Local failure after stereotactic radiosurgery (SRS) for intracranial metastasis: analysis from a cooperative, prospective national registry.

INTRODUCTION: Stereotactic radiosurgery (SRS) has been increasingly employed to treat patients with intracranial metastasis, both as a salvage treatment after failed whole brain radiation therapy (WBRT) and as an initial treatment. "Several studies have shown that SRS may be as effective as WBRT with the added benefit of preserving neuro-cognition". However, some patients may have local failure following SRS for intracranial metastasis, defined as increase in total lesion volume by 25% after at least 3 months of follow up. METHODS: The SRS registry, established by the Neuro point alliance (NPA) under the auspices of the American Association of Neurological Surgeons (AANS), was queried for patients with intracranial metastasis receiving SRS at the participating sites. Demographic, clinical symptoms, tumor, and treatment characteristics as well as follow up status were summarized for the cohort. A multivariable explanatory cox- regression was performed to evaluate the impact of each of the factors on time to local failure.at last follow-up. RESULTS: A total of 441 patients with 1255 intracranial metastatic lesions undergoing SRS were identified. The most common primary cancer histology was non-small cell lung cancer (43.8%, n = 193). More than half of the cohort had more than 1 metastatic lesion (2-3 lesions: 29.5%, n = 130; more than 3 lesions: 25.2% (n = 111). The average duration of follow-up for the cohort was found to be 8.4 months (SD = 7.61). The mean clinical treatment volume (CTV), after adding together the volume of each lesion for each patient was 5.39 cc (SD = 7.6) at baseline. A total of 20.2% (n = 89) had local failure (increase in volume by > 25%) with a mean time to progression of 7.719 months (SD = 6.09). The progression free survival (PFS) for the cohort at 3, 6 and 12 months were found to be 94.9%, 84.3%, and 69.4%, respectively. On multivariable cox regression analysis, factors associated with increased hazard of local failure included male gender (HR 1.65, 95% CI 1.03-2.66, p = 0.037), chemotherapy at or before SRS (HR = 2.39, 95% CI 1.41-4.05, p = 0.001), WBRT at or before SRS (HR = 2.21, 95% CI 1.16- 4.22, p = 0.017), while surgical resection (HR 0.45, 95% CI 0.21-0. 97, p = 0.04) and immunotherapy (0.34, 95% CI 0.16-0.50, p = 0.014) were associated with lower hazard of local failure. CONCLUSION: Factors found to be predictive of local failure included higher RPA score and those receiving chemotherapy, while patients undergoing surgical resection and those with occipital lobe lesions were less likely to experience local failure. Our analyses not only corroborate those previously reported but also demonstrate the utility of a multi-institutional registry to advance real-world SRS research for patients with intracranial metastatic lesions.

Stereotactic radiosurgery for IDH wild type glioblastoma: an international, multicenter study.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutation status is recommended used for diagnosis and prognostication of glioblastoma patients. We studied efficacy and safety of stereotactic radiosurgery (SRS) for patients with recurrent IDH-wt glioblastoma. METHODS: Consecutive patients treated with SRS for IDH-wt glioblastoma were pooled for this retrospective observational international multi-institutional study from institutions participating in the International Radiosurgery Research Foundation. RESULTS: Sixty patients (median age 61 years) underwent SRS (median dose 15 Gy and median treatment volume: 7.01 cm3) for IDH-wt glioblastoma. All patients had histories of surgery and chemotherapy with temozolomide, and 98% underwent fractionated radiation therapy. MGMT status was available for 42 patients, of which half of patients had MGMT mutant glioblastomas. During median post-SRS imaging follow-up of 6 months, 52% of patients experienced tumor progression. Median post-SRS progression free survival was 4 months. SRS prescription dose of > 14 Gy predicted longer progression free survival [HR 0.357 95% (0.164-0.777) p = 0.009]. Fifty-percent of patients died during post-SRS clinical follow-up that ranged from 1 to 33 months. SRS treatment volume of > 5 cc emerged as an independent predictor of shorter post-SRS overall survival [HR 2.802 95% CI (1.219-6.444) p = 0.02]. Adverse radiation events (ARE) suggestive of radiation necrosis were diagnosed in 6/55 (10%) patients and were managed conservatively in the majority of patients. CONCLUSIONS: SRS prescription dose of > 14 Gy is associated with longer progression free survival while tumor volume of > 5 cc is associated with shorter overall survival after SRS for IDH-wt glioblastomas. AREs are rare and are typically managed conservatively.

Stereotactic radiosurgery for clinoid meningiomas: a multi-institutional study.

