Treatment Of Radiation Necrosis Research Articles

154 Elucidating the Immune Landscape of Radiation Necrosis Through Single Cell Analysis of Recurrent Brain Lesions in Patients After Stereotactic Radio Surgery

INTRODUCTION: Radiation necrosis (RN), a common and morbid side effect of radiosurgical treatment of brain metastasis, is becoming more prevalent as immunotherapy options and patient survival improve. Thought to be immunologically driven, the pathophysiology of RN remains poorly defined. Further, RN is often indistinguishable from regrowing metastases after stereotactic radiosurgery (SRS), requiring invasive brain biopsy for diagnosis. METHODS: We collected 20 intraoperative samples from patients undergoing craniotomy for RN and/or metastatic tumor, as well as time-matched blood and CSF. We created a tissue bank, processed samples, and using fluorescence-activated cell sorting (FACS) and 10x Genomics single cell RNA sequencing, analyzed the cellular immune profile of lesional tissue, blood, and CSF. RESULTS: RN tissue demonstrates a robust, detectable expression of immune cells, including CD8+ and CD4+ T cells, natural killer (NK) and myeloid cells. Importantly, clustering of RN-derived immune cells (including T cells, myeloid cells, and NK cells) is reflected in the blood and CSF, with similar immune profiles. We demonstrate a subpopulation of myeloid cells with a microglia signature (CD14+, LYZ-, MS4A7+), and a separate population expressing interferon-stimulated gene (ISG). Supporting these findings, pathway analysis of top blood markers reveals pathways involved in innate and inflammatory immune responses in the blood of RN patients. CONCLUSIONS: These findings demonstrate the feasibility of extracting live cells from RN tissue for scRNAseq analysis and suggest that there are unique signatures of RN that can be detected in the blood and CSF of patients. This work has the potential to open new avenues for improved diagnostic and therapeutic approaches to allow earlier detection and more effective treatment of RN in patients with metastatic brain tumors.

Cluster-based radiomics reveal spatial heterogeneity of bevacizumab response for treatment of radiotherapy-induced cerebral necrosis

BackgroundBevacizumab is used in the treatment of radiation necrosis (RN), which is a debilitating toxicity following head and neck radiotherapy. However, there is no biomarker to predict if a patient would respond to bevacizumab. PurposeWe aimed to develop a cluster-based radiomics approach to characterize the spatial heterogeneity of RN and map their responses to bevacizumab. Methods118 consecutive nasopharyngeal carcinoma patients diagnosed with RN were enrolled. We divided 152 lesions from the patients into 101 for training, and 51 for validation. We extracted voxel-level radiomics features from each lesion segmented on T1-weighted+contrast and T2 FLAIR sequences of pre- and post-bevacizumab magnetic resonance images, followed by a three-step analysis involving individual- and population-level clustering, before delta-radiomics to derive five radiomics clusters within the lesions. We tested the association of each cluster with response to bevacizumab and developed a clinico-radiomics model using clinical predictors and cluster-specific features. Results71 (70.3%) and 34 (66.7%) lesions had responded to bevacizumab in the training and validation datasets, respectively. Two radiomics clusters were spatially mapped to the edema region, and the volume changes were significantly associated with bevacizumab response (OR:11.12 [95% CI: 2.54–73.47], P = 0.004; and 1.63[1.07–2.78], P = 0.042). The combined clinico-radiomics model based on textural features extracted from the most significant cluster improved the prediction of bevacizumab response, compared with a clinical-only model (AUC:0.755 [0.645–0.865] to 0.852 [0.764–0.940], training; 0.708 [0.554–0.861] to 0.816 [0.699–0.933], validation). ConclusionOur radiomics approach yielded intralesional resolution, enabling a more refined feature selection for predicting bevacizumab efficacy in the treatment of RN.

