Pre-operative vs. post-operative stereotactic radiosurgery for operative metastatic brain tumors: study protocol for a phase III clinical trial.

BACKGROUND AND OBJECTIVES: Almost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS. METHODS: This randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS. EXPECTED OUTCOMES: If pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline. DISCUSSION: Emerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease. TRIAL REGISTRATION NUMBER: NCT03750227 (Registration date: 21/11/2018).

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Development and validation of a recursive partitioning analysis-based pretreatment decision-making tool identifying ideal candidates for spine stereotactic body radiation therapy.

BACKGROUND: This study was aimed at developing and validating a decision-making tool predictive of overall survival (OS) for patients receiving stereotactic body radiation therapy (SBRT) for spinal metastases. METHODS: Three hundred sixty-one patients at one institution were used for the training set, and 182 at a second institution were used for external validation. Treatments most commonly involved one or three fractions of spine SBRT. Exclusion criteria included proton therapy and benign histologies. RESULTS: The final model consisted of the following variables and scores: Spinal Instability Neoplastic Score (SINS) ≥ 6 (1), time from primary diagnosis < 21 months (1), Eastern Cooperative Oncology Group (ECOG) performance status = 1 (1) or ECOG performance status > 1 (2), and >1 organ system involved (1). Each variable was an independent predictor of OS (p < .001), and each 1-point increase in the score was associated with a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25; p < .0001). The concordance value was 0.75 (95% CI, 0.71-0.78). The scores were discretized into three groups-favorable (score = 0-1), intermediate (score = 2), and poor survival (score = 3-5)-with 2-year OS rates of 84% (95% CI, 79%-90%), 46% (95% CI, 36%-59%), and 21% (95% CI, 14%-32%), respectively (p < .0001 for each). In the external validation set (182 patients), the score was also predictive of OS (p < .0001). Increasing SINS was predictive of decreased OS as a continuous variable (p < .0001). CONCLUSIONS: This novel score is proposed as a decision-making tool to help to optimize patient selection for spine SBRT. SINS may be an independent predictor of OS.

Preoperative stereotactic radiosurgery as neoadjuvant therapy for resectable brain tumors.

PURPOSE: Stereotactic radiosurgery (SRS) is a method of delivering conformal radiation, which allows minimal radiation damage to surrounding healthy tissues. Adjuvant radiation therapy has been shown to improve local control in a variety of intracranial neoplasms, such as brain metastases, gliomas, and benign tumors (i.e., meningioma, vestibular schwannoma, etc.). For brain metastases, adjuvant SRS specifically has demonstrated positive oncologic outcomes as well as preserving cognitive function when compared to conventional whole brain radiation therapy. However, as compared with neoadjuvant SRS, larger post-operative volumes and greater target volume uncertainty may come with an increased risk of local failure and treatment-related complications, such as radiation necrosis. In addition to its role in brain metastases, neoadjuvant SRS for high grade gliomas may enable dose escalation and increase immunogenic effects and serve a purpose in benign tumors for which one cannot achieve a gross total resection (GTR). Finally, although neoadjuvant SRS has historically been delivered with photon therapy, there are high LET radiation modalities such as carbon-ion therapy which may allow radiation damage to tissue and should be further studied if done in the neoadjuvant setting. In this review we discuss the evolving role of neoadjuvant radiosurgery in the treatment for brain metastases, gliomas, and benign etiologies. We also offer perspective on the evolving role of high LET radiation such as carbon-ion therapy. METHODS: PubMed was systemically reviewed using the search terms "neoadjuvant radiosurgery", "brain metastasis", and "glioma". ' Clinicaltrials.gov ' was also reviewed to include ongoing phase III trials. RESULTS: This comprehensive review describes the evolving role for neoadjuvant SRS in the treatment for brain metastases, gliomas, and benign etiologies. We also discuss the potential role for high LET radiation in this setting such as carbon-ion radiotherapy. CONCLUSION: Early clinical data is very promising for neoadjuvant SRS in the setting of brain metastases. There are three ongoing phase III trials that will be more definitive in evaluating the potential benefits. While there is less data available for neoadjuvant SRS for gliomas, there remains a potential role, particularly to enable dose escalation and increase immunogenic effects.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

PURPOSE: Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. METHODS: A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). RESULTS: The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2 months. The median age was 67 years. The median margin SRS dose was 19 Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). CONCLUSION: The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Contemporary radiotherapy and radiosurgery techniques for refractory pituitary adenomas.