PURPOSE: Resection of clinoid meningiomas can be associated with significant morbidity. Experience with stereotactic radiosurgery (SRS) for clinoid meningiomas remains limited. We studied the safety and effectiveness of SRS for clinoid meningiomas. METHODS: From twelve institutions participating in the International Radiosurgery Research Foundation, we pooled patients treated with SRS for radiologically suspected or histologically confirmed WHO grade I clinoid meningiomas. RESULTS: Two hundred seven patients (median age: 56 years) underwent SRS for clinoid meningiomas. Median treatment volume was 8.02 cm3, and 87% of tumors were immediately adjacent to the optic apparatus. The median tumor prescription dose was 12 Gy, and the median maximal dose to the anterior optic apparatus was 8.5 Gy. During a median post-SRS imaging follow-up of 51.1 months, 7% of patients experienced tumor progression. Greater margin SRS dose (HR = 0.700, p = 0.007) and pre-SRS radiotherapy (HR = 0.004, p < 0.001) were independent predictors of better tumor control. During median visual follow-up of 48 months, visual function declined in 8% of patients. Pre-SRS visual deficit (HR = 2.938, p = 0.048) and maximal radiation dose to the optic apparatus of ≥ 10 Gy (HR = 11.297, p = 0.02) independently predicted greater risk of post-SRS visual decline. Four patients experienced new post-SRS cranial nerve V neuropathy. CONCLUSIONS: SRS allows durable control of clinoid meningiomas and visual preservation in the majority of patients. Greater radiosurgical prescription dose is associated with better tumor control. Radiation dose to the optic apparatus of ≥ 10 Gy and visual impairment before the SRS increase risk of visual deterioration.

Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK.

The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that plays an important role in cell proliferation, growth, and survival. It remains unclear whether AMPK functions as a tumor suppressor or a contextual oncogene. This is because although on one hand active AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesis--two crucial arms of cancer growth--AMPK also ensures viability by metabolic reprogramming in cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin (now in over 50 clinical trials on cancer) has been correlated with reduced cancer cell proliferation and viability. Surprisingly, we found that compared with normal tissue, AMPK is constitutively activated in both human and mouse gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, but through unique AMPK-independent mechanisms and both reduced tumor growth in vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no effect on proliferation, uncoupling high AMPK activity from inhibition of proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal degradation of the G2M phosphatase cdc25c. Together, our results suggest that although AICAR and metformin are potent AMPK-independent antiproliferative agents, physiological AMPK activation in glioma may be a response mechanism to metabolic stress and anticancer agents.

Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation.

Next generation sequencing has become a powerful tool in dissecting and identifying mutations and genomic structural variants that accompany tumourigenesis. Sequence analysis of glioblastoma multiforme (GBM) illustrates the ability to rapidly identify mutations that may affect phenotype. Approximately 50% of human GBMs overexpress epidermal growth factor receptor (EGFR) which renders the EGFR protein a compelling therapeutic target. In brain tumours, attempts to target EGFR as a cancer therapeutic, however, have achieved little or no benefit. The mechanisms that drive therapeutic resistance to EGFR inhibitors in brain tumours are not well defined, and drug resistance contributes to the deadly and aggressive nature of the disease. Whole genome sequencing of four primary GBMs revealed multiple pathways by which EGFR protein abundance becomes deregulated in these tumours and will guide the development of new strategies for treating EGFR overexpressing tumours. Each of the four tumours displayed a different mechanism leading to increased EGFR protein levels. One mechanism is mediated by gene amplification and tandem duplication of the kinase domain. A second involves an intragenic deletion that generates a constitutively active form of the protein. A third combines the loss of a gene which encodes a protein that regulates EGFR abundance as well as an miRNA that modulates EGFR expression. A fourth mechanism entails loss of an ubiquitin ligase docking site in the C-terminal part of the protein whose absence inhibits turnover of the receptor.

The AANS/CNS Section on Tumors: a summary of 40 years of advocacy to advance the care of patients with brain and spine tumors.

The AANS/CNS Section on Tumors was founded 40 years ago in 1984 to assist in the education of neurosurgeons interested in neuro-oncology, and serves as a resource for other national organizations regarding the clinical treatment of nervous system tumors. The Section on Tumors was the first national physicians' professional organization dedicated to the study and treatment of patients with brain and spine tumors. Over the past 40 years, the Section on Tumors has built solid foundations, including establishing the tumor section satellite meetings, founding the Journal of Neuro-Oncology (the first medical journal dedicated to brain and spine surgical oncology), advancing surgical neuro-oncology education and research, promoting neurosurgical involvement in neuro-oncology clinical trials, and advocating for patients with brain and spine tumors. This review provides a synopsis of the Section on Tumors' history, its challenges, and its opportunities, drawing on the section's archives and input from the 17 section chairs who led it during its first 40 years.