SURG-32. EFFICACY OF LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR BIOPSY-PROVEN RADIATION NECROSIS IN RADIOGRAPHICALLY RECURRENT BRAIN METASTASES

Abstract BACKGROUND Evidence is growing for the efficacy of laser interstitial thermal therapy (LITT) for radiation necrosis (RN) following stereotactic radiosurgery (SRS) for patients with brain metastases. Questions remain regarding local control, symptom control, and concurrent use of therapies. METHODS Demographics, intraprocedural data, safety, Karnofsky performance status (KPS) and survival data were prospectively collected from the LAANTERN multi-center registry (NCT02392078) then analyzed on patients consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 U.S. centers. Data was monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan Meier estimated survival. RESULTS Ninety patients met inclusion criteria. Median hospitalization time was 32.5hrs. Median time to corticosteroid cessation after LITT was 13 days (range 0 - 1229) and cumulative incidence of lesional progression was 19% at 1-year. Median post-procedure overall-survival was 2.6 years [1.7, NR] and 77% at one year as estimated by Kaplan Meier. Median KPS remained 80 through 2-year follow-up. Seizure prevalence improved from 34.4% pre-procedure to 12% 1-month post-LITT and 7.9% at 3-months. There was no significant difference in risk of radiographic progression in total and near-total ablations (91% or greater ablative coverage) versus sub-total ablations (< 90%). Lesion size was not a significant predictor of future radiographic progression. CONCLUSIONS LITT is an effective, minimally invasive, safe treatment for RN, in terms of both local control and symptom management. LITT is effective in the management of lesion-related seizures in addition to averting expected neurological death. LITT facilitates ongoing systemic therapy (particularly immunotherapy) by enabling the rapid cessation of corticosteroids. Effective management options for RN could facilitate the more aggressive use of combined systemic and radiotherapeutic treatment options for brain metastases patients in order to avoid failure due to tumor recurrence and extend survival.

Initial Report of Boswellia Serrata for Management of Cerebral Radiation Necrosis after Stereotactic Radiosurgery for Brain Metastases

Radiation necrosis (RN) is a concerning late toxicity after radiation therapy (RT) for brain metastases. Oral corticosteroids are the mainstay of management; however, they are not optimal for long-term use given multiple side effects and drug interactions, particularly with the emergence of immunotherapy for several cancers. Boswellia serrata (BS) is an over-the-counter supplement used for its anti-inflammatory properties and has been recently shown to reduce cerebral edema after brain RT. We evaluated the response rates with BS in a series of patients with brain metastases treated with stereotactic radiosurgery (SRS) who developed RN. We included patients who developed RN after SRS for brain metastases at our institution from 2020-2022 and were treated with BS. Patients were prescribed over the counter BS 4.2-4.5g daily in divided doses. Follow-up MRI imaging was obtained every 2-3 months after starting BS. Response was assessed using Response Assessment in Neuro-Oncology (RANO) criteria. Primary endpoint was ≥25% decrease in edema volume on T2-FLAIR MRI from baseline. Patients were censored if they had tumor progression or repeat RT to necrotic area, or death. Kaplan-Meier curves were used for survival estimates. A total of 50 patients received BS for Grade 1-3 CTCAE v5.0 RN (G1 = 11, G2 = 36, and G3 = 3). Median age was 62.8 years (range 36.9 - 50) and median RT dose was 24 Gy in 3 fractions. Median time to RN after SRS was 10 months(m). Median follow-up after starting BS was 6m and 40 patients had at least 1 follow up MRI available to evaluate response. The best response was complete response (CR) in 15% patients and partial response (PR) in 40% while 35% had stable disease (SD) and 10% had progressive disease. Median time to CR was 9m (6-12m) and PR was 6m (3-12m). Percentage of patients who had any response (CR or PR) at 3, 6, 9 and 12 months was 25%, 60%, 43% and 50%, respectively. 56% patients had symptomatic RN, of which 35.7% had improvement in symptoms with BS alone, while 64% required steroid use. Overall, median duration of response in patients with CR, PR or SD was 7.5m(range 2-31m). Salvage treatment for RN was steroids (33), surgery (4), Bevacizumab (5) or hyperbaric oxygen therapy (1). No patients had any CTCAE grade 3 or higher toxicities. 3 patients (6%) had any side-effects all of whom had Grade 1-2 gastrointestinal intolerance or diarrhea. 2 patients stopped treatment due to enrolment on an immunotherapy clinical trial. Overall, 39 patients remained on BS at last follow-up or death. We observed >50% response rates with use of BS in our cohort of patients with Grade 1-3 RN after SRS. More than 1/3rd patients with symptomatic RN were able to avoid long-term steroid use. BS is an easily available over-the-counter drug that appears to be a safe and promising treatment option for RN, and can potentially decrease steroid dependence in these patients, reducing the risk of several side-effects. Further prospective studies to compare Boswellia with placebo is warranted.