The pituitary gland is a potential site for a range of pathologies, for which treatment can involve resection and/or ionizing radiation. Modern stereotactic radiosurgery (SRS) involves highly conformal radiation, allowing for the delivery of high doses to the tumor while simultaneously sparing nearby healthy structures. SRS has become a standard treatment option for residual or recurrent pituitary adenomas. It has been used for both functioning and nonfunctioning pituitary adenomas, with reported local tumor control over 90% and moderate rates of endocrine remission in functioning adenomas. We aim to briefly review the existing indictions and supporting literature for the use of SRS for refractory adenomas.

Current advances in the surgical treatment of glossopharyngeal neuralgia.

Glossopharyngeal neuralgia (GPN) is a neurological condition characterized by paroxysmal, stabbing-like pain along the distribution of the glossopharyngeal nerve that lasts from a couple of seconds to minutes. Pharmacological treatment with anticonvulsants is the first line of treatment; however, about 25% of patients remain symptomatic and require surgical intervention, which is usually done via microvascular decompression (MVD) with or without rhizotomy. More recently, the use of stereotactic radiosurgery (SRS) has been utilized as an alternative treatment method to relieve patient symptoms by causing nerve ablation. We conducted a systematic review to analyze whether MVD without rhizotomy is an equally effective treatment for GPN as MVD with the use of concurrent rhizotomy. Moreover, we sought to explore if SRS, a minimally invasive alternative surgical option, achieves comparable outcomes. We included retrospective studies and case reports in our search. We consulted PubMed and Medline, including articles from the year 2000 onwards. A total of 36 articles were included for review. Of all included patients with glossopharyngeal neuralgia, the most common offending artery compressing the glossopharyngeal nerve was the posterior inferior cerebellar artery (PICA). MVD alone was successful achieving pain relief immediately postoperatively in about 85% of patients, and also long term in 65-90% of patients. The most common complication found on MVD surgery was found to be transient hoarseness and transient dysphagia. Rhizotomy alone shows an instant pain relief in 85-100% of the patients, but rate of long-term pain relief was lower compared to MVD. The most common adverse effects observed after a rhizotomy were dysphagia and dysesthesia along the distribution of the glossopharyngeal nerve. SRS had promising results in pain reduction when using 75 Gy radiation or higher; however, long-term rates of pain relief were lower. MVD, rhizotomy, and SRS are effective methods to treat GPN as they help achieve instant pain relief and the decrease use of medication. Patients with MVD alone presented with less adverse effects than the group that underwent MVD plus rhizotomy. Although SRS may be a viable alternative treatment for GPN, further studies must be done to evaluate long-term treatment efficacy.

Pan-cancer analysis of prognostic metastatic phenotypes.

Although cancer is highly heterogeneous, all metastatic cancer is considered American Joint Committee on Cancer (AJCC) Stage IV disease. The purpose of this project was to redefine staging of metastatic cancer. Internal validation of nationally representative patient data from the National Cancer Database (n = 461 357; 2010-2013), and external validation using the Surveillance, Epidemiology and End Results database (n = 106 595; 2014-2015) were assessed using the concordance index for evaluation of survival prediction. A Cox proportional hazards model was used for overall survival by considering identified phenotypes (latent classes) and other confounding variables. Latent class analysis was performed for phenotype identification, where Bayesian information criterion (BIC) and sample-size-adjusted BIC were used to select the optimal number of distinct clusters. Kappa coefficients assessed external cluster validation. Latent class analysis identified five metastatic phenotypes with differences in overall survival (P < .0001): (Stage IVA) nearly exclusive bone-only metastases (n = 59 049, 12.8%; median survival 12.7 months; common in lung, breast and prostate cancers); (IVB) predominant lung metastases (n = 62 491, 13.5%; 11.4 months; common in breast, stomach, kidney, ovary, uterus, thyroid, cervix and soft tissue cancers); (IVC) predominant liver/lung metastases (n = 130 014, 28.2%; 7.0 months; common in colorectum, pancreatic, lung, esophagus and stomach cancers); (IVD) bone/liver/lung metastases predominant over brain (n = 61 004, 13.2%; 5.9 months; common in lung and breast cancers); and (IVE) brain/lung metastases predominant over bone/liver (n = 148 799, 32.3%; 5.7 months; lung cancer and melanoma). Long-term survivors were identified, particularly in Stages IVA-B. A pan-cancer nomogram model to predict survival (STARS: site, tumor, age, race, sex) was created, validated and provides 13% better prognostication than AJCC: 1-month concordance index of 0.67 (95% confidence interval [CI]: 0.66-0.67) vs 0.61 (95% CI: 0.60-0.61). STARS is simple, uses easily accessible variables, better prognosticates survival outcomes and provides a platform to develop novel metastasis-directed clinical trials.