Impact of Multiple Sclerosis Subtypes on Pain Management in Patients With Trigeminal Neuralgia After Stereotactic Radiosurgery: An International Multicenter Analysis.

BACKGROUND AND OBJECTIVES: Trigeminal neuralgia affects approximately 2% of patients with multiple sclerosis (MS) and often shows higher rates of pain recurrence after treatment. Previous studies on the effectiveness of stereotactic radiosurgery (SRS) for trigeminal neuralgia did not consider the different MS subtypes, including remitting relapsing (RRMS), primary progressive (PPMS), and secondary progressive (SPMS). Our objective was to investigate how MS subtypes are related to pain control (PC) rates after SRS. METHODS: We conducted a retrospective multicenter analysis of prospectively collected databases. Pain status was assessed using the Barrow National Institute Pain Intensity Scales. Time to recurrence was estimated through the Kaplan-Meier method and compared groups using log-rank tests. Logistic regression was used to calculate the odds ratio (OR). RESULTS: Two hundred and fifty-eight patients, 135 (52.4%) RRMS, 30 (11.6%) PPMS, and 93 (36%) SPMS, were included from 14 institutions. In total, 84.6% of patients achieved initial pain relief, with a median time of 1 month; 78.7% had some degree of pain recurrence with a median time of 10.2 months for RRMS, 8 months for PPMS, 8.1 months for SPMS ( P = .424). Achieving Barrow National Institute-I after SRS was a predictor for longer periods without recurrence ( P = .028). Analyzing PC at the last available follow-up and comparing with RRMS, PPMS was less likely to have PC (OR = 0.389; 95% CI 0.153-0.986; P = .047) and SPMS was more likely (OR = 2.0; 95% CI 0.967-4.136; P = .062). A subgroup of 149 patients did not have other procedures apart from SRS. The median times to recurrence in this group were 11.1, 9.8, and 19.6 months for RRMS, PPMS, and SPMS, respectively (log-rank, P = .045). CONCLUSION: This study is the first to investigate the relationship between MS subtypes and PC after SRS, and our results provide preliminary evidence that subtypes may influence pain outcomes, with PPMS posing the greatest challenge to pain management.

The relevance of biologically effective dose for pain relief and sensory dysfunction after Gamma Knife radiosurgery for trigeminal neuralgia: an 871-patient multicenter study.

OBJECTIVE: Recent studies have suggested that biologically effective dose (BED) is an important correlate of pain relief and sensory dysfunction after Gamma Knife radiosurgery (GKRS) for trigeminal neuralgia (TN). The goal of this study was to determine if BED is superior to prescription dose in predicting outcomes in TN patients undergoing GKRS as a first procedure. METHODS: This was a retrospective study of 871 patients with type 1 TN from 13 GKRS centers. Patient demographics, pain characteristics, treatment parameters, and outcomes were reviewed. BED was compared with prescription dose and other dosimetric factors for their predictive value. RESULTS: The median age of the patients was 68 years, and 60% were female. Nearly 70% of patients experienced pain in the V2 and/or V3 dermatomes, predominantly on the right side (60%). Most patients had modified BNI Pain Intensity Scale grade IV or V pain (89.2%) and were taking 1 or 2 pain medications (74.1%). The median prescription dose was 80 Gy (range 62.5-95 Gy). The proximal trigeminal nerve was targeted in 77.9% of cases, and the median follow-up was 21 months (range 6-156 months). Initial pain relief (modified BNI Pain Intensity Scale grades I-IIIa) was noted in 81.8% of evaluable patients at a median of 30 days. Of 709 patients who achieved initial pain relief, 42.3% experienced at least one pain recurrence after GKRS at a median of 44 months, with 49.0% of these patients undergoing a second procedure. New-onset facial numbness occurred in 25.3% of patients after a median of 8 months. Age ≥ 63 years was associated with a higher probability of both initial pain relief and maintaining pain relief. A distal target location was associated with a higher probability of initial and long-term pain relief, but also a higher incidence of sensory dysfunction. BED ≥ 2100 Gy2.47 was predictive of pain relief at 30 days and 1 year for the distal target, whereas physical dose ≥ 85 Gy was significant for the proximal target, but the restricted range of BED values in this subgroup could be a confounding factor. A maximum brainstem point dose ≥ 29.5 Gy was associated with a higher probability of bothersome facial numbness. CONCLUSIONS: BED and physical dose were both predictive of pain relief and could be used as treatment planning goals for distal and proximal targets, respectively, while considering maximum brainstem point dose < 29.5 Gy as a potential constraint for bothersome numbness.

