Responder Analysis of Pain Relief After Surgery for the Treatment of Spinal Metastatic Tumors.

BACKGROUND: Central tendency analysis studies demonstrate that surgery provides pain relief in spinal metastatic tumors. However, they preclude patient-specific probability of treatment outcome. OBJECTIVE: To use responder analysis to study the variability of pain improvement. METHODS: In this single-center, retrospective analysis, 174 patients were studied. Logistic regression modeling was used to associate preoperative characteristics with rating the Brief Pain Inventory (BPI) worst pain item 0 to 4. Linear regression modeling was used to associate preoperative characteristics with minimal clinically important improvement (MCI) in physical functioning defined by a 1-point decrease in the BPI Interference Construct score from preoperative baseline to 6 months postoperatively. RESULTS: Patient-level analysis revealed that 60% of patients experienced an improvement in pain. At least half experienced a decrease in pain resulting in MCI in physical functioning. Cutpoint analysis revealed that 48% were responders. Increasing scores on the preoperative pain intensity BPI items, the MD Anderson Symptom Inventory (MDASI) Core Symptom Severity Construct, the MDASI Spine Tumor-Specific Construct, the presence of preoperative neurologic deficits, and postoperative complications were associated with lower probability of treatment success while increasing severity in all BPI pain items, and MDASI constructs were associated with increased probability of MCI in physical function. Significant mortality and loss to follow-up intrinsic to this patient population limit the strength of these data. CONCLUSION: Although patients with milder preoperative symptoms are likely to achieve better pain relief after surgery, patients with worse preoperative symptom also benefit from surgery with adequate pain relief with an improvement in physical function.

A retrospective, quantitative assessment of disease burden in patients with leptomeningeal metastases from non-small-cell lung cancer.

BACKGROUND: Improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted therapies have altered disease management. A barrier to formal study of these therapies in LM is quantification of disease burden. Also, outcomes of patients with targetable mutations in LC-LM are not well defined. This study employs molecular and radiographic measures of LM disease burden and correlates these with outcome. METHODS: We reviewed charts of 171 patients with LC-LM treated at Memorial Sloan Kettering. A subset had MRI and CSF studies available. Radiographic involvement (n = 76) was scored by number of gadolinium-enhancing sites in 8 locations. CSF studies included cytopathology, circulating tumor cell (CTC) quantification (n = 16), and cell-free DNA (cfDNA) analysis (n = 21). Clinical outcomes were compared with Kaplan-Meier log-rank test and Cox proportional hazards methodologies. RESULTS: Median overall survival was 4.2 months (95% CI: 3.6-4.9); 84 patients (49%) harbored targetable mutations. Among bevacizumab-naïve patients with MRI and CSF cytology at time of LC-LM diagnosis, extent of radiographic involvement correlated with risk of death (hazard ratio [HR]: 1.16; 95% CI: 1.02-1.33; P = 0.03), as did CSF CTC (HR: 3.39, 95% CI: 1.01-11.37; P = 0.048) and CSF cfDNA concentration (HR: 2.58; 95% CI: 0.94-7.05; P = 0.06). Those without a targetable mutation were almost 50% more likely to die (HR: 1.49; 95% CI: 1.06-2.11; P = 0.02). CONCLUSIONS: Extent of radiographic involvement and quantification of CSF CTC and cfDNA show promise as prognostic indicators. These findings support molecular characterization and staging for clinical management, prognostication, and clinical trial stratification of LC-LM.

Prognostic and radiographic correlates of a prospectively collected molecularly profiled cohort of IDH1/2-wildtype astrocytomas.