Pentoxifylline and Vitamin E Can Restrict Radiation Necrosis via Vascular Pathways, Experimental Study in an Animal Model

Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required. The iatrogenic RN model included 50 Sprague-Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma-Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30mg/kg/day in a single dose) and pentoxifylline (50mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations. The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups.When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern. Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment.

Outcomes with bevacizumab for radiation induced-brain necrosis.

e14006 Background: Radiation necrosis (RN) is post-radiation complication that leads to increased permeability and disruption of the blood brain barrier (BBB). This in turn leads to a pro-inflammatory state and an increased production of vascular-endothelial growth factor (VEGF). Bevacizumab is a monoclonal antibody against VEGF and is a potential treatment for RN. The objective of the study is to assess effectiveness of bevacizumab (BEV) for the treatment of brain RN in adults. Methods: Retrospective chart review of 22 patients with various solid malignancies including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), metastatic melanoma and breast cancer with clinical or radiographic diagnosis of RN seen at Memorial Cancer Institute (MCI) in a 3-year period, from January 1st, 2019 to January 1st, 2023. Radiation doses ranged from 18-24 Gy (single fraction) or 24-27 Gy (3-fraction) for radiosurgery and 30-37.5 Gy for whole brain radiotherapy. Patients were identified that developed RN and VEGF inhibitors were subsequently given to assess effectiveness in the treatment of the condition. We evaluated the dose, frequency, number of treatments received, adverse effects and therapeutic benefits of BEV. Therapeutic benefit was defined as patients that received bevacizumab had a radiological and clinical improvement of the RN (clinical benefit). Brain imaging with MRI or PET/CT scan was completed both pre and post treatment to evaluate efficacy of treatment. Patients were initially given 4 cycles with a subsequent 4 more cycles if it was beneficial and tolerated treatment. Results: 22 patients were included in the study, 9 were males (41%) and median age 66 (range 31-81). 91% (20/22) had a diagnosis of lung cancer. 1 patient had a diagnosis of SCLC, while 19 were diagnosed with NSCLC. The study had a good representation of different races including Non-Hispanic Whites 7 (32%), Hispanics 10 (45%), Blacks 13% (3) and Asians 10% (2). Over 95% (21/22) of patients achieved a clinical benefit, while one patient did not (5%). Patients experienced improvement in cognitive function, headaches, dizziness, weakness, and other symptoms with BEV. MRIs showed improvement in edema and a reduction/stabilization of brain lesions. The most frequent dosing regimen used was BEV 10 mg/kg every two weeks. The median number of cycles given was 4 cycles (1-12). The most common adverse events were hypertension, minor nose bleeding, an occasional protein found in urine. There were no severe AEs or discontinuation of therapy with bevacizumab. Conclusions: This study demonstrated treatment with BEV 10 mg/kg every two weeks for a total of 12 cycles is well tolerated and has potential clinical benefit in RN in lung cancer patients with CNS metastasis. The therapeutic effects of VEGF inhibitors were seen in our small population study but warrants further investigation in a larger population study.

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.

Clinical Outcomes of Stereotactic Radiosurgery-Related Radiation Necrosis in Patients with Intracranial Metastasis from Melanoma.

Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Efficacy of laser interstitial thermal therapy for biopsy-proven radiation necrosis in radiographically recurrent brain metastases.

Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies. Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival. Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure. LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients.