Vestibular Schwannoma International Study of Active Surveillance Versus Stereotactic Radiosurgery: The VISAS Study.

PURPOSE: The present study assesses the safety and efficacy of stereotactic radiosurgery (SRS) versus observation for Koos grade 1 and 2 vestibular schwannoma (VS), benign tumors affecting hearing and neurological function. METHODS AND MATERIALS: This multicenter study analyzed data from Koos grade 1 and 2 VS patients managed with SRS (SRS group) or observation (observation group). Propensity score matching balanced patient demographics, tumor volume, and audiometry. Outcomes measured were tumor control, serviceable hearing preservation, and neurological outcomes. RESULTS: In 125 matched patients in each group with a 36-month median follow-up (P = .49), SRS yielded superior 5- and 10-year tumor control rates (99% CI, 97.1%-100%, and 91.9% CI, 79.4%-100%) versus observation (45.8% CI, 36.8%-57.2%, and 22% CI, 13.2%-36.7%; P < .001). Serviceable hearing preservation rates at 5 and 9 years were comparable (SRS 60.4% CI, 49.9%-73%, vs observation 51.4% CI, 41.3%-63.9%, and SRS 27% CI, 14.5%-50.5%, vs observation 30% CI, 17.2%-52.2%; P = .53). SRS were associated with lower odds of tinnitus (OR = 0.39, P = .01), vestibular dysfunction (OR = 0.11, P = .004), and any cranial nerve palsy (OR = 0.36, P = .003), with no change in cranial nerves 5 or 7 (P > .05). Composite endpoints of tumor progression and/or any of the previous outcomes showed significant lower odds associated with SRS compared with observation alone (P < .001). CONCLUSIONS: SRS management in matched cohorts of Koos grade 1 and 2 VS patients demonstrated superior tumor control, comparable hearing preservation rates, and significantly lower odds of experiencing neurological deficits. These findings delineate the safety and efficacy of SRS in the management of this patient population.

Clinical and Imaging Outcomes After Trigeminal Schwannoma Radiosurgery: Results From a Multicenter, International Cohort Study.

BACKGROUND AND OBJECTIVES: An international, multicenter, retrospective study was conducted to evaluate the long-term clinical outcomes and tumor control rates after stereotactic radiosurgery (SRS) for trigeminal schwannoma. METHODS: Patient data (N = 309) were collected from 14 international radiosurgery centers. The median patient age was 50 years (range 11-87 years). Sixty patients (19%) had prior resections. Abnormal facial sensation was the commonest complaint (49%). The anatomic locations were root (N = 40), ganglion (N = 141), or dumbbell type (N = 128). The median tumor volume was 4 cc (range, 0.2-30.1 cc), and median margin dose was 13 Gy (range, 10-20 Gy). Factors associated with tumor control, symptom improvement, and adverse radiation events were assessed. RESULTS: The median and mean time to last follow-up was 49 and 65 months (range 6-242 months). Greater than 5-year follow-up was available for 139 patients (45%), and 50 patients (16%) had longer than 10-year follow-up. The overall tumor control rate was 94.5%. Tumors regressed in 146 patients (47.2%), remained unchanged in 128 patients (41.4%), and stabilized after initial expansion in 20 patients (6.5%). Progression-free survival rates at 3 years, 5 years, and 10 years were 91%, 86%, and 80 %. Smaller tumor volume (less than 8 cc) was associated with significantly better progression-free survival ( P = .02). Seventeen patients with sustained growth underwent further intervention at a median of 27 months (3-144 months). Symptom improvement was noted in 140 patients (45%) at a median of 7 months. In multivariate analysis primary, SRS ( P = .003) and smaller tumor volume ( P = .01) were associated with better symptom improvement. Adverse radiation events were documented in 29 patients (9%). CONCLUSION: SRS was associated with long-term freedom (10 year) from additional management in 80% of patients. SRS proved to be a valuable salvage option after resection. When used as a primary management for smaller volume tumors, both clinical improvement and prevention of new deficits were optimized.

Hypofractionated stereotactic radiotherapy for unifocal and multifocal recurrence of malignant gliomas.

