and Limitations for CNS Radiosurgery.

Stereotactic radiosurgery (SRS) is highly conformal, high-dose radiation therapy delivered in 1-5 fractions, and is considered the standard of care for several central nervous system (CNS) indications. Particle therapies, such as protons, have physical and dosimetric advantageous properties compared to photons. However, proton SRS (PSRS) is not widely performed given the few particle therapy facilities, high-cost, and limited outcomes research as a sole modality and in comparative studies. The data available differs from each pathology. For AVMs, especially those with deep or eloquent locations, PSRS obliteration rates outcomes appear favorable and superior. For meningiomas, PSRS has been used for grade 1 alone, and for higher grades a PSRS boost has been considered. For vestibular schwannoma, PSRS seems to have favorable control rates with modest toxicity outcomes. For pituitary tumors, data shows excellent results with PSRS for functional and non-functioning adenomas. For brain metastasis, moderate doses of PSRS achieves high local control rates with low rates of radiation necrosis. For uveal melanoma, dedicated eyeline PSRS (4-5 fractions) are associated with very high tumor control and eye retention rates. PSRS is effective and safe for various intracranial pathologies. Limited data, usually retrospective and single institution series exist. There are numerous advantages of protons over photons, so it is important to understand limitations with further studies. Published clinical outcomes and widespread adoption of proton therapy will be key to unlocking the potential benefits of PSRS.

Hypo-fractionated Gamma Knife Radiosurgery for Intra-cranial Pathologies: A Single-Center Prospective Analysis of Feasibility, Safety, Efficacy, and Complication Profile.

Single-session stereotactic radiosurgery (SRS) is a proven and effective treatment modality for various benign, malignant, and functional intra-cranial pathologies. In certain situations, single-fraction SRS is limited because of lesion size and location. Hypo-fractionated gamma knife radiosurgery (hfGKRS) is an alternative approach for such unconventional indications. To evaluate the feasibility, efficacy, safety, and complication profile of hfGKRS with evaluation of different fractionation schemes and dosing patterns. The authors prospectively evaluated 202 patients treated with frame-based hfGKRS over a 9-year period. GKRS was administered fractionated because of either a large volume (>14 cc) or an inability to spare neighboring organs at risk from permissible radiation in single-session GKRS. The inter-fraction interval was kept at 24 hours, and the dose calculation was performed with linear quadratic equations. Patients with more than 3 years of clinical and radiological follow-up were included in prospective analysis. At pre-decided follow-up criteria, treatment effects and side effects were documented on objective scales. A total of 169/202 patients met inclusion criteria. 41% patients received treatment in three fractions, whereas 59% received two-fraction GKRS. Two patients of giant cavernous sinus hemangiomas were treated with 5 Gy in the five-fraction regimen. In patients with more than 3 years of follow-up, the obliteration rate was 88% for complex arteriovenous malformations (AVMs) treated with hfGKRS because of eloquent locations, whereas it was 62% for Spetzler-Martin grade 4-5 AVMs. For non-AVM pathologies (meningiomas, schwannomas, pituitary adenomas, paragangliomas, hypothalamic hamartomas, etc.), the 5-year progression free survival was 95%. Tumor failure was noted in 0.05% patient population. Radiation necrosis developed in 8.1% patients, and radiation-induced brain edema developed in 12% patients. It was resistant to treatment in 4% patients. No patient developed radiation-induced malignancy. Hypo-fractionation did not provide any hearing improvement in giant vestibular schwannomas. hfGKRS is a valuable standalone treatment option for candidates unsuitable for single-session GKRS. The dosing parameters need to be tailored as per the pathology and neighboring structures. It provides comparable results to single-session GKRS with an acceptable safety and complication profile.

Outcomes of intraventricular 131-I-omburtamab and external beam radiotherapy in patients with recurrent medulloblastoma and ependymoma

