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Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery
Shin, Samuel M; Cooper, Benjamin T; Chachoua, Abraham; Butler, James; Donahue, Bernadine; Silverman, Joshua S; Kondziolka, Douglas
We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7 %, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.
PMID: 26520640
ISSN: 1573-7373
CID: 1825672
Randomized controlled trials and neurosurgery: the ideal fit or should alternative methodologies be considered?
Mansouri, Alireza; Cooper, Benjamin; Shin, Samuel M; Kondziolka, Douglas
OBJECT Randomized-controlled trials (RCTs) are advocated to provide high-level medical evidence. However, in neurosurgery, there are barriers to conducting RCTs. The authors of this study sought to analyze the quality of neurosurgical RCTs since 2000 to determine the adequacy of their design and reporting. METHODS A search of the MEDLINE and EMBASE databases (2000-2014) was conducted. The medical subject heading (MeSH) terms used in the search included: "neurosurgery" OR "neurosurgical procedure," "brain neoplasms," "infarction" and "decompression," "carotid stenosis," "cerebral hemorrhage," and "spinal fusion." These studies were limited to RCTs, in humans, and in the English language. The Consolidated Standards for Reporting of Trials (CONSORT) and Jadad scales were used to assess the quality of RCT design and reporting. The standardized median times cited (median citations divided by years since publication) were used to assess impact. A pragmatic-explanatory continuum indicator summary-based scale was used to assess the design of the studies as primarily pragmatic or explanatory. RESULTS Sixty-one articles were identified, and the following subspecialties were the most common: vascular (23, 37%), followed by functional neurosurgery and neurooncology (both 13, 21%). The following nations were the primary leaders in RCTs: US (25 studies, 41%), Germany (8 studies, 13%), and the United Kingdom (7 studies, 11%). Median sample size was 100 (interquartile range [IQR] 41.5-279). The majority of the studies (40, 66%) had pragmatic objectives. The median number of times cited overall was 69 (IQR 20.5-193). The combined median CONSORT score was 36 (IQR 27.5-39). Blinding was most deficiently reported. Other areas with a relatively low quality of reporting were sample size calculation (34.2% of surgical, 38.5% of drug, and 20% of device studies), allocation concealment (28.9% of surgical, 23.1% of drug, and 50% of device studies), and protocol implementation (18.4% of surgical, 23% of drug, and 20% of device studies). The quality of reporting did not correlate with the study impact. All studies had a median Jadad score = 3. Thirty-three pragmatic studies (83%) and 5 explanatory studies (25%) met the design objectives. All pragmatic studies based on drug and device trials met their objectives, while 74% of pragmatic surgical trials met their objectives. CONCLUSIONS The prevalence of neurosurgical RCTs is low. The quality of RCT design and reporting in neurosurgery is also low. Many study designs are not compatible with stated objectives. Pragmatic studies were more likely to meet design objectives. Given the role of RCTs as one of the highest levels of evidence, it is critical to improve on their methodology and reporting.
PMID: 26315006
ISSN: 1933-0693
CID: 1761502
Evaluating innovation. Part 1: The concept of progressive scholarly acceptance
Schnurman, Zane; Kondziolka, Douglas
Understanding how the relevant medical community accepts new therapies is vital to patients, physicians, and society. Increasingly, focus is placed on how medical innovations are evaluated. But recognizing when a treatment has become accepted practice-essentially, acceptance by the scientific community-remains a challenge and a barrierto investigating treatment development. This report aims to demonstrate the theory, method, and limitations of a model for measuring a new metric that the authors term "progressive scholarly acceptance." A model was developed to identify when the scientific community has accepted an innovation, by observing when researchers have moved beyond the initial study of efficacy. This model could enable further investigations into the methods and influences of treatment development.
PMID: 26252458
ISSN: 1933-0693
CID: 1709302
Evaluating innovation. Part 2: Development in neurosurgery
Schnurman, Zane; Kondziolka, Douglas
OBJECT Patients, practitioners, payers, and regulators are advocating for reform in how medical advances are evaluated. Because surgery does not adhere to a standardized developmental pathway, how the medical community accepts a procedure remains unclear. The authors developed a new model, using publication data and patterns, that quantifies this process. Using this technique, the authors identified common archetypes and influences on neurosurgical progress from idea inception to acceptance. METHODS Seven neurosurgical procedures developed in the past 15-25 years were used as developmental case studies (endovascular coil, deep brain stimulation, vagus nerve stimulation, 1,3-bis(2-chloroethyl)-l-nitrosourea wafer, and 3 radiosurgery procedures), and the literature on each topic was evaluated. A new metric the authors termed "progressive scholarly acceptance" (PSA) was used as an end point for community acceptance. PSA was reached when the number of investigations that refine or improve a procedure eclipsed the total number of reports assessing initial efficacy. Report characteristics, including the number of patients studied, study design, and number of authoring groups from the first report to the point of PSA, were assessed. RESULTS Publication data implicated factors that had an outsized influence on acceptance. First, procedural accessibility to investigators was found to influence the number of reports, number of patients studied, and number of authoring groups contributing. Barriers to accessibility included target disease rarity, regulatory restrictions, and cost. Second, the ease or difficulty in applying a randomized controlled trial had an impact on study design. Based on these 2 factors, 3 developmental archetypes were characterized to generally describe the development of surgery. CONCLUSIONS Common surgical development archetypes can be described based on factors that impact investigative methods, data accumulation, and ultimate acceptance by society. The approach and proposed terminologies in this report could inform future procedural development as well as any attempts to regulate surgical innovation.