To evaluate the efficacy and safety of stereotactic radiotherapy (SRT) for unifocal and multifocal recurrence of malignant gliomas. Between June 2007 and October 2010, 35 consecutive patients with 47 recurrent lesions were treated with salvage SRT at the University of Cincinnati. Thirty-three patients treated had a diagnosis of high grade glioma, four Grade III and twenty-nine Grade IV, while two patients initially were diagnosed with grade II tumors but recurred as high grade lesions. All patients had previously received a median dose of 59.4 Gy. Twenty-six patients were treated for a single lesion, and nine patients were treated for multiple lesions. Using SRT, patients were re-treated with a median total dose of 30 Gy in a median of five fractions. Median survival from diagnosis was 22 months and median survival following SRT was 8.6 months. The median survival following SRT for those patients treated for multifocal recurrence was 7.9 versus 10 months for those treated for unifocal recurrence (p = 0.7). Multivariate analysis showed local control of the SRT treated lesion(s) 6 months after SRT was associated with a significant improvement in survival (p ≤ 0.01). All patients tolerated their treatment well and completed their prescribed SRT as planned. Three patients (9 %) were felt to possibly have developed radiation necrosis following therapy. SRT was both well tolerated and efficacious with the local control provided by SRT resulting in improved overall survival. This benefit also seems to be apparent for patients with multi-focal recurrence.

Detection of EGFRvIII mutant DNA in the peripheral blood of brain tumor patients.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens including surgical resection, radiation and chemotherapy. EGFRvIII is a truncated extracellular mutant of the EGF receptor (EGFR) found in about a third of GBMs. It confers enhanced tumorigenic behavior and is associated with chemo- and radio-resistance. GBM patients testing positive for EGFRvIII have a bleaker prognosis than those who do not. Targeting EGFRvIII positive tumors via vaccines or antibody-drug-conjugates represents a new challenging therapeutic avenue with potential great clinical benefits. In this study, we developed a strategy to detect EGFRvIII deletion in the circulating tumor DNA. The overall goal is to identify a simple and robust biomarker in the peripheral blood of patients diagnosed with GBM in order to follow their disease status while on treatment. Thirteen patients were included in this study, three of which were found to carry the EGFRvIII deletion. The circulating DNA status for EGFRvIII correlates with the analysis performed on the respective tumor samples, and its level seems to correlate with the extent of the tumor resection. This semi-quantitative blood biomarker may represent a strategy to (1) screen patients for an anti-EGFRvIII therapy and (2) monitor the patients' response to treatment.

Treatment of adverse radiation effects with Boswellia serrata after failure of pentoxifylline and vitamin E: illustrative cases.

BACKGROUND: Adverse radiation effects (AREs) can occur after stereotactic radiosurgery (SRS), and symptomatic cases are often treated with corticosteroids, pentoxifylline, and vitamin E. The supplement 5-Loxin (Boswellia serrata) is an extract of Indian frankincense that inhibits vascular endothelial growth factor expression and has been shown to reduce perilesional edema in brain tumor patients undergoing fractionated radiation. OBSERVATIONS: Three patients underwent SRS for meningioma or metastasis and developed symptomatic AREs at 4 to 8 months. They were initially treated with corticosteroids, pentoxifylline, and vitamin E with transient improvement followed by recurrent neurological symptoms and imaging findings as steroids were tapered off. All patients were rescued by the administration of 5-Loxin with resolution of neurological symptoms and imaging changes, discontinuation of steroids, and no medication side effects. LESSONS: The author's early experience with 5-Loxin has been encouraging, and this supplement has become the author's first-line treatment for acute radiation effects after SRS. The author reserves bevacizumab for significant mass effect or failure of oral therapy. 5-Loxin has many advantages including low cost, ease of use, and patient tolerability. More experience is needed to confirm the role of 5-Loxin in the upfront treatment of AREs.

Selected-Lesion Stereotactic Radiosurgery (SL-SRS) as a Novel Strategy in the Treatment of Patients With Multiple Brain Metastases.