IMMU-01. DEFINING THE IMMUNE PROFILE OF RADIATION NECROSIS THROUGH SINGLE-CELL ANALYSIS OF INTRACRANIAL LESIONS

Abstract 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. We sought to define the neuroimmune profile of RN to better understand the underlying pathophysiological mechanisms and improve patient 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, 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, metastatic tissue demonstrates an antigen-reactive profile, including commonly observed exhaustion signatures. Importantly, blood samples from patients also reflect these differences. Interestingly, increased IL7R is implicated in autoimmune disorders, suggesting an iatrogenically-induced autoreactive process underlying RN. DISCUSSION 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.

DIPG-02. Role of a Bevacizumab-based regime in the treatment of children with diffuse intrinsic pontine glioma (DIPG): a systematic review

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour. There are no effective treatments and median survival is 11.2 months, therefore maintaining quality of life (QOL) is a priority for many families. Bevacizumab, an anti-VEGF IgG antibody, has the potential to improve QOL and survival in DIPG, but has never been evaluated systematically. AIM: To collate the evidence and assess the role of this drug, in the treatment of DIPG. METHODS: MEDLINE, EMBASE, Scopus and Web of Science were searched for relevant studies using terms developed from PICO criteria, including alternatives for Bevacizumab and DIPG. One reviewer screened titles and abstracts, then two reviewers screened full texts. Data were extracted into tables and study quality assessed using MINORS and JBI tools. RESULTS: Searching revealed 1,001 papers; after deduplication 851 remained. After screening of titles and abstracts, 28 full texts were screened, resulting in the inclusion of 11 studies. All studies evaluated more than one outcome. Four studies reported a median overall survival longer than historical data, however, two determined no significant impact. Five studies reported a radiological response in a proportion of participants and two reported no response. Three studies evaluating clinical response, reported improvement in a proportion of patients. Three studies evaluating QOL reported stability or improvement. Four studies evaluating steroid use reported reductions in the proportion of patients receiving steroids. In the treatment of radiation necrosis, Bevacizumab led to clinical improvement in 6/12 patients in 2 studies and permitted a reduction in steroid use in the majority of patients. CONCLUSION: Insufficient evidence means the role of Bevacizumab in the treatment of DIPG is unclear. However, Bevacizumab may be beneficial to some patients. The review highlights the need for further research in this area, particularly randomised controlled trials. More effective therapies are desperately needed.

Voxel-based radiomics outlines spatial heterogeneity of cerebral radiation necrosis (RN) associated with bevacizumab (Bev) response in head and neck radiotherapy (RT) patients.

e18063 Background: RN is a debilitating toxicity of head and neck RT, with incidences of 4% to 24%. Bev is a promising drug for managing RN, but there is currently no biomarker that could predict a priori if a patient would benefit from Bev. Here, we aimed to use radiomics to predict Bev response. However, current radiomics tools suffer from issues of interrater contouring variability and explanability of the radiomics models. We therefore investigated a voxel-based radiomics approach to characterize the spatial heterogeneity of RN, and define subregions that are associated with Bev response. Methods: 118 consecutive nasopharyngeal carcinoma (NPC) patients who were diagnosed with RN post-RT, and were treated with Bev between Jul 2012 and Mar 2019 at the Sun Yat-Sen Memorial Hospital were enrolled into the study. 77 patients with 101 brain lesions treated between Jul 2012 and Dec 2017 were assigned to the training set, and 41 patients with 51 brain lesions treated between Jan 2018 and Mar 2019 were used for validation. All patients received Bev prescribed at 5 mg/kg every fortnightly for up to 4 courses. We extracted voxel-based radiomics features from each segment drawn on T2 FLAIR MRI images, followed by a 3-step analysis (individual- and population-level clustering, before delta-radiomics) to obtain a clustered heat map of subregions within the RN lesion. Anatomical correlation to areas of edema, necrosis, and their interphase was performed. Delta-radiomics tracked the ∆ of each cluster to Bev. Features were then extracted from each radiomics cluster for model building. Results: 71 (70.3%) and 34 (66.7%) lesions had documented radiological responses to Bev in the training and validation sets, respectively. Responders (N = 105) and non-responders (N = 47) showed a 71.8% (IQR: 54.7-87.5) and 13.2% (IQR: 7.98-21.4) reduction in RN volumes, respectively. Five optimal clusters were determined using the shoulder method with ΔK metric. Spatial analyses revealed that 2 of the 5 clusters were associated with the edema areas, with 92.6% and 74.3% of the voxels located within this anatomic subregion. The two corresponding clusters were significantly associated with a response to Bev (Odds ratio [OR]: 11.12 (95% CI: 2.54-73.47), P = 0.004; OR: 1.63 [1.07-2.78], P = 0.042). Finally, we developed and validated a clinicoradiomics model based on features extracted from the 2 clusters that improved the prediction of Bev response, compared with a clinical-only model for both the training (AUC 0.852 vs 0.755) and validation (AUC 0.816 vs 0.691) cohorts. Conclusions: Our spatial radiomics approach revealed anatomic subregions that contain relevant radiomics features that could predict Bev efficacy in the treatment of RN in NPC patients. This method would improve the interpretability of radiomics, compared with current methods that lack spatial resolution.