BACKGROUND: In the molecular era, the relevance of tumor grade for prognostication of IDH1/2-wildtype (WT) gliomas has been debated. It has been suggested that histologic grade II and III astrocytomas with molecular features of glioblastoma, IDH1/2-WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials. METHODS: We integrated prospective clinical sequencing from 564 patients with IDH1/2-WT gliomas (26 grade II, 71 grade III and 467 grade IV) with clinical and radiographic data to assess associations between molecular features, grade and outcome. RESULTS: Compared to histologic grade IV IDH1/2-WT astrocytomas, histologic grade II astrocytomas harbor fewer chromosome 7/10 alterations (P = 0.04), EGFR amplifications (P = 0.022) and alterations in cell-cycle effectors (P = 1.9e-11), but a similar frequency of TERT promoter mutations. In contrast, there is no difference in the frequency of these canonical molecular features in histologic grade III vs. IV IDH1/2-WT disease. Progression-free (PFS) and overall survival (OS) for histologic grade II tumors were significantly longer than grade III tumors (P = 0.02 and P = 0.008, respectively), whereas there was no difference in PFS and OS for histologic grade III compared to grade IV tumors. Median PFS for histologic grade II, III and IV tumors was 19, 11 and 9 months, respectively. Median OS for the same tumors was 44, 23 and 23 months, respectively. In histologic grade II and III IDH1/2 WT tumors, gliomatosis is associated with the absence of cell-cycle alterations (P = 0.008) and enriched in grade II features (P = 0.1) and alterations in the PI3K-AKT pathway (P = 0.09). CONCLUSIONS: Grade II histology has genotypic and phenotypic associations with prognostic implications in IDH1/2-WT astrocytomas.

Genomic Correlates of Disease Progression and Treatment Response in Prospectively Characterized Gliomas.

PURPOSE: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. RESULTS: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. CONCLUSIONS: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Spinal Instability Neoplastic Score component validation using patient-reported outcomes.

OBJECTIVE: The Spinal Instability Neoplastic Score (SINS) correlates with preoperative disability and response to stabilization, with patients with higher scores experiencing greater relief after surgery. However, there is a paucity of data demonstrating the extent to which each component contributes to preoperative clinical status and response to stabilization surgery. The objectives of this study were 2-fold. First, to determine how SINS components correlate with pre- and postoperative patient-reported outcomes (PROs). Second, to determine whether patients with higher SINS (10-12) in the "indeterminate" group respond differently to surgery compared to patients with lower SINS (7-9). METHODS: SINS and PROs were prospectively collected in 131 patients undergoing stabilization surgery for metastatic spinal disease. Association of SINS components and their individual scores with preoperative symptom burden and PRO symptom change after surgery was analyzed using the Spearman rank correlation coefficient (rho) and the Kruskal-Wallis test. SINS and association with preoperative PRO scores and mean differences in post- and preoperative PRO scores were compared for 2 SINS categories within the indeterminate group (7-9 vs 10-12) using the Wilcoxon 2-sample test and Wilcoxon signed-rank test. RESULTS: The presence of mechanical pain, followed by metastatic location, correlated most strongly with preoperative functional disability measures and lower disability PRO scores following surgical stabilization. Blastic rather than lytic bone lesions demonstrated stronger association with pain reduction following stabilization. Following surgery, patients with SINS 10-12 demonstrated markedly greater improvement in pain and disability PRO scores nearly across the board compared to patients with SINS 7-9. CONCLUSIONS: The presence of mechanical pain has the strongest correlation with preoperative disability and improvement in pain and disability PRO scores after surgery. Radiographic components of SINS also correlate with preoperative symptom severity and postoperative PRO, supporting their utilization in evaluation of spinal instability. Among patients with indeterminate SINS, patients with higher scores experience greater reduction in pain and disability PRO scores following surgical stabilization, suggesting that the indeterminate-SINS group includes distinct populations.

Minimal Access Surgery for Spinal Metastases: Prospective Evaluation of a Treatment Algorithm Using Patient-Reported Outcomes.

BACKGROUND: Minimal access surgery (MAS) allows for an early return to systemic and radiation therapy in patients with cancer, leading to its increasing usage in the treatment of spinal metastases. Systematic examination of surgical indications resulted in the development of an algorithm for implementation of MAS in the treatment of spinal metastases. The objective of the present study was to evaluate a spine tumor MAS treatment algorithm using patient-reported outcomes for patients with cancer undergoing treatment of spinal metastases. METHODS: We performed a prospective cohort study of patients who had undergone spinal percutaneous instrumented stabilization with the addition of MAS spinal cord or nerve root decompression and/or kyphoplasty when indicated at a tertiary cancer center from December 2013 to August 2016. Validated patient-reported outcome measures, including the Brief Pain Inventory and the MD Anderson Symptom Inventory-spine module, were used. The patient-reported outcome measures were collected and compared at baseline, 3 months, and long-term follow-up (range, 4.5-12 months). RESULTS: A total of 51 patients were included. MAS resulted in a statistically significant decrease in the severity of pain and improved activity, ability to work, and enjoyment of life (P < 0.001). The improvement was reported at the short- and long-term follow-up points. CONCLUSIONS: We present our treatment algorithm for MAS implementation in the treatment of thoracolumbar spinal metastases. Prospectively collected data have demonstrated that using this algorithm, MAS surgery for the treatment of spinal metastases results in significant decreases in pain severity and symptom interference with daily activities.