INTRODUCTION: With the diminishing use of whole-brain radiotherapy (WBRT), there is increasing debate regarding the maximum number of brain metastases that should be treated with stereotactic radiosurgery (SRS). In patients with >10-15 lesions, some groups are proposing a new approach - selected-lesion SRS (SL-SRS) - where only a subset of intracranial lesions are chosen for irradiation. This study is an initial look into this practice. METHODS: This is a cross-sectional exploratory survey study. A survey of 19 questions was created by the International Radiosurgery Research Foundation (IRRF) using open-ended and multiple-choice style questions on SL-SRS practices and indications with the goal of qualitatively understanding how SL-SRS is being implemented worldwide. The survey was distributed to physicians in the United States (US) and internationally who are members of the IRRF and who perform SRS frequently. Ten out of 50 IRRF institutions provided responses reflecting the practices of 16 physicians. RESULTS: SL-SRS is being performed at 8/10 institutions. The most common reasons for using SL-SRS included patients with prior WBRT, patients with progressing systemic disease with central nervous system (CNS)-penetrating or immunotherapies available, specific requests from medical oncology, and cooperative studies using this approach. Lesion size was cited as the most important factor when choosing to irradiate any single lesion. The majority of respondents reported 30 mm and 40 mm as size cutoffs (by largest dimension) for treatment of a lesion in eloquent and non-eloquent locations, respectively. Eloquence of lesion location and attributable symptoms were also considered important. Progression of untreated lesions was the most common reason reported for bringing patients back for additional treatment. CONCLUSION: The responses to this survey show that SL-SRS is being used, allowing for small/asymptomatic brain metastases to be left safely unirradiated. It is currently used in patients who have >10-15 lesions with prior WBRT, those with progression of extracranial disease but with acceptable systemic treatment options, and those with poor functional status. The incorporation of this new approach into clinical trials should be considered for the safe study of the efficacy of new CNS-penetrating systemic therapies.

Stereotactic radiosurgery in the management of non-small cell lung cancer brain metastases: a prospective study using the NeuroPoint Alliance Stereotactic Radiosurgery Registry.

OBJECTIVE: The literature on non-small cell lung cancer (NSCLC) brain metastases (BMs) managed using stereotactic radiosurgery (SRS) relies mainly on single-institution studies or randomized controlled trials (RCTs). There is a literature gap on clinical and radiological outcomes of SRS for NSCLC metastases in real-world practice. The objective of this study was to benchmark mortality and progression outcomes in patients undergoing SRS for NSCLC BMs and identify risk factors for these outcomes using a national quality registry. METHODS: The SRS Registry of the NeuroPoint Alliance was used for this study. This registry included patients from 16 enrolling sites who underwent SRS from 2017 to 2022. Data are prospectively collected without a prespecified research purpose. The main outcomes of this analysis were overall survival (OS), out-of-field recurrence, local progression, and intracranial progression. All time-to-event investigations included Kaplan-Meier analyses and multivariable Cox regressions. RESULTS: Two hundred sixty-four patients were identified, with a mean age of 66.7 years and a female proportion of 48.5%. Most patients (84.5%) had a Karnofsky Performance Status (KPS) score of 80-100, and the mean baseline EQ-5D score was 0.539 quality-adjusted life years. A single lesion was present in 53.4% of the patients, and 29.1% of patients had 3 or more lesions. The median OS was 28.1 months, and independent predictors of mortality included no control of primary tumor (hazard ratio [HR] 2.1), KPS of 80 (HR 2.4) or lower (HR 2.4), coronary artery disease (HR 2.8), and 5 or more lesions present at the time of SRS treatment (HR 2.3). The median out-of-field progression-free survival (PFS) was 24.8 months, and the median local PFS was unreached. Intralesional hemorrhage was an independent risk factor of local progression, with an HR of 6.0. The median intracranial PFS was 14.0 months and was predicted by the number of lesions at the time of SRS (3-4 lesions, HR 2.2; 5-14 lesions, HR 2.5). CONCLUSIONS: In this real-world prospective study, the authors used a national quality registry and found favorable OS in patients with NSCLC BMs undergoing SRS compared with results from previously published RCTs. The intracranial PFS was mainly driven by the emergence of new lesions rather than local progression. A greater number of lesions at baseline was associated with out-of-field progression, while intralesional hemorrhage at baseline was associated with local progression.

Silent Corticotroph Staining Pituitary Neuroendocrine Tumors: Prognostic Significance in Radiosurgery.

