Frank D. Vrionis

Central Nervous System Cancers

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.

A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group.

Study Design. Systematic review and modified Delphi technique. Objective. To use an evidence-based medicine process using the best available literature and expert opinion consensus to develop a comprehensive classification system to diagnose neoplastic spinal instability. Summary of Background Data. Spinal instability is poorly defined in the literature and presently there is a lack of guidelines available to aid in defining the degree of spinal instability in the setting of neoplastic spinal disease. The concept of spinal instability remains important in the clinical decision-making process for patients with spine tumors. Methods. We have integrated the evidence provided by systematic reviews through a modified Delphi technique to generate a consensus of best evidence and expert opinion to develop a classification system to define neoplastic spinal instability. Results. A comprehensive classification system based on patient symptoms and radiographic criteria of the spine was developed to aid in predicting spine stability of neoplastic lesions. The classification system includes global spinal location of the tumor, type and presence of pain, bone lesion quality, spinal alignment, extent of vertebral body collapse, and posterolateral spinal element involvement. Qualitative scores were assigned based on relative importance of particular factors gleaned from the literature and refined by expert consensus. Conclusion. The Spine Instability Neoplastic Score is a comprehensive classification system with content validity that can guide clinicians in identifying when patients with neoplastic disease of the spine may benefit from surgical consultation. It can also aid surgeons in assessing the key components of spinal instability due to neoplasia and may become a prognostic tool for surgical decision-making when put in context with other key elements such as neurologic symptoms, extent of disease, prognosis, patient health factors, oncologic subtype, and radiosensitivity of the tumor.

Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial

BACKGROUND Non-randomised trials have reported benefits of kyphoplasty in patients with cancer and vertebral compression fractures (VCFs). We aimed to assess the efficacy and safety of balloon kyphoplasty compared with non-surgical management for patients with cancer who have painful VCFs. METHODS The Cancer Patient Fracture Evaluation (CAFE) study was a randomised controlled trial at 22 sites in Europe, the USA, Canada, and Australia. We enrolled patients aged at least 21 years who had cancer and one to three painful VCFs. Patients were randomly assigned by a computer-generated minimisation randomisation algorithm to kyphoplasty or non-surgical management (control group). Investigators and patients were not masked to treatment allocation. The primary endpoint was back-specific functional status measured by the Roland-Morris disability questionnaire (RDQ) score at 1 month. Outcomes at 1 month were analysed by modified intention to treat, including all patients with data available at baseline and at 1 month follow-up. Patients in the control group were allowed to crossover to receive kyphoplasty after 1 month. This study is registered with ClinicalTrials.gov, NCT00211237. FINDINGS Between May 16, 2005, and March 11, 2008, 134 patients were enrolled and randomly assigned to kyphoplasty (n=70) or non-surgical management (n=64). 65 patients in the kyphoplasty group and 52 in the control group had data available at 1 month. The mean RDQ score in the kyphoplasty group changed from 17·6 at baseline to 9·1 at 1 month (mean change -8·3 points, 95% CI -6·4 to -10·2; p<0·0001). The mean score in the control group changed from 18·2 to 18·0 (mean change 0·1 points; 95% CI -0·8 to 1·0; p=0·83). At 1 month, the kyphoplasty treatment effect for RDQ was -8·4 points (95% CI -7·6 to -9·2; p<0·0001). The most common adverse events within the first month were back pain (four of 70 in the kyphoplasty group and five of 64 in the control group) and symptomatic vertebral fracture (two and three, respectively). One patient in the kyphoplasty group had an intraoperative non-Q-wave myocardial infarction, which resolved and was attributed to anaesthesia. Another patient in this group had a new VCF, which was thought to be device related. INTERPRETATION For painful VCFs in patients with cancer, kyphoplasty is an effective and safe treatment that rapidly reduces pain and improves function. FUNDING Medtronic Spine LLC.