Hybrid surgery-radiosurgery therapy for metastatic epidural spinal cord compression: A prospective evaluation using patient-reported outcomes.

BACKGROUND: Patient-reported outcomes (PRO) represent an important measure of cancer therapy effect. For patients with metastatic epidural spinal cord compression (MESCC), hybrid therapy using separation surgery and stereotactic radiosurgery preserves neurologic function and provides tumor control. There is currently a paucity of data reporting PRO after such combined modality therapy for MESCC. Delineation of hybrid surgery-radiosurgery therapy effect on PRO validates the hybrid approach as an effective therapy resulting in meaningful symptom relief. PATIENTS AND METHODS: Brief Pain Inventory (BPI) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP), PROs validated in the cancer population, were prospectively collected. Patients with MESCC who underwent separation surgery followed by stereotactic radiosurgery were included. Separation surgery included a posterolateral approach without extensive cytoreductive tumor excision. A median postoperative radiosurgery dose of 2700 cGy was delivered. The change in PRO 3 months after the hybrid therapy represented the primary study outcome. Preoperative and postoperative evaluations were analyzed using the Wilcoxon signed-rank test for matched pairs. RESULTS: One hundred eleven patients were included. Hybrid therapy resulted in a significant reduction in the BPI items "worst" and "right now" pain (P < .0001), and in all BPI constructs (severity, interference with daily activities, and pain experience, P < .001). The MDASI-SP demonstrated reduction in spine-specific pain severity and interference with general activity (P < .001), along with decreased symptom interference (P < .001). CONCLUSIONS: Validated PRO instruments showed that in patients with MESCC, hybrid therapy with separation surgery and radiosurgery results in a significant decrease in pain severity and symptom interference. These prospective data confirm the benefit of hybrid therapy for treatment of MESCC and should facilitate referral of patients with MESCC for surgical evaluation.

The Role of Extent of Resection in IDH1 Wild-Type or Mutant Low-Grade Gliomas.

BACKGROUND: Maximizing extent of resection (EOR) improves outcomes in adults with World Health Organization (WHO) grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. OBJECTIVE: To assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS) in mtIDH and wtIDH LGGs. METHODS: We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing resection at a single institution. EOR was assessed with quantitative 3-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan-Meier method. RESULTS: Fifty-two (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median preoperative tumor volume was 37.4 cm3; median EOR of 57.6% was achieved. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, stratifying by IDH status demonstrates that greater EOR independently prolonged MPFS and OS for wtIDH patients (hazard ratio [HR] = 0.002 [95% confidence interval {CI} 0.000-0.074] and HR = 0.001 [95% CI 0.00-0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17-4.13] and HR = 2.99 [95% CI 0.15-61.66], respectively). CONCLUSION: Increasing EOR confers oncologic and survival benefits in IDH1 wtLGGs, but the impact on IDH1 mtLGGs requires further study.

Corrigenda: Hybrid surgery-radiosurgery therapy for metastatic epidural spinal cord compression: A prospective evaluation using patient-reported outcomes.

[This corrects the article DOI: 10.1093/nop/npx017.][This corrects the article DOI: 10.1093/nop/npx017.].

Patient-reported outcomes after surgical stabilization of spinal tumors: symptom-based validation of the Spinal Instability Neoplastic Score (SINS) and surgery.