Cost effectiveness of treatment strategies for high risk prostate cancer.

BACKGROUND: Patients with high-risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost. METHODS: The authors compared quality-adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external-beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low-dose-rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479). RESULTS: Treatment strategies were compared using the incremental cost-effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost-effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost-effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost. CONCLUSIONS: EBRT with LDR brachytherapy boost may be a cost-effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high-value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost-effective care, despite no change in overall survival.

Radiation necrosis in renal cell carcinoma brain metastases treated with checkpoint inhibitors and radiosurgery: An international multicenter study.

BACKGROUND: Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. METHODS: RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN. RESULTS: Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow-up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole-brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06-42.38 cm3 ); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27-111.22 cm3 ). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. CONCLUSIONS: Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.

A deep learning model for discriminating true progression from pseudoprogression in glioblastoma patients.

INTRODUCTION: Glioblastomas (GBMs) are highly aggressive tumors. A common clinical challenge after standard of care treatment is differentiating tumor progression from treatment-related changes, also known as pseudoprogression (PsP). Usually, PsP resolves or stabilizes without further treatment or a course of steroids, whereas true progression (TP) requires more aggressive management. Differentiating PsP from TP will affect the patient's outcome. This study investigated using deep learning to distinguish PsP MRI features from progressive disease. METHOD: We included GBM patients with a new or increasingly enhancing lesion within the original radiation field. We labeled those who subsequently were stable or improved on imaging and clinically as PsP and those with clinical and imaging deterioration as TP. A subset of subjects underwent a second resection. We labeled these subjects as PsP, or TP based on the histological diagnosis. We coregistered contrast-enhanced T1 MRIs with T2-weighted images for each patient and used them as input to a 3-D Densenet121 model and using five-fold cross-validation to predict TP vs PsP. RESULT: We included 124 patients who met the criteria, and of those, 63 were PsP and 61 were TP. We trained a deep learning model that achieved 76.4% (range 70-84%, SD 5.122) mean accuracy over the 5 folds, 0.7560 (range 0.6553-0.8535, SD 0.069) mean AUROCC, 88.72% (SD 6.86) mean sensitivity, and 62.05% (SD 9.11) mean specificity. CONCLUSION: We report the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice.

The early infiltrative phase of GBM hypothesis: are molecular glioblastomas histological glioblastomas in the making? A preliminary multicenter study.

PURPOSE: The presence of necrosis or microvascular proliferation was previously the hallmark for glioblastoma (GBM) diagnosis. The 2021 WHO classification now considers IDH-wildtype diffuse astrocytic tumors without the histological features of glioblastoma (that would have otherwise been classified as grade 2 or 3) as molecular GBM (molGBM) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/-10 copy changes. We hypothesize that these tumors are early histological GBM and will eventually develop the classic histological features. METHODS: Medical records from 65 consecutive patients diagnosed with molGBM at three tertiary-care centers from our institution were retrospectively reviewed from November 2017-October 2021. Only patients who underwent reoperation for tumor recurrence and whose tissue at initial diagnosis and recurrence was available were included in this study. The detailed clinical, histopathological, and radiographic scenarios are presented. RESULTS: Five patients were included in our final cohort. Three (60%) patients underwent reoperation for recurrence in the primary site and 2 (40%) underwent reoperation for distal recurrence. Microvascular proliferation and pseudopalisading necrosis were absent at initial diagnosis but present at recurrence in 4 (80%) patients. Radiographically, all tumors showed contrast enhancement, however none of them showed the classic radiographic features of GBM at initial diagnosis. CONCLUSIONS: In this manuscript we present preliminary data for a hypothesis that molGBMs are early histological GBMs diagnosed early in their natural history of disease and will eventually develop necrosis and microvascular proliferation. Further correlative studies are needed in support of this hypothesis.