PurposeIntraventricular compartmental radioimmunotherapy (cRIT) with 131-I-omburtamab is a potential therapy for recurrent primary brain tumors that can seed the thecal space. These patients often previously received external beam radiotherapy (EBRT) to a portion or full craniospinal axis (CSI) as part of upfront therapy. Little is known regarding outcomes after re-irradiation as part of multimodality therapy including cRIT. This study evaluates predictors of response, patterns of failure, and radiologic events after cRIT.MethodsPatients with recurrent medulloblastoma or ependymoma who received 131-I-omburtamab on a prospective clinical trial were included. Extent of disease at cRIT initiation (no evidence of disease [NED] vs measurable disease [MD]) was assessed as associated with progression-free (PFS) and overall survival (OS) by Kaplan–Meier analysis.ResultsAll 27 patients (20 medulloblastoma, 7 ependymoma) had EBRT preceding cRIT: most (22, 81%) included CSI (median dose 2340 cGy, boost to 5400 cGy). Twelve (44%) also received EBRT at relapse as bridging to cRIT. There were no cases of radionecrosis. At cRIT initiation, 11 (55%) medulloblastoma and 3 (43%) ependymoma patients were NED, associated with improved PFS (p = 0.002) and OS (p = 0.048) in medulloblastoma. Most relapses were multifocal. With medium follow-up of 3.0 years (95% confidence interval, 1.8–7.4), 6 patients remain alive with NED.ConclusionFor patients with medulloblastoma, remission at time of cRIT was associated with significantly improved survival outcomes. Relapses are often multifocal, particularly in the setting of measurable disease at cRIT initiation. EBRT is a promising tool to achieve NED status at cRIT initiation, with no cases of radiation necrosis.

Radiation necrosis and therapeutic outcomes in patients treated with linear accelerator-based hypofractionated stereotactic radiosurgery for intact intracranial metastases.

Balancing disease control and treatment-related toxicities can be challenging when treating higher-risk brain metastases (BMs) that are larger in size or eloquent anatomical locations. Hypofractionated stereotactic radiosurgery (hfSRS) is expected to offer superior or equal efficacy with lower toxicity profile compared with single-fraction SRS (sfSRS). We report the efficacy and toxicity profiles of hfSRS in a consecutive cohort of patients to support this predicted benefit from hfSRS for high-risk BMs. We retrospectively analysed 185 consecutive individual lesions from 152 patients with intact BMs treated with hfSRS between 1 July 2016 and 31 October 2019 and followed up to 30 April 2022 with serial brain magnetic resonance imaging (MRI). The primary endpoint was the event of radiation necrosis (RN). Local control (LC) rate and distant brain failure (DBF) were reported as secondary outcomes. Kaplan-Meier method was used to report the cumulative incidence of RN and overall survival and the incidence of DBF. Potential risk factors for RN were assessed using univariable Cox regression analysis. The median follow-up was 38.0months, and the median survival post-SRS was 9.5 months. The cumulative incidence rate of RN was 13.2% (95% CI: 7.0-24.7%), and 18.1% of patients with confirmed RN were symptomatic. Higher mean dose delivered to planning target volume (PTV) (HR 1.22, 95% CI: 1.05-1.42, P=0.01), higher mean BED10 (biological equivalent dose assuming a tissue ratio of 10) (HR 1.12, 95% CI: 1.04-1.2, P <0.001), and higher mean BED2 (HR 1.02, 95% CI: 1-1.04, P=0.04) delivered to the lesion was associated with increased risk of RN. LC rate was 86% and the cumulative incidence of DBF was 36% with a median onset of 28.4 months. Our results support the predicted radiobiological benefit of the use of hfSRS in high-risk BMs to limit treatment-related toxicity with low risk for symptomatic RN comparable with lower risk population receiving sfSRS while achieving satisfactory local disease control.

Posterior Cranial Retraction Combined With Bilateral Parietal Distraction for Children With Nonsyndromic Craniosynostosis.

The nonsyndromic craniosynostosis is the most common of craniosynostoses in childhood. There are many treatments. We aim to treat 12 cases of nonsyndromic craniosynostosis via posterior cranial vault distraction osteogenesis combined with bilateral parietal distraction. Data of a total of 12 patients (7 boys and 5 girls) with nonsyndromic sagittal synostosis who underwent distraction osteogenesis between January 2015 and August 2020 were retrospectively analyzed. Bilateral parietal bone flaps and posterior occipital flaps were designed and cut. Then, distraction device was placed, which was distracted at 5 days after surgery (twice per day, 0.4-0.6 mm/d, and lasting for 10-15 days). After 6 months of fixation, the secondary surgery was performed to remove the device. The scaphocephaly was corrected, and the appearance was satisfactory. Postoperative follow-up time was 6 to 14 months, with an average of 10 months, and the mean CI was 63.2 and 78.25 before and after surgery, respectively; the mean anterior-posterior skull diameter was shortened (12.63 ± 3.47) mm, the transverse diameter of both temporal regions was lengthened (15.4 ± 4.18) mm, and the scaphocephalic deformity was significantly improved. There was no detachment or rupture of the extender postoperatively. No severe complications, such as radiation necrosis or intracranial infection, were observed. Posterior cranial retraction combined with bilateral parietal distraction in children with nonsyndromic craniosynostosis, in which the proposed technique did not exhibit severe complications, and it is worthy of further promotion and application in clinical practice.