BACKGROUND CONTEXT: Neoplastic spinal instability is movement-related pain or neurologic compromise under physiologic loads with the Spinal Instability Neoplastic Score (SINS) developed to facilitate diagnosis. There is a paucity of evidence that mechanical instability correlates with patient-reported symptoms and that surgical stabilization significantly improves these patient-reported outcomes (PROs). PURPOSE: The objective of this study was to determine if SINS correlates with patient-reported preoperative pain and disability, and if surgical stabilization significantly improves PRO. STUDY DESIGN: A single-institution prospective cohort study was carried out. PATIENT SAMPLE: A total of 131 patients who underwent stabilization for metastatic spinal tumor treatment between July 2014 and August 2016 were included. OUTCOMES MEASURES: Preoperative baseline and mean difference in perioperative PROs as assessed by the Brief Pain Inventory (BPI) and MD Anderson Symptom Inventory (MDASI) were the outcome measures. METHODS: The SINS was analyzed as a continuous, ordinal, and categorical variable (Stable: 0-6, Indeterminate: 7-12, Unstable: 13-18). Statistical analysis was performed using Spearman rank coefficient (rho), the Kruskal-Wallis test, and an extension of the Cochran-Armitage trend test. The SINS and association between the mean differences in post- and preoperative PRO scores was analyzed using the Wilcoxon signed-rank test. RESULTS: There was a statistically significant positive correlation between increasing SINS and severity of preoperative pain with BPI average pain (rho=0.20; p=.03) and MDASI pain (rho=0.19; p=.03). Increasing SINS correlated with severity of preoperative disability with BPI walking (rho=0.19; p=.04), MDASI activity (rho=0.24; p=.006), and MDASI walking (rho=0.20; p=.03). Similar associations were noted when SINS was analyzed as an ordinal categorical variable. Stabilization significantly improved nearly all PRO measures for patients with indeterminate and unstable SINS. Significant correlations persisted when controlling for neurologic status and were not affected based on the technique of surgical stabilization used. CONCLUSIONS: Patient-related outcome-based validation of SINS confirms this scoring system for diagnosing neoplastic spinal instability and provides surgeons with a tool to determine which patients will benefit from stabilization. Surgical stabilization of cancer patients with SINS consistent with mechanical instability provides significant reduction in pain and improves patient mobility independent of neurologic status and stabilization technique.

Predictors of quality of life improvement after surgery for metastatic tumors of the spine: prospective cohort study.

BACKGROUND CONTEXT: Surgical decompression and stabilization followed by radiosurgery represents an effective method for local tumor control and neurologic preservation for patients with metastatic epidural spinal cord compression (MESCC). We have previously demonstrated improvement in health-related quality of life (HrQOL) after this combined modality treatment ("hybrid therapy"). PURPOSE: The current analysis focuses on delineation of patient-specific prognostic factors predictive of HrQOL change after combined surgery-stereotactic radiosurgery (SRS) treatment of MESCC. STUDY DESIGN: This is a prospective, single-center, cohort study. PATIENT SAMPLE: One hundred and eleven patients with MESCC who underwent separation surgery followed by SRS were included. OUTCOME MEASURES: Prognostic factors associated with improved patient-reported outcome (PRO) measures. METHODS: Patient-reported outcome tools, that is, Brief Pain Inventory (BPI) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP), both validated in the cancer population, were prospectively collected. Numeric prognostic factors were correlated with PRO measures using the Spearman rank correlation coefficient. Categorical prognostic factors were correlated with PRO measures using the Wilcoxon two-sample test (for two categories) or the Kruskal-Wallis test (for three or more categories). All statistical tests were two-sided with a level of significance <.05 for correlation of prognostic factors with PRO constructs and a level of significance <.0014 for correlation of prognostic factors with PRO items. Statistical analyses were done in SAS (version 9.4, Cary, NC, USA). RESULTS: One hundred and eleven patients were included in this analysis. Patients with lower preoperative Medical Research Council (MRC) motor scores experienced a greater decrease in symptom interference (BPI interference construct (p=.03) and individual functional measures including general activity (p=.001), walking (p=.001), and normal work (p=.006)). Lumbar location was associated with better outcomes than cervical or thoracic as noted on the BPI pain experience construct (p=.03) and MDASI-SP interference (p=.01) and core symptom (p=.002) constructs. Patients with American Spinal Injury Association (ASIA) scores of C or D benefit more than those with ASIA E on BPI interference construct (p=.04). Patients with higher Eastern Cooperative Oncology Group (ECOG) scores at presentation benefit more than those with low ECOG scores on MDASI-SP interference construct (p=.03). Women benefit more than men on BPI interference (p=.03) and pain experience (p=.04) constructs. Patients with prior spinal surgery at the current level of interest benefit less than those who are naïve surgical patients in MDASI-SP interference construct (p=.04). CONCLUSIONS: Delineation of patient characteristics associated with HrQOL improvement provides crucial information for patient selection, patient education, and setting treatment expectations. For patients with MESCC treated with hybrid therapy using surgery and radiosurgery, the presence of neurologic deficits and diminished performance status, lumbar tumor level, and female gender were associated with greater PRO improvement.