Time to Steroid Independence After Laser Interstitial Thermal Therapy vs Medical Management for Treatment of Biopsy-Proven Radiation Necrosis Secondary to Stereotactic Radiosurgery for Brain Metastasis.

Radiation necrosis (RN) after stereotactic radiosurgery (SRS) for brain metastases (BM) can result in significant morbidity, compounded by the effects of extended steroid therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that can offer definitive treatment for RN while potentially obviating the need for prolonged steroid use. To compare LITT vs medical management (MM) in the treatment of RN. A multicenter, retrospective study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM. Clinical outcome data were compared by treatment modality. Seventy-two patients met criteria with a median follow-up of 10.0 months (4.2-25.1), and 57 patients (79%) underwent LITT. Four MM (27%) and 3 LITT patients (5%) demonstrated radiographic progression (P = .031) at a median of 5.3 and 4.0 months (P = .40). There was no significant difference in overall survival (LITT median of 15.2 vs 11.6 months, P = .60) or freedom from local progression (13.6 vs 7.06 months, P = .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days (P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point (P = .003). These data suggest that LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Prospective trials should be designed to further validate the utility of LITT for RN and its impact on steroid-induced morbidity.

A Single-Institution Retrospective Study of Patients Treated With Laser-Interstitial Thermal Therapy for Radiation Necrosis of the Brain.

ObjectLaser-interstitial thermal therapy (LITT) has been proposed as an alternative treatment to surgery for radiation necrosis (RN) in patients treated with stereotactic radiosurgery (SRS) for brain metastases. The present study sought to retrospectively analyze LITT outcomes in patients with RN from SRS.MethodsThis was a single-institution retrospective study of 30 patients treated from 2011-2018 with pathologically-proven RN after SRS for brain metastases (n=28) or proximally treated extracranial lesions treated with external beam radiotherapy (n=2). Same-day biopsy was performed in all cases. Patients were prospectively followed with Functional Assessment of Cancer Therapy - Brain (FACT-Br), EuroQol-5 Dimension (EQ-5D), Hopkins Verbal Learning Test (HVLT) and clinical history and examination. Adjusted means, standard errors and tests comparing visits to pre-LITT were generated. Kaplan-Meier method was used to estimate time overall survival. Competing risk analysis was used to estimate cumulative incidence of LITT failure.ResultsIn our patient population, median time from radiotherapy to LITT was 13.1 months. Median SRS dose and median LITT treatment target volume were 20 Gy (IQR 18-22) and 3.5 cc (IQR 2.2-4.6), respectively. Seventy-seven percent of our patients tapered off steroids within one month. There were only two instances of RN recurrence after LITT, with recurrence defined as recurrence of symptoms after initial improvement. These recurrences occurred at 1.9 and 3.4 months. The three-, six- and nine-month freedom from recurrence rates were 95.7%, 90.9%, and 90.9%. Median survival in our patient population with pathologically confirmed RN treated with LITT was 2.1 years. Regarding the quality of life questionnaires with which some patients were followed as part of different prospective studies, completion rates were 22/30 for FACT-Br, 16/30 for the EQ-5D and 8/30 for HVLT. Quality of life questionnaire results were overall stable from baseline. Mean FACT-Br scores were stable from baseline (17.9, 16.6, 21.4 and 22.8) to three months (18.8, 15.4, 18.4 and 23.4) (p=0.38, 0.53, 0.09 and 0.59). The mean EQ-5D Aggregate score was stable from baseline (7.1) to one month (7.6) (p=0.25). Mean HVLT-R Total Recall was stable from baseline (20.6) to three months (18.4) (p=0.09). There was a statistically significant decrease in mean Karnofsky Performance Scale (KPS) score from baseline (84) to three-month follow-up (75) (p=0.03).ConclusionsLITT represents a safe and durably effective treatment option for RN in the brain. Results demonstrate a median survival of 2.1 years from LITT with only two recurrences, both within four months of treatment and salvageable. Patient-reported outcomes showed no severe declines after LITT. Quality of life questionnaires demonstrated stable well-being and functionality from baseline. LITT should be considered for definitive treatment of RN, especially in cases where patients have significant side effects from standards medical therapies such as steroids or if steroids are minimally effective.