Focused versus conventional radiotherapy in spinal oncology: is there any difference in fusion rates and pseudoarthrosis?

INTRODUCTION: Radiotherapy is considered standard of care for adjuvant peri-operative treatment of many spinal tumors, including those with instrumented fusion. Unfortunately, radiation treatment has been linked to increased risk of pseudoarthrosis. Newer focused radiotherapy strategies with enhanced conformality could offer improved fusion rates for these patients, but this has not been confirmed. METHODS: We performed a retrospective analysis of patients at three tertiary care academic institutions with primary and secondary spinal malignancies that underwent resection, instrumented fusion, and peri-operative radiotherapy. Two board certified neuro-radiologists used the Lenke fusion score to grade fusion status at 6 and 12-months after surgery. Secondary outcomes included clinical pseudoarthrosis, wound complications, the effect of radiation timing and radiobiological dose delivered, the use of photons versus protons, tumor type, tumor location, and use of autograft on fusion outcomes. RESULTS: After review of 1252 spinal tumor patients, there were 60 patients with at least 6 months follow-up that were included in our analyses. Twenty-five of these patients received focused radiotherapy, 20 patients received conventional radiotherapy, and 15 patients were treated with protons. There was no significant difference between the groups for covariates such as smoking status, obesity, diabetes, intraoperative use of autograft, and use of peri-operative chemotherapy. There was a significantly higher rate of fusion for patients treated with focused radiotherapy compared to those treated with conventional radiotherapy at 6-months (64.0% versus 30.0%, Odds ratio: 4.15, p = 0.036) and 12-months (80.0% versus 42.1%, OR: 5.50, p = 0.022). There was a significantly higher rate of clinical pseudoarthrosis in the conventional radiotherapy cohort compared to patients in the focused radiotherapy cohort (19.1% versus 0%, p = 0.037). There was no difference in fusion outcomes for any of the secondary outcomes except for use of autograft. The use of intra-operative autograft was associated with an improved fusion at 12-months (66.7% versus 37.5%, OR: 3.33, p = 0.043). CONCLUSION: Focused radiotherapy may be associated with an improved rate of fusion and clinical pseudoarthrosis when compared to conventional radiation delivery strategies in patients with spinal tumors. Use of autograft at the time of surgery may be associated with improved 12-month fusion rates. Further large-scale prospective and randomized controlled studies are needed to better stratify the effects of radiation delivery modality in these patients.

The survival outcomes of molecular glioblastoma IDH-wildtype: a multicenter study.

PURPOSE: Histological diagnosis of glioblastoma (GBM) was determined by the presence of necrosis or microvascular proliferation (histGBM). The 2021 WHO classification now considers IDH-wildtype diffuse astrocytic tumors without the histological features of glioblastoma (that would have otherwise been classified as grade 2 or 3) as molecular GBM (molGBM, WHO grade 4) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/- 10 copy changes. The objective of this study was to explore and compare the survival outcomes between histGBM and molGBM. METHODS: Medical records for patients diagnosed with GBM at the three tertiary care academic centers of our institution from November 2017 to October 2021. Only patients who underwent adjuvant chemoradiation were included. Patients without molecular feature testing or with an IDH mutation were excluded. Univariable and multivariable analyses were performed to evaluate progression-free (PFS) and overall- survival (OS). RESULTS: 708 consecutive patients were included; 643 with histGBM and 65 with molGBM. Median PFS was 8 months (histGBM) and 13 months (molGBM) (p = 0.0237) and median OS was 21 months (histGBM) versus 26 months (molGBM) (p = 0.435). Multivariable analysis on the molGBM sub-group showed a worse PFS if there was contrast enhancement on MRI (HR 6.224 [CI 95% 2.187-17.714], p < 0.001) and a superior PFS on patients with MGMT methylation (HR 0.026 [CI 95% 0.065-0.655], p = 0.007). CONCLUSIONS: molGBM has a similar OS but significantly longer PFS when compared to histGBM. The presence of contrast enhancement and MGMT methylation seem to affect the clinical behavior of this subset of tumors.