Prior malignancies in patients harboring glioblastoma: an institutional case-study of 2164 patients.

More patients are surviving long-term following a cancer diagnosis and as such are at risk for second malignancies. As the most common primary brain tumor, glioblastoma (GBM) will not infrequently occur in this population. No study has examined the incidence of prior cancer (PC) in patients harboring GBM. Here we evaluate the epidemiological features, as well as the molecular and clinical characteristics of GBM as a second cancer. Utilizing a web-based cancer data management system at our institution, we identified 2164 patients harboring GBM from 2007 to 2014. We collected baseline demographic, molecular, and clinical data. Univariate analysis was performed to compare the cohort of GBM patients with and without PC diagnosis. Survival differences were analyzed with Kaplan-Meier and log-rank testing. A Cox-proportional hazards model was fit for multivariable analysis. 170 patients (7.9%) harboring GBM had a PC diagnosis. The median interval between diagnoses was 79 months. The most common pathologies were breast (18.8%) and prostate (18.8%) cancer. Patients with a PC were older at the time of GBM diagnosis than those without PC (66 vs. 59 years, p < 0.001) and were more likely to be white (88.2 vs. 72.8%, p < 0.001). Patients with PC were more likely to harbor an EGFR (20 vs. 12.3%, p < 0.001) or MGMT mutation (17.6 vs. 11.6%, p < 0.001). Median survival was 13 months in the PC cohort and 15 months in the cohort without PC (p = NS). Age, KPS, and diagnosis year were the only factors which influenced outcome in multivariable analysis. Patients who develop GBM following a prior malignancy constitute ~8% of patients with GBM. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of GBM should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies.

Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid.

PURPOSE: Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue. MATERIALS AND METHODS: We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer. RESULTS: We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations. CONCLUSION: The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.

Survival in patients treated for anaplastic meningioma.

OBJECT: While most meningiomas are benign, 1%-3% display anaplastic features, with little current understanding regarding the molecular mechanisms underlying their formation. In a large single-center cohort, the authors tested the hypothesis that two distinct subtypes of anaplastic meningiomas, those that arise de novo and those that progress from lower grade tumors, exist and exhibit different clinical behavior. METHODS: Pathology reports and clinical data of 37 patients treated between 1999 and 2012 for anaplastic meningioma at Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively reviewed. Patients were divided into those whose tumors arose de novo and those whose tumors progressed from previously documented benign or atypical meningiomas. RESULTS: Overall, the median age at diagnosis was 59 years and 57% of patients were female. Most patients (38%) underwent 2 craniotomies (range 1-5 surgeries) aimed at gross-total resection (GTR; 59%), which afforded better survival when compared with subtotal resection according to Kaplan-Meier estimates (median overall survival [OS] 3.2 vs 1.3 years, respectively; p = 0.04, log-rank test). Twenty-three patients (62%) presented with apparently de novo anaplastic meningiomas. Compared with patients whose tumors had progressed from a lower grade, those patients with de novo tumors were significantly more likely to be female (70% vs 36%, respectively; p = 0.04), experience better survival (median OS 3.0 vs 2.4 years, respectively; p = 0.03, log-rank test), and harbor cerebral hemispheric as opposed to skull base tumors (91% vs 43%, respectively; p = 0.002). CONCLUSIONS: Based on this single-center experience at MSKCC, anaplastic meningiomas, similar to glial tumors, can arise de novo or progress from lower grade tumors. These tumor groups appear to have distinct clinical behavior. De novo tumors may well be molecularly distinct, which is under further investigation. Aggressive GTR appears to confer an OS advantage in patients with anaplastic meningioma, and this is likely independent of tumor progression status. Similarly, those patients with de novo tumors experience a survival advantage likely independent of extent of resection.