Low-Dosage Bevacizumab Treatment: Effect on Radiation Necrosis After Gamma Knife Radiosurgery for Brain Metastases.

Cerebral radiation necrosis (RN), a complication of Gamma Knife radiosurgery, is difficult to treat, although bevacizumab seems to be effective. However, clinical data pertaining to bevacizumab treatment for RN are scarce, and its high price is problematic. This study explored the effectiveness of low-dose bevacizumab for RN caused by Gamma Knife. We retrospectively analyzed 22 patients who suffered cerebral RN post-Gamma Knife, and received bevacizumab treatment because of the poor efficacy of glucocorticoids. Low-dose bevacizumab (3 mg/kg) was administered for two cycles at 2-week intervals. T1- and T2-enhanced magnetic resonance imaging (MRI) images were examined for changes in RN status. We also monitored the dose of glucocorticoid, Karnofsky Performance Status (KPS) score, and adverse drug reactions. The mean volume of RN lesions decreased by 45% on T1-weighted images with contrast enhancement, and by 74% on T2-weighted images. All patients discontinued the use of glucocorticoids. According to the KPS scores, all patients showed an improvement in their symptoms and neurological function. No side effects were observed. Low-dosage bevacizumab at a dose of 3 mg/kg every 2 weeks is effective for treating cerebral RN after Gamma knife for brain metastases.

Bevacizumab for stereotactic radiosurgery-induced radiation necrosis in patients with non-small cell lung cancer treated with immune check-point inhibitors

BackgroundBevacizumab was shown to be effective in the treatment of brain radiation necrosis (RN) attributed to the use of stereotactic radiosurgery (SRS). Data on its efficacy and safety in non-small cell lung cancer (NSCLC) patients treated with immune check-point inhibitors (ICI) is lacking. MethodsA multi-center retrospective analysis of all consecutive patients with NSCLC treated with ICI, who received bevacizumab for post-SRS RN between April 2017 and June 2020. Improvement in RN-associated symptoms, RN radiological improvement, and decrease in corticosteroid dose following bevacizumab initiation were assessed. ResultsThirteen patients were identified. The median time from diagnosis of RN to initiation of bevacizumab was 3 months (range 1.1–7.8 months), and the median number of bevacizumab cycles before assessment was 2 (range, 1–5). Patients continued ICI during treatment with bevacizumab. Improvement in RN-associated symptoms was observed in 11 patients (85%). In ten patients (77%) the daily dose of dexamethasone was decreased. Radiological improvement of RN occurred in all 11 cases available for radiological assessment (100%). Treatment was withheld in two patients for grade 3–4 toxicity. At a median follow up of 11.9 months (range 2.0–35.4 months), one patient experienced a recurrent episode of RN; the estimated median survival since RN diagnosis was 21.9 months (95% CI 3.8–40.2 months). ConclusionTreatment with bevacizumab appears to be safe and effective for the treatment of SRS-induced RN in patients with NSCLC treated with ICI. This is the first series to report on the use of bevacizumab in this clinical scenario.