High-dose proton beam therapy versus conventional fractionated radiation therapy for newly diagnosed glioblastoma: a propensity score matching analysis

BackgroundHigh-dose proton beam therapy (PBT) uses excellent dose concentricity based on the unique characteristic termed the Bragg peak. PBT is a highly feasible treatment option that improves survival in select patients with newly diagnosed glioblastoma (GBM). However, selection bias remains an issue in prior studies that evaluated the efficacy of PBT. The aim of the present study was to compare the survival outcomes and toxicities of high-dose PBT and conventional radiation therapy (CRT) using propensity score-matched treatment cohorts.MethodsThe analysis included patients with newly diagnosed GBM treated with high-dose PBT of 96.6 Gy (RBE) or CRT of 60 Gy from 2010 to 2020. Propensity score generation and 1:1 matching of patients were performed based on the following covariates: age, sex, tumor location, extent of resection, chemotherapy, immunotherapy, and pre-radiation Karnofsky performance scale score.ResultsFrom a total of 235 patients, 26 were selected in each group by propensity score matching. The median overall survival (OS) of the PBT group was 28.3 months, while the median OS of the CRT group was 21.2 months. Although acute radiation-related toxicities were equivalent between the PBT and CRT groups, radiation necrosis as a late radiation-related toxicity was observed significantly more frequently in the PBT group.ConclusionsHigh-dose PBT provided significant survival benefits for patients with newly diagnosed GBM compared to CRT as shown by propensity score matching analysis. Radiation necrosis remains an issue in high-dose PBT; thus, the establishment of an effective treatment strategy centered on bevacizumab would be essential.

Patterns of Progression in Patients With Newly Diagnosed Glioblastoma Treated With 5-mm Margins in a Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With Concurrent and Adjuvant Temozolomide

In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5-fraction stereotactic radiosurgery with 5-mm margins. Thirty adult patients with newly diagnosed GBM were treated with 5-fraction stereotactic radiosurgery in escalated doses from 25 to 40 Gy with a 5-mm total treatment margin. Progression was scored as "in-field" if the recurrent tumor was within or contiguous with the 5-mm margin, "marginal" if between 5 and 20 mm, and "distant" if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equi-effective dose in 2 Gy (EQD2) per day at the site of tumor recurrence. Progression was "dosimetrically in-field" if covered by a minimum EQD2 per day of 48 Gy10. From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%), and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field), and 7 Gy10 (ie, dosimetrically out-of-field). Median overall survival was 12.1 months for in-field (95% confidence interval [CI], 8.9-17.6), 15.1 months (95% CI, 10.1 to not achieved) for marginal, and 21.4 months (95% CI, 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared with those without radiation necrosis (16 of 20; 80%; P=.003); those with necrosis had a median overall survival of 27.2 months (95% CI, 11.2-48.3) compared with 11.7 months (95% CI, 8.9-17.6) for patients with no necrosis (P=.077). In patients with newly diagnosed GBM treated with a 5-mm clinical target volume margin, 3 patients (11%) had marginal progression within 5 to 20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20-mm margins. Radiation necrosis was associated with in-field tumor control.

Imaging Recommendations for the Diagnosis, Staging, and Management of Adult Brain Tumors

AbstractNeuroimaging plays a pivotal role in the clinical practice of brain tumors aiding in the diagnosis, genotype prediction, preoperative planning, and prognostication. The brain tumors most commonly seen in adults are extra-axial lesions like meningioma, intra-axial lesions like gliomas and lesions of the pituitary gland. Clinical features may be localizing like partial seizures, weakness, and sensory disturbances or nonspecific like a headache. On clinical suspicion of a brain tumor, the primary investigative workup should focus on imaging. Other investigations like fundoscopy and electroencephalography may be performed depending on the clinical presentation. Obtaining a tissue sample after identifying a brain tumor on imaging is crucial for confirming the diagnosis and planning further treatment. Tissue sample may be obtained by techniques such as stereotactic biopsy or upfront surgery. The magnetic resonance (MR) imaging protocol needs to be standardized and includes conventional sequences like T1-weighted (T1W) imaging with and without contrast, T2w imaging, fluid-attenuated axial inversion recovery, diffusion-weighted imaging (DWI), susceptibility-weighted imaging, and advanced imaging sequences like MR perfusion and MR spectroscopy. Various tumor characteristics in each of these sequences can help us narrow down the differential diagnosis and also predict the grade of the tumor. Multidisciplinary co-ordination is needed for proper management and care of brain tumor patients. Treatment protocols need to be adapted and individualized for each patient depending on the age, general condition of the patient, histopathological characteristics, and genotype of the tumor. Treatment options include surgery, radiotherapy, and chemotherapy. Imaging also plays a vital role in post-treatment follow-up. Sequences like DWI, MR perfusion, and MR spectroscopy are useful to distinguish post-treatment effects like radiation necrosis and pseudoprogression from true recurrence. Radiological reporting of brain tumor images should follow a structured format to include all the elements that could have an impact on the treatment decisions in patients.