BACKGROUND AND OBJECTIVES: There is conflicting evidence on the significance of adrenocorticotrophic hormone (ACTH) staining in the prognosis of nonfunctioning pituitary neuroendocrine tumors (NFpitNETs). The objective of this study was to define the effect of ACTH immunostaining on clinical and radiographic outcomes of stereotactic radiosurgery (SRS) for NFpitNETs. METHODS: This retrospective, multicenter study included patients managed with SRS for NFpitNET residuals. The patients were divided into 2 cohorts: (1) silent corticotroph (SC) for NFpitNETs with positive ACTH immunostaining and (2) non-SC NFpitNETs. Rates of local tumor control and the incidence of post-treatment pituitary and neurological dysfunction were documented. Factors associated with radiological and clinical outcomes were also analyzed. RESULTS: The cohort included 535 patients from 14 centers with 84 (15.7%) patients harboring silent corticotroph NFpitNETs (SCs). At last follow-up, local tumor progression occurred in 11.9% of patients in the SC compared with 8.1% of patients in the non-SC cohort (P = .27). No statistically significant difference was noted in new-onset hypopituitarism rates (10.7% vs 15.4%, P = .25) or visual deficits (3.6% vs 1.1%, P = .088) between the 2 cohorts at last follow-up. When controlling for residual tumor volume, maximum dose, and patient age and sex, positive ACTH immunostaining did not have a significant correlation with local tumor progression (hazard ratio = 1.69, 95% CI = 0.8-3.61, P = .17). CONCLUSION: In contemporary radiosurgical practice with a single fraction dose of 8-25 Gy (median 15 Gy), ACTH immunostaining in NFpitNETs did not appear to confer a significantly reduced rate of local tumor control after SRS.

Stereotactic Radiosurgery for Intraventricular Metastases: A Multicenter Study.

BACKGROUND: Intraventricular metastases (IVMs) are uncommon, and their optimal management remains debatable. OBJECTIVE: To define the safety and efficacy of stereotactic radiosurgery (SRS) in the treatment of IVMs. METHODS: This retrospective, multicenter study included patients managed with SRS for IVMs. SRS-induced adverse events, local tumor or intracranial progression, and the frequency of new-onset hydrocephalus or leptomeningeal spread were documented. Analyses of variables related to patient neuroimaging or clinical outcomes were also performed. RESULTS: The cohort included 160 patients from 11 centers who underwent SRS for treatment of 1045 intracranial metastases, of which 196 were IVMs. The median survival from SRS was 10 months. Of the 154 patients and 190 IVMs with imaging follow-up, 94 patients (61%) experienced distant intracranial disease progression and 16 IVMs (8.4%) progressed locally. The 12- and 24-month local IVM control rates were 91.4% and 86.1%, respectively. Sixteen (10%) and 27 (17.5%) patients developed hydrocephalus and leptomeningeal dissemination post-SRS, respectively. Adverse radiation effects were documented in 24 patients (15%). Eleven patients (6.9%) died because of intracranial disease progression. CONCLUSION: SRS is an effective treatment option for IVMs, with a local IVM control rate comparable with SRS for parenchymal brain metastases. Leptomeningeal spread and hydrocephalus in patients with IVM occur in a minority of patients, but these patients warrant careful follow-up to detect these changes.

Stereotactic radiosurgery for haemorrhagic cerebral cavernous malformation: a multi-institutional, retrospective study.

BACKGROUND: Cerebral cavernous malformations (CCMs) frequently manifest with haemorrhages. Stereotactic radiosurgery (SRS) has been employed for CCM not suitable for resection. Its effect on reducing haemorrhage risk is still controversial. The aim of this study was to expand on the safety and efficacy of SRS for haemorrhagic CCM. METHODS: This retrospective multicentric study included CCM with at least one haemorrhage treated with single-session SRS. The annual haemorrhagic rate (AHR) was calculated before and after SRS. Recurrent event analysis and Cox regression were used to evaluate factors associated with haemorrhage. Adverse radiation effects (AREs) and occurrence of new neurological deficits were recorded. RESULTS: The study included 381 patients (median age: 37.5 years (Q1-Q3: 25.8-51.9) with 414 CCMs. The AHR from diagnosis to SRS excluding the first haemorrhage was 11.08 per 100 CCM-years and was reduced to 2.7 per 100 CCM-years after treatment. In recurrent event analysis, SRS, HR 0.27 (95% CI 0.17 to 0.44), p<0.0001 was associated with a decreased risk of haemorrhage, and the presence of developmental venous anomaly (DVA) with an increased risk, HR 1.60 (95% CI 1.07 to 2.40), p=0.022. The cumulative risk of first haemorrhage after SRS was 9.4% (95% CI 6% to 12.6%) at 5 years and 15.6% (95% CI% 9 to 21.8%) at 10 years. Margin doses> 13 Gy, HR 2.27 (95% CI 1.20 to 4.32), p=0.012 and the presence of DVA, HR 2.08 (95% CI 1.00 to 4.31), p=0.049 were factors associated with higher probability of post-SRS haemorrhage. Post-SRS haemorrhage was symptomatic in 22 out of 381 (5.8%) patients, presenting with transient (15/381) or permanent (7/381) neurological deficit. ARE occurred in 11.1% (46/414) CCM and was responsible for transient neurological deficit in 3.9% (15/381) of the patients and permanent deficit in 1.1% (4/381) of the patients. Margin doses >13 Gy and CCM volume >0.7 cc were associated with increased risk of ARE. CONCLUSION: Single-session SRS for haemorrhagic CCM is associated with a decrease in haemorrhage rate. Margin doses ≤13 Gy seem advisable.