Bevacizumab for radiation necrosis following radiotherapy of brain metastatic disease: a systematic review & meta-analysis

BackgroundRadiotherapy is the mainstay of brain metastasis (BM) management. Radiation necrosis (RN) is a serious complication of radiotherapy. Bevacizumab (BV), an anti-vascular endothelial growth factor monoclonal antibody, has been increasingly used for RN treatment. We systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab for treatment of RN in BM patients.Materials and methodsPubMed, Medline, EMBASE, and Cochrane library were searched with various search keywords such as “bevacizumab” OR “anti-VEGF monoclonal antibody” AND “radiation necrosis” OR “radiation-induced brain necrosis” OR “RN” OR “RBN” AND “Brain metastases” OR “BM” until 1st Aug 2020. Studies reporting the efficacy and safety of BV treatment for BM patients with RN were retrieved. Study selection and data extraction were carried out by independent investigators. Open Meta Analyst software was used as a random effects model for meta-analysis to obtain mean reduction rates.ResultsTwo prospective, seven retrospective, and three case report studies involving 89 patients with RN treated with BV were included in this systematic review and meta-analysis. In total, 83 (93%) patients had a recorded radiographic response to BV therapy, and six (6.7%) had experienced progressive disease. Seven studies (n = 73) reported mean volume reductions on gadolinium-enhanced T1 (mean: 47.03%, +/− 24.4) and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI images (mean: 61.9%, +/− 23.3). Pooling together the T1 and T2 MRI reduction rates by random effects model revealed a mean of 48.58 (95% CI: 38.32–58.85) for T1 reduction rate and 62.017 (95% CI: 52.235–71.799) for T2W imaging studies. Eighty-five patients presented with neurological symptoms. After BV treatment, nine (10%) had stable symptoms, 39 (48%) had improved, and 34 (40%) patients had complete resolution of their symptoms. Individual patient data was available for 54 patients. Dexamethasone discontinuation or reduction in dosage was observed in 30 (97%) of 31 patients who had recorded dosage before and after BV treatment. Side effects were mild.ConclusionsBevacizumab presents a promising treatment strategy for patients with RN and brain metastatic disease. Radiographic response and clinical improvement was observed without any serious adverse events. Further class I evidence would be required to establish a bevacizumab recommendation in this group of patients.

Bevacizumab as a treatment for radiation necrosis following stereotactic radiosurgery for brain metastases: clinical and radiation dosimetric impacts.

Brain necrosis (RN) is a common radiotherapy sequela for brain metastases. Bevacizumab is identified as a therapeutic strategy for RN. This study aimed to study the clinical and radiobiological impacts on the efficacy of Bevacizumab in treating RN following stereotactic radiosurgery (SRS) for brain metastases. From April 2011 to November 2019, 40 patients diagnosed with RN after SRS for brain metastases were retrospectively analyzed. Patients were treated with Bevacizumab for RN and follow-up for 6 months using MR imaging at different timepoints. Linear regression was performed to evaluate the relationship between these variables. The median time course from the end of radiotherapy to the onset of RN was 11 months (range, 7-35 months). No significant difference was found in the edema volume between the chemotherapy group and non-chemotherapy group (P>0.05). Patients received with SRS + WBRT exhibited relatively larger edema volumes post radiotherapy than those without WBRT (P<0.05). Interestingly, the ratio of BED/GTV (Gy/cm3 ) correlated positively with the severity (time for half-reduction dose of corticosteroids) (r2 =0.13, P<0.05), and negatively with the latency period (time course for development of radiation-induced brain necrosis) (r2 =0.21, P<0.01). A new radiation doses volume index, BED × GTV (Gy·cm3 ), was proposed to facilitate the risk stratifications of patients for radiation-induced brain necrosis. Furthermore, no significant difference was found in alleviating brain edema between different regimens of Bevacizumab, i.e., 5 vs. 10 mg/kg, 2 vs. >2 cycles (both P>0.05). Bevacizumab is a feasible and favorable salvage treatment of BN after SRS for patients with BM. The efficacy is mainly manifested in radiological improvement and symptoms alleviation. The development of RN was found to be largely associated with radiation dose and gross tumor volume, and thus we proposed two new indexes, i.e., BED/GTV (Gy/cm3 ) for quantitative assessment of the severity and latency time, and BED × GTV (Gy·cm3 ) for risk stratifications for BN. A low dose with two cycles of Bevacizumab is recommended.