Early Therapeutic Interventions for Newly Diagnosed Glioblastoma: Rationale and Review of the Literature.

PURPOSE OF REVIEW: Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically. RECENT FINDINGS: Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and several radiotherapy techniques. We critically appraise and compare these strategies in terms of their efficacy, toxicity, challenges and potential to prolong survival. Finally, we discuss the most promising strategies that could benefit future glioblastoma patients. There is biological rationale to suggest that early interventions could improve the outcome of glioblastoma patients and they should be investigated in future trials.

Treatment of recurrent and persistent Cushing's disease after first transsphenoidal surgery: lessons learned from an international meta-analysis.

PURPOSE: Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's Disease (CD). Recurrence rates after a first TSS range between 3 and 22% within 3 years. Management of recurrent or persistent CD may include repeat TSS or stereotactic radiosurgery (SRS). We performed a meta-analysis to explore the overall efficacy of TSS and SRS for patients with CD after an initial surgical intervention. METHODS: EMBASE, PubMed, SCOPUS, and Cochrane databases were searched from their dates-of-inception up to December 2021. Inclusion criteria were comprised of patients with an established diagnosis of CD who presented with persistent or biochemically recurrent disease after a first TSS for tumor resection and were treated with a second TSS or SRS. RESULTS: Search criteria yielded 2,116 studies of which 37 articles from 15 countries were included for analysis. Mean age ranged between 29.9 and 47.9 years, and mean follow-up was 11-104 months. TSS was used in 669 (67.7%) patients, while SRS was used in 320 (32.4%) patients, and remission rates for CD were 59% (95%CI 0.49-0.68) and 74% (95%CI 0.54-0.88), respectively. There was no statistically significant difference in the remission rate between TSS and SRS (P = 0.15). The remission rate of patients with recurrent CD undergoing TSS was 53% (95%CI 0.32-0.73), and for persistent CD was 41% (95%CI 0.28-0.56) (P = 0.36). CONCLUSION: Both TSS and SRS are possible approaches for the treatment of recurrent or persistent CD after a first TSS. Our data show that either TSS or SRS represent viable treatment options to achieve remission for this subset of patients.

Impact of Facility Surgical Volume on Survival in Patients With Cancer.

BACKGROUND: Increased facility surgical treatment volume is sometimes associated with improved survival in patients with cancer; however, published studies evaluating volume are heterogeneous and disparate in their patient inclusion and definition of volume. The purpose of this work was to evaluate uniformly the impact of surgical facility volume on survival in patients with cancer. METHODS: The National Cancer Database was searched for patients diagnosed in 2004 through 2013 with the 12 cancers most commonly treated surgically. Facilities were stratified by 4 categories using the overall population (low, intermediate, high, and very high), each including 25% of patients, and then stratified by each individual disease site. Five-year postsurgery survival was estimated using both the Kaplan-Meier method and corresponding log-rank tests for group comparisons. Cox proportional hazard models were used to evaluate the effects of facility volume on 5-year postsurgery survival further, adjusted for multiple covariates. RESULTS: A total of 3,923,618 patients who underwent surgery were included from 1,139 facilities. Of these, 40.4% had breast cancer, 12.8% prostate cancer, and 10.0% colon cancer. Most patients were female (65.0%), White (86.4%), and privately insured (51.6%) with stage 0-III disease (64.8%). For all cancers, the risk of death for patients undergoing surgery at very high-volume facilities was 88% of that for those treated at low-volume facilities. Hazard ratios (HRs) were greatest (very high vs low volume) for cancer of the prostate (HR, 0.66; 95% CI, 0.63-0.69), pancreas (HR, 0.75; 95% CI, 0.71-0.78), and esophagus (HR, 0.78; 95% CI, 0.73-0.83), and for melanoma (HR, 0.81; 95% CI, 0.78-0.84); differences were smallest for uterine and non-small cell lung cancers. Overall survival differences were greatest for cancers of the brain, pancreas, and esophagus. CONCLUSIONS: Patients treated surgically at higher-volume facilities consistently had improved overall survival compared with those treated at low-volume centers, although the magnitude of difference was cancer-specific.