Diagnostic Accuracy of Arterial Spin-Labeling, Dynamic Contrast-Enhanced, and DSC Perfusion Imaging in the Diagnosis of Recurrent High-Grade Gliomas: A Prospective Study.

For patients with high-grade gliomas, the appearance of a new, enhancing lesion after surgery and chemoradiation represents a diagnostic dilemma. We hypothesized that MR perfusion without and with contrast can differentiate tumor recurrence from radiation necrosis. In this prospective study, we performed 3 MR perfusion methods: arterial spin-labeling, DSC, and dynamic contrast enhancement. For each lesion, we measured CBF from arterial spin-labeling, uncorrected relative CBV, and leakage-corrected relative CBV from DSC imaging. The volume transfer constant and plasma volume were obtained from dynamic contrast-enhanced imaging without and with T1 mapping using modified Look-Locker inversion recovery (MOLLI). The diagnosis of tumor recurrence or radiation necrosis was determined by either histopathology for patients who underwent re-resection or radiologic follow-up for patients who did not have re-resection. There were 26 patients with 32 lesions, 19 lesions with tumor recurrence and 13 lesions with radiation necrosis. Compared with radiation necrosis, lesions with tumor recurrence had higher CBF (P = .033), leakage-corrected relative CBV (P = .048), and plasma volume using MOLLI T1 mapping (P = .012). For differentiating tumor recurrence from radiation necrosis, the areas under the curve were 0.81 for CBF, 0.80 for plasma volume using MOLLI T1 mapping, and 0.71 for leakage-corrected relative CBV. A correlation was found between CBF and leakage-corrected relative CBV (r s = 0.54), volume transfer constant, and plasma volume (0.50 < r s< 0.77) but not with uncorrected relative CBV (r s = 0.20, P = .29). In the differentiation of tumor recurrence from radiation necrosis in a newly enhancing lesion, the diagnostic value of arterial spin-labeling-derived CBF is similar to that of DSC and dynamic contrast-enhancement-derived blood volume.

A Survey on Prophylactic Corticosteroids Use in Stereotactic Radiosurgery Treatments From Ibero and Latin America Centers.

Introduction Radiosurgery is a treatment in which a high dose of ionizing radiation is administered to a small field with high-precision techniques, and is a common treatment for tumors and other diagnoses. A typical complication is the development of radiation-induced edema that can progress to radiation necrosis in some cases.The administration of corticosteroids has been used empirically as a prophylaxis in patients who will be treated by stereotactic radiosurgery with intracranial tumors and other pathologies with the intention to prevent radiation-induced edema and or necrosis. Objective The aim of our study is to describe the actual use of corticosteroids in hospitals that perform stereotactic radiosurgery treatments in Latin America and Spain through a survey applied to neurosurgeons and radiation oncologists and expose the implications of the results, as well as to analyze the available literature on it. Methods We designed a questionnaire of 15 items related to the use of corticosteroids as prophylaxis in patients who will be treated with radiosurgery. The questionnaire was answered by 121 Ibero-Latin Americans through Google Drive considering a database from the Iberolatinoamerican Radiosurgery Association. Results We found that the preference for the use of corticosteroids as prophylaxis for radiosurgery is associated with informal training in radiosurgery, and it was more used by radiation oncologists compared to neurosurgeons (p=0.023). Side effects can exceed the benefit of its use. Conclusions There is practically no literature on the use of corticosteroids as prophylaxis for radiation necrosis in stereotactic radiosurgery. This is a controversial inter- and intra-specialty issue, and its empirical use has a relatively high prevalence, making us reconsider the value of experience in a medical environment that should be fundamentally guided by evidence-based medicine.

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases

Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P=.03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P< 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.