Spinal Instability Neoplastic Score: An Analysis of Reliability and Validity From the Spine Oncology Study Group

PURPOSE Standardized indications for treatment of tumor-related spinal instability are hampered by the lack of a valid and reliable classification system. The objective of this study was to determine the interobserver reliability, intraobserver reliability, and predictive validity of the Spinal Instability Neoplastic Score (SINS). METHODS Clinical and radiographic data from 30 patients with spinal tumors were classified as stable, potentially unstable, and unstable by members of the Spine Oncology Study Group. The median category for each patient case (consensus opinion) was used as the gold standard for predictive validity testing. On two occasions at least 6 weeks apart, each rater also scored each patient using SINS. Each total score was converted into a three-category data field, with 0 to 6 as stable, 7 to 12 as potentially unstable, and 13 to 18 as unstable. RESULTS The κ statistics for interobserver reliability were 0.790, 0.841, 0.244, 0.456, 0.462, and 0.492 for the fields of location, pain, bone quality, alignment, vertebral body collapse, and posterolateral involvement, respectively. The κ statistics for intraobserver reliability were 0.806, 0.859, 0.528, 0.614, 0.590, and 0.662 for the same respective fields. Intraclass correlation coefficients for inter- and intraobserver reliability of total SINS score were 0.846 (95% CI, 0.773 to 0.911) and 0.886 (95% CI, 0.868 to 0.902), respectively. The κ statistic for predictive validity was 0.712 (95% CI, 0.676 to 0.766). CONCLUSION SINS demonstrated near-perfect inter- and intraobserver reliability in determining three clinically relevant categories of stability. The sensitivity and specificity of SINS for potentially unstable or unstable lesions were 95.7% and 79.5%, respectively.

Systematic Review of the Diagnosis and Management of Malignant Extradural Spinal Cord Compression: The Cancer Care Ontario Practice Guidelines Initiative‘s Neuro-Oncology Disease Site Group

Purpose This systematic review describes the diagnosis and management of adult patients with a suspected or confirmed diagnosis of extradural malignant spinal cord compression (MSCC). Methods MEDLINE, CANCERLIT, and the Cochrane Library databases were searched to January 2004 using the following terms: spinal cord compression, nerve compression syndromes, spinal cord neoplasms, clinical trial, meta-analysis, and systematic review. Results Symptoms for MSCC include sensory changes, autonomic dysfunction, and back pain; however, back pain was not predictive of MSCC. The sensitivity and specificity for magnetic resonance imaging (MRI) range from 0.44 to 0.93 and 0.90 to 0.98, respectively, in the diagnosis of MSCC. The sensitivity and specificity for myelography range from 0.71 to 0.97 and 0.88 to 1.00, respectively. A randomized study detected higher ambulation rates in patients with MSCC who received high-dose dexamethasone before radiotherapy (RT) compared with patients who did not receive corticosteroids...

Poor drug distribution as a possible explanation for the results of the PRECISE trial

OBJECT Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Reliability analysis of the epidural spinal cord compression scale.

OBJECTIVE The evolution of imaging techniques, along with highly effective radiation options has changed the way metastatic epidural tumors are treated. While high-grade epidural spinal cord compression (ESCC) frequently serves as an indication for surgical decompression, no consensus exists in the literature about the precise definition of this term. The advancement of the treatment paradigms in patients with metastatic tumors for the spine requires a clear grading scheme of ESCC. The degree of ESCC often serves as a major determinant in the decision to operate or irradiate. The purpose of this study was to determine the reliability and validity of a 6-point, MR imaging-based grading system for ESCC. METHODS To determine the reliability of the grading scale, a survey was distributed to 7 spine surgeons who participate in the Spine Oncology Study Group. The MR images of 25 cervical or thoracic spinal tumors were distributed consisting of 1 sagittal image and 3 axial images at the identical level including T1-weighted, T2-weighted, and Gd-enhanced T1-weighted images. The survey was administered 3 times at 2-week intervals. The inter- and intrarater reliability was assessed. RESULTS The inter- and intrarater reliability ranged from good to excellent when surgeons were asked to rate the degree of spinal cord compression using T2-weighted axial images. The T2-weighted images were superior indicators of ESCC compared with T1-weighted images with and without Gd. CONCLUSIONS The ESCC scale provides a valid and reliable instrument that may be used to describe the degree of ESCC based on T2-weighted MR images. This scale accounts for recent advances in the treatment of spinal metastases and may be used to provide an ESCC classification scheme for multicenter clinical trial and outcome studies.