PMID: 26252459
ISSN: 1933-0693
CID: 1709312
Quantitative tumor volumetric responses after Gamma Knife radiosurgery for meningiomas
Harrison, Gillian; Kano, Hideyuki; Lunsford, L Dade; Flickinger, John C; Kondziolka, Douglas
OBJECT The reported tumor control rates for meningiomas after stereotactic radiosurgery (SRS) are high; however, early imaging assessment of tumor volumes may not accurately predict the eventual tumor response. The objective in this study was to quantitatively evaluate the volumetric responses of meningiomas after SRS and to determine whether early volume responses are predictive of longer-term tumor control. METHODS The authors performed a retrospective review of 252 patients (median age 56 years, range 14-87 years) who underwent Gamma Knife radiosurgery between 2002 and 2010. All patients had evaluable pre- and postoperative T1-weighted contrast-enhanced MRIs. The median baseline tumor volume was 3.5 cm3 (range 0.2-33.8 cm3) and the median follow-up was 19.5 months (range 0.1-104.6 months). Follow-up tumor volumes were compared with baseline volumes. Tumor volume percent change and the tumor volume rate of change were compared at 3-month intervals. Eventual tumor responses were classified as progressed for > 15% volume change, regressed for = 15% change, and stable for +/- 15% of baseline volume at time of last follow-up. Volumetric data were compared with the final tumor status by using univariable and multivariable logistic regression. RESULTS Tumor volume regression (median decrease of -40.2%) was demonstrated in 168 (67%) patients, tumor stabilization (median change of -2.7%) in 67 (26%) patients, and delayed tumor progression (median increase of 104%) in 17 (7%) patients (p < 0.001). Tumors that eventually regressed had an average volume reduction of -18.2% at 3 months. Tumors that eventually progressed all demonstrated volume increase by 6 months. Transient progression was observed in 15 tumors before eventual decrease, and transient regression was noted in 6 tumors before eventual volume increase. CONCLUSIONS The volume response of meningiomas after SRS is dynamic, and early imaging estimations of the tumor volume may not correlate with the final tumor response. However, tumors that ultimately regressed tended to respond in the first 3 months, whereas tumors that ultimately progressed showed progression within 6 months.
PMID: 26162039
ISSN: 1933-0693
CID: 1668562
Brain arteriovenous malformations
Lawton, Michael T; Rutledge, W Caleb; Kim, Helen; Stapf, Christian; Whitehead, Kevin J; Li, Dean Y; Krings, Timo; terBrugge, Karel; Kondziolka, Douglas; Morgan, Michael K; Moon, Karam; Spetzler, Robert F
An arteriovenous malformation is a tangle of dysplastic vessels (nidus) fed by arteries and drained by veins without intervening capillaries, forming a high-flow, low-resistance shunt between the arterial and venous systems. Arteriovenous malformations in the brain have a low estimated prevalence but are an important cause of intracerebral haemorrhage in young adults. For previously unruptured malformations, bleeding rates are approximately 1% per year. Once ruptured, the subsequent risk increases fivefold, depending on associated aneurysms, deep locations, deep drainage and increasing age. Recent findings from novel animal models and genetic studies suggest that arteriovenous malformations, which were long considered congenital, arise from aberrant vasculogenesis, genetic mutations and/or angiogenesis after injury. The phenotypical characteristics of arteriovenous malformations differ among age groups, with fistulous lesions in children and nidal lesions in adults. Diagnosis mainly involves imaging techniques, including CT, MRI and angiography. Management includes observation, microsurgical resection, endovascular embolization and stereotactic radiosurgery, alone or in any combination. There is little consensus on how to manage patients with unruptured malformations; recent studies have shown that patients managed medically fared better than those with intervention at short-term follow-up. By contrast, interventional treatment is preferred following a ruptured malformation to prevent rehaemorrhage. Management continues to evolve as new mechanistic discoveries and reliable animal models raise the possibility of developing drugs that might prevent the formation of arteriovenous malformations, induce obliteration and/or stabilize vessels to reduce rupture risk. For an illustrated summary of this Primer, visit: http://go.nature.com/TMoAdn.