Epilepsy associated with cerebral cavernous malformations managed with stereotactic radiosurgery: an international, multicenter study.

OBJECTIVE: Stereotactic radiosurgery (SRS) has been proposed as an alternative to resection for epilepsy control in patients with cerebral cavernous malformations (CCM) located in critical areas. METHODS: This multicentric, retrospective study evaluated seizure control in patients with a solitary CCM and a history of at least one seizure prior to SRS. RESULTS: 109 patients (median age at diagnosis 28.9 years, interquartile range (IQR) 16.4 years] were included. Prior to SRS, 2 (1.8%) were seizure-free without medication, 35 (32.1%) were seizure-free with antiseizure medications (ASM), 17 (15.6%) experienced an improvement of at least 50% in seizure frequency/intensity with ASM, and 55 (50.5%) experienced an improvement of less than 50% in seizure frequency/intensity with ASM. At a median follow-up of 3.5 years post-SRS (IQR: 4.9), 52 (47.7%) patients were Engel class I, 13 (11.9%) class II, 17 (15.6%) class III, 22 (20.2%) class IVA or IVB and 5 (4.6%) class IVC. For the 72 patients who had seizures despite medication prior to SRS, a delay > 1.5 years between epilepsy presentation and SRS decreased the probability to become seizure-free, HR 0.25 (95% CI 0.09-0.66), p = 0.006. The probability of achieving Engel I at the last follow-up was 23.6 (95% CI 12.7-33.1) and 31.3% (95% CI 19.3-50.8) at 2 and 5 years respectively. 27 patients were considered as having drug-resistant epilepsy. At a median follow-up of 3.1 years (IQR: 4.7), 6 (22.2%) of them were Engel I, 3 (11.1%) Engel II, 7 (25.9%) Engel III, 8 (29.6%) Engel IVA or IVB and 3 (11.1%) Engel IVC. INTERPRETATION: 47.7% of patients managed with SRS for solitary CCM presenting with seizures achieved Engel class I at the last follow-up.

Clinical outcomes following stereotactic radiosurgery for cerebral cavernous malformations of the basal ganglia and thalamus.

OBJECTIVE: There are few reports of outcomes following stereotactic radiosurgery (SRS) for the management of cerebral cavernous malformations (CCMs) of the basal ganglia or thalamus. Therefore, the authors aimed to clarify these outcomes. METHODS: Centers participating in the International Radiosurgery Research Foundation were queried for CCM cases managed with SRS from October 2001 to February 2021. The primary outcome of interest was hemorrhage-free survival (HFS) with a secondary outcome of symptomatic adverse radiation events (AREs). Assessment of the association of prognostic factors with HFS was conducted via Kaplan-Meier analysis and log-rank test. Chi-square tests were conducted to assess potential factors associated with the incidence of AREs. RESULTS: Seventy-three patients were identified. The median patient age was 43.5 years (range 4.4-79.5 years). Fifty-nine (80.8%) patients had hemorrhage prior to SRS. The median treatment volume was 0.9 cm3 (range 0.07-10.1 cm3) with a median margin prescription dose (MPD) of 12 Gy (range 10-20 Gy). One-, 3-, 5-, and 10-year HFS were 93.0%, 89.9%, 89.9%, and 83.0%, respectively, with one hemorrhage-related death approximately 1 year after SRS and nearly 60% and 30% of patients having improvement or stability of symptoms, respectively. There was no correlation between lesion size or MPD and HFS. Seven (9.6%) patients experienced AREs (MPDs > 12 Gy in all cases). Lesion size > 1.0 cm3 was correlated with the incidence of an ARE (p = 0.019). Forty-two (93.3%) of 45 patients treated with an MPD ≤ 12 Gy experienced neither hemorrhage nor AREs following SRS versus 17 (60.7%) of 28 patients treated with an MPD > 12 Gy (p = 0.0006). CONCLUSIONS: SRS is a reasonable treatment strategy and confers clinical stability or improvement and hemorrhage avoidance in patients harboring CCMs of the basal ganglia or thalamus. An MPD of approximately 12 Gy is recommended for the management of CCM.