Experience of Using Hyperbaric Oxygenation in the Treatment of Radionecrosis That Developed as a Complication of Stereotactic Radiosurgical Treatment of Meningioma on the Example of a Clinical Case

In contrast to conventional microsurgery, stereotactic radiosurgery has an advantage in the treatment of intracranial masses, avoiding severe complications associated with open surgery. In rare cases, the use of the method is associated with the development of radiation-induced injuries, one of which is radiation necrosis (RN). This is a late complication of radiosurgery, developing mainly 6 months after radiation exposure. The neurological manifestations of this complication depend on location, and the clinical picture is very diverse. The method of magnetic resonance imaging (MRI) with intravenous contrast enhancement is quite often the first link in neuroimaging, which helps to suggest the presence of this complication based on the X-ray picture and to clarify the location of changes.We presented the experience of radiation necrosis treatment in a 47-year-old patient who was referred to our department with a diagnosis of frontal meningioma. The patient underwent stereotactic radiosurgical treatment using the Elekta Leksell Gamma Knife Perfextion device, and 6 months later the gradual deterioration began, the patient complained of headache, nausea; central prosoparesis developed. Considering the clinical picture and control MRI data, the changes were interpreted as radionecrosis. In order to control the complication, the patient underwent standard glucocroticosteroid therapy, supplemented by hyperbaric oxygenation (HBO), which made it possible to achieve regression of the adverse clinical and radiological manifestations of the complication. Thus, on a clinical example, it was demonstrated that the combined use of glucocorticosteroids and HBOs is highly effective in the treatment of RN.

Clinical Experience of Bevacizumab for Radiation Necrosis in Patients with Brain Metastasis.

BackgroundAs the application of radiotherapy to brain metastasis (BM) increases, the incidence of radiation necrosis (RN) as a late toxicity of radiotherapy also increases. However, no specific treatment for RN is indicated except long-term steroids. Here, we summarize the clinical results of bevacizumab (BEV) for RN.MethodsTen patients with RN who were treated with BEV monotherapy (7 mg/kg) were retrospectively reviewed. RN diagnosis was made using MRI with or without perfusion MRI. Radiological response was based on Response Assessment in Neuro-Oncology criteria for BM. The initial response was observed after 2 cycles every 2 weeks, and maintenance observed after 3 cycles every 3–6 weeks of increasing length intervals.ResultsThe initial response of gadolinium (Gd) enhancement diameter maintained stable disease (SD) in 9 patients, and 1 patient showed partial response (PR). The initial fluid-attenuated inversion recovery (FLAIR) response showed PR in 4 patients and SD in 6 patients. The best radiological response was observed in 9 patients. Gd enhancement response was 6 PR and 3 SD between 15–43 weeks. Reduction of FLAIR showed PR in 5 patients and SD in 4 patients. Clinical improvement was observed in all but 1 patient. Five patients were maintained on protocol with durable response up to 23 cycles. However, 2 patients stopped treatment due to primary cancer progression, 1 patient received surgical removal from tumor recurrence, and 1 patient changed to systemic chemotherapy for new BM. Grade 3 intractable hypertension occurred in 1 patient who had already received antihypertensive medication.ConclusionBEV treatment for RN from BM radiotherapy resulted in favorable radiological (60%) and clinical responses (90%). Side effects were expectable and controllable. We anticipate prospective clinical trials to verify the effect of BEV monotherapy for RN.