Management of spinal meningiomas: surgical results and a review of the literature

OBJECT In this report, the authors describe their experience in the surgical management of spinal meningiomas at two neurosurgical centers. The results of a literature review are also presented. METHODS Eighty consecutive patients (22 men and 58 women) with spinal meningiomas who had undergone an operation at two specific neurosurgical centers were included in this study. Functional outcomes were evaluated using univariate and multivariate analyses. A review of the literature yielded an additional 651 patients with spinal meningiomas from 9 large studies. RESULTS On multivariate analysis, the variable of a poor preoperative neurological state (p < 0.02, odds ratio [OR] 13.6, 95% confidence interval [CI] 2.6-71.4) and invasion of the arachnoid/pia mater (p < 0.03, OR 15.2, 95% CI 2.5-90.4) were independent predictors of a poor outcome, whereas invasion of the arachnoid/pia (p < 0.02, OR 8.9, 95% CI 2.2-35) and duration of symptoms (p < 0.001, OR 1.12/month, 95% CI 1.05-1.2) predicted no improvement (stable or deteriorated condition). The Cox proportional hazards regression analysis showed three significant predictor variables for recurrence: invasion of the arachnoid/pia (p < 0.05; hazard ratio [HR] 1.8, 95% CI 1.2-3.6), Simpson resection grade (p < 0.012, HR 6.8, 95% CI 1.5-3.0), and histological tumor grade (Grade I; p < 0.001, HR 0.001-0.17). CONCLUSIONS Because of the excellent outcome of surgery for benign spinal meningiomas and the association between duration of symptoms and neurological compromise with a poor functional outcome, early operation is the treatment of choice. In cases of malignant transformation, adjuvant therapies must be considered.

An Assessment of the Reliability of the Enneking and Weinstein-Boriani-Biagini Classifications for Staging of Primary Spinal Tumors by the Spine Oncology Study Group

Study Design. Reliability analysis based on expert panel case series review and grading per the Enneking and Weinstein-Boriani-Biagini classification systems. Objective. To assess the reliability of the Enneking and Weinstein-Boriani-Biagini classification systems. Summary of Background Data. The Enneking and Weinstein-Boriani-Biagini (WBB) classifications were developed to stage and facilitate treatment planning in patients with primary spine tumors. To date, their interobserver and intraobserver reliability has not been assessed–a fundamental step in facilitating broader clinical and research use. Methods. Clinical information, imaging studies, and biopsy results were compiled from 15 selected patients with primary spinal tumors. Eighteen spine surgeons independently estimated and scored the cases for Enneking grade, tumor and metastasis categories, Enneking stage, Enneking-recommended surgical margin, WBB zones and layers, and WBB-recommended surgical procedures, with a second assessment performed after random resorting of cases. Interobserver and intraobserver reliability of each category were assessed by percent agreement or proportional overlap. The Fleiss, Cohen, and Mezzich &kgr; statistics (&kgr;) were then applied, determined by the type of variable analyzed. Results. The &kgr; statistics for interobserver reliability were 0.82, 0.22, 0.00, 0.57, 0.47, 0.31, 0.58, and 0.54 for the fields of Enneking grade, tumor and metastasis categories, Enneking stage, Enneking-recommended surgical margin, WBB zones and layers, and WBB-recommended surgical procedures, respectively. The &kgr; statistics for intraobserver reliability were 0.97, 0.53, 0.47, 0.82, 0.67, 0.63, 0.79, and 0.79 for the same respective fields. According to Landis and Koch, the ranges of &kgr; values of 0.00 to 0.20, 0.21 to 0.40, 0.41 to 0.60, 0.61 to 0.80, and >0.80 imply slight, fair, moderate, substantial, and near-perfect agreement, respectively. Conclusion. Results indicate moderate interobserver reliability and substantial and near-perfect intraobserver reliability for both the Enneking and WBB classification in terms of staging and guidance for treatment, despite a less than moderate interobserver reliability in interpreting the Enneking local tumor extension and WBB sector. Before incorporating the classifications in the clinical practice and research studies, further work is required to investigate the validity of the classifications.

The role of vertebral augmentation in multiple myeloma: International Myeloma Working Group Consensus Statement

The role of vertebral augmentation in multiple myeloma: International Myeloma Working Group Consensus Statement