Integration of immuno-oncology with stereotactic radiosurgery in the management of brain metastases.

AIM: Brain metastases traditionally carried a poor prognosis with treatment being a combination of surgery, whole-brain radiation therapy, and glucocorticoids; however, this treatment paradigm carried a significant amount of morbidity. In recent years, stereotactic radiosurgery (SRS), which involves the delivery of a highly conformal dose of radiation over a single session, has been shown to be an effective alternative to WBRT with excellent rates of local control and improved quality of life; however, a survival benefit has not been demonstrated. Recent developments have challenged the traditional view of the central nervous system being "immunologically privileged" which has led to a greater focus on treating these patients with systemic therapies. Immune checkpoint inhibitors (ICI) have been shown to improve survival in multiple malignancies. As a result, there has been increased utilization in combining these therapies in this setting. METHODS: We conducted a literature search of medical databases (e.g. PubMed) for articles involving the use of immune checkpoint inhibitors and stereotactic radiosurgery in managing brain metastases. RESULTS: Published evidence utilizing SRS and ICI is largely limited to single institution and retrospective in nature with the most common histology being melanoma. CONCLUSION: Combination therapy with SRS and ICI appears to improve survival in patients with brain metastases. The available data are largely retrospective; therefore, ongoing and planned prospective studies are needed to further validate these findings.

Stereotactic radiosurgery training patterns across neurosurgical programs: a multi-national survey.

INTRODUCTION: The field of neurosurgery has witnessed a dramatic increase in the use of stereotactic radiosurgery (SRS) as a modality to treat various cranial and spinal pathologies. However, studies have consistently demonstrated disparities in SRS training. Accordingly, the present study represents a cross-sectional analysis of current SRS training and practice patterns. METHODS: An online survey was utilized to collect data from participants. Two-sided t-tests were used in order to compare frequency tables for statistically significant differences between groups. Qualitative analyses were performed by modified thematic analyses, employing open and axial coding. RESULTS: A total of 67 participants completed the online survey (16.4% response rate). The majority of participants were neurosurgery attendings (58.2%), followed by neurosurgery residents (25.4%). The majority of participants reported that resident exposure to SRS was gained primarily through non-SRS focused rotations (52.2%). The survey found that exposure to tumor cases was most frequent, followed by functional, vascular, and spine indications. The majority of participants (49.3%) indicate that residents are not competent or exhibit a low level of competency in SRS at the completion of neurosurgical residency. Qualitative analyses demonstrated that respondents believe SRS is a critical modality in current cranial neurosurgical care and that increased training is needed. CONCLUSIONS: This study provides a multi-national analysis of SRS residency training and practice patterns, and aims to stimulate improvement in SRS in training worldwide. Enhanced resident training in SRS must include wider exposure to vascular, neoplastic, functional and pediatric indications for SRS.

The evolution of stereotactic radiosurgery in neurosurgical practice.

INTRODUCTION: Stereotactic radiosurgery (SRS) was born in an attempt to treat complex intracranial pathologies in a fashion whereby open surgery would create unnecessary or excessive risk. To create this innovation, it was necessary to harness advances in other fields such as engineering, physics, radiology, and computer science. METHODS: We review the history of SRS to provide context to today's current state, as well as guide future advancement in the field. RESULTS: Since time of Lars Leksell, the young Swedish neurosurgeon who pioneered the development of the SRS, the collegial and essential partnership between neurosurgeons, radiation oncologists and physicists has given rise to radiosurgery as a prominent and successful tool in neurosurgical practice. CONCLUSION: We examine how neurosurgeons have helped foster the SRS evolution and how this evolution has impacted neurosurgical practice as well as that of radiation oncology and neuro-oncology.