PMID: 27188382
ISSN: 2056-676x
CID: 4837072
Gamma Knife radiosurgery with CT image-based dose calculation
Xu, Andy Yuanguang; Bhatnagar, Jagdish; Bednarz, Greg; Niranjan, Ajay; Kondziolka, Douglas; Flickinger, John; Lunsford, L Dade; Huq, M Saiful
The Leksell GammaPlan software version 10 introduces a CT image-based segmentation tool for automatic skull definition and a convolution dose calculation algorithm for tissue inhomogeneity correction. The purpose of this work was to evaluate the impact of these new approaches on routine clinical Gamma Knife treatment planning. Sixty-five patients who underwent CT image-guided Gamma Knife radiosurgeries at the University of Pittsburgh Medical Center in recent years were retrospectively investigated. The diagnoses for these cases include trigeminal neuralgia, meningioma, acoustic neuroma, AVM, glioma, and benign and metastatic brain tumors. Dose calculations were performed for each patient with the same dose prescriptions and the same shot arrangements using three different approaches: 1) TMR 10 dose calculation with imaging skull definition; 2) convolution dose calculation with imaging skull definition; 3) TMR 10 dose calculation with conventional measurement-based skull definition. For each treatment matrix, the total treatment time, the target coverage index, the selectivity index, the gradient index, and a set of dose statistics parameters were compared between the three calculations. The dose statistics parameters investigated include the prescription isodose volume, the 12 Gy isodose volume, the minimum, maximum and mean doses on the treatment targets, and the critical structures under consideration. The difference between the convolution and the TMR 10 dose calculations for the 104 treatment matrices were found to vary with the patient anatomy, location of the treatment shots, and the tissue inhomogeneities around the treatment target. An average difference of 8.4% was observed for the total treatment times between the convolution and the TMR algorithms. The maximum differences in the treatment times, the prescription isodose volumes, the 12 Gy isodose volumes, the target coverage indices, the selectivity indices, and the gradient indices from the convolution and the TMR 10 calculations are 14.9%, 16.4%, 11.1%, 16.8, 6.9%, and 11.4%, respectively. The maximum differences in the minimum and the mean target doses between the two calculation algorithms are 8.1% and 4.2% of the corresponding prescription doses. The maximum differences in the maximum and the mean doses for the critical structures between the two calculation algorithms are 1.3 Gy and 0.7 Gy. The results from the two skull definition methods with the TMR 10 algorithm agree either within ± 2.5% or 0.3 Gy for the dose values, except for a 4.9% difference in the treatment times for a lower cerebellar lesion. The imaging skull definition method does not affect Gamma Knife dose calculation considerably when compared to the conventional measurement-based skull definition method, except in some extreme cases. Large differences were observed between the TMR 10 and the convolution calculation method for the same dose prescription and the same shot arrangements, indicating that the implementation of the convolution algorithm in routine clinical use might be desirable for optimal dose calculation results.
PMCID:5691031
PMID: 26699563
ISSN: 1526-9914
CID: 3588972
Development, Implementation, and Use of a Local and Global Clinical Registry for Neurosurgery
Kondziolka, Douglas; Cooper, Benjamin T; Lunsford, L Dade; Silverman, Joshua
Physicians are being challenged to obtain data for outcomes research and measures of quality practice in medicine. We developed a prospective data collection system (registry) that provides data points across all elements of a neurosurgical stereotactic radiosurgery practice. The registry architecture is scalable and suitable for any aspect of neurosurgical practice. Our purpose was to outline the challenges in creating systems for high quality data acquisition and describe experiences in initial testing and use. Over a two year period, a multicenter team working with software engineers developed a comprehensive radiosurgery registry based on a MS-Sequel(R) server platform. Three neurosurgeons at one center were responsible for final editing. Alpha testing began in September 2012 and server-based beta testing began in February 2013. The major elements included demographics, disease-based items (47 categories for different brain tumors, vascular malformations, and functional disorders) with relevant clinical grading systems, treatment-based items (imaging, physics, clinical), and follow-up data (clinical, imaging, subsequent therapeutics). Nine hundred patients were entered into the registry at one test center, with new entries and follow-up data entered daily at the point of contact. With experience, the mean time for one new entry was 6 minutes. Mean time for one follow-up entry was 45 seconds. The system was made secure for individual use and amenable for both data entry and research. Analytics used different filters to create customized outcomes charts as selected by the user (e.g., survival, neurologic function, complications). A local or multicenter prospective data collection registry was created for use across 47 clinical indications for stereotactic cranial radiosurgery. Further refinement of fields and logic is ongoing. The system is reliable, robust, and allows use of rapid analytical tools. Large medical registries will become widely used for collection and analysis of large data sets and should have broad applicability to many other elements of neurosurgical and medical practice.
PMID: 27447432
ISSN: 2167-647x
CID: 2191082
Does Reducing Cochlear Dose Through Beam Sector Blocking Improve Hearing Preservation Following Vestibular Schwannoma Radiosurgery? [Meeting Abstract]
Mousavi, H; Lehocky, CA; Flickinger, JC., Sr; Kano, H; Arai, Y; Niranjan, A; Kondziolka, D; Lunsford, LD
ISI:000373215300286
ISSN: 1879-355x
CID: 2097872
Number of Brain Metastases Treated With Radiosurgery Is Not Associated With Long-term Survival [Meeting Abstract]
Knoll, MA; Oermann, E; Yang, AI; Green, S; Collins, BT; Collins, SP; Ewend, M; Kondziolka, D
ISI:000373215300180
ISSN: 1879-355x
CID: 2097842