Abstract
BACKGROUND
Clinical outcome assessments (COAs) are a key component of patient-centered assessment of net clinical benefit in trials. In neuro-oncology, unique symptoms, treatment-related ...toxicities, and overall poor prognosis further necessitate a focus on symptom management and quality of life. We conducted a computational survey of trends of COA use in past and ongoing neuro-oncology trials.
METHODS
Neuro-oncology trials on ClinicalTrials.gov were identified using primary malignant CNS tumor terms. Instrument names from PROQOLID (n= 2695) were used to determine COA use. Regression and interrupted time-series analyses assessed chronological and design-related trends.
RESULTS
Among 3584 adult neuro-oncology studies, 20% reported using a specific COA instrument: 21% among (n= 3038) interventional and 16% among (n= 524) observational trials. Among interventional studies, most trials used one instrument (91%) as a secondary outcome (81%). 269 unique COAs were reported overall, most frequently patient-reported (72%) and clinician-reported outcomes (44%) indicated for general neoplasms (59%), all conditions (30%), and brain tumors (21%). Most commonly used instruments among treatment-focused trials (n= 523 reporting COAs) included Performance Status (KPS 18%, ECOG 9%), EORTC QLQ-C30 and QLQ-BN20 (9%), and MMSE (7%). Among supportive care studies (n= 47), HADS (13%), FACT-Br (11%), and KPS (11%) were most frequent. COAs use was more likely in phase 3 versus early phase 1 and phase 1 (OR= 0.12 (95% CI:) 0.02-0.42; OR= 0.22 0.09-0.52) but not versus phase 2 (OR= 0.60 0.26-1.36), and was more likely in supportive care trials (versus diagnostics and prevention: OR= 0.10 0.01-0.65; OR= 0.05 0.00-0.79). The rate of COA use increased linearly over time (1998-2020; β= 1.1 0.8–1.4), with no significant changes surrounding individual regulatory events.
CONCLUSION
A growing proportion of neuro-oncology trials specified COA use, reflecting positive changes toward patient-centered drug evaluation. Further investigation of COA use by phase and trial focus may inform future trial design.
Abstract
We utilized the longitudinal clinical outcomes registry XCELSIOR (NCT03793088) to understand real world outcomes and treatment patterns among patients with diffuse midline glioma. A total of ...74 patients were identified with a diagnosis of diffuse midline glioma by pathology or imaging (36 pediatric and 38 adult patients). Median age at diagnosis was 20 years. As of 6/1/2022, 45 patients had expired. Median overall survival (mOS) of the entire cohort was 16.2 months. Cox proportional hazard ratio analysis identified age as the only significant covariate for OS (pediatric HR = 1.59, p=0.04). Pediatric patients had a mOS of 12.9 months and adult patients a mOS of 18.9 months from diagnosis. Frequency of primary tumor location in this dataset was brainstem (35%), thalamus (23%), and pons (20%). Pons location was associated with worst survival (mOS 11.4 months, n=15 patients). The most common anti-cancer interventions among all patients were ONC201 (39 patients), temozolomide (37 patients), bevacizumab (23 patients), panobinostat (8 patients), and immune checkpoint inhibitors (3 patients each, pembrolizumab and nivolumab). In this dataset, no interventions were statistically significant in a Cox proportional hazard model, but both immune checkpoint inhibitors (HR = -1.24, p=0.11) and ONC201 (HR = -0.38, p=0.27) trended toward benefit in the entire population. The subpopulation of patients treated with ONC201 whose tumor also harbored a TP53 mutation displayed a tendency toward activity (n=8); TP53-mutant patients treated with ONC201 had a mOS of 25.0 months vs. TP53 wild-type patients treated with ONC201 had a mOS of 20.3 months. Annotation of data for additional patients is ongoing and updated analyses will be presented at the meeting.
Abstract
The IDH-wild-type lower-grade astrocytomas are a heterogeneous entity. According to 2021 WHO classification, IDH-wild-type astrocytomas with any of the following factors show poor prognosis: ...combination of chromosome 7 gain and 10 loss (+7/-10), and/or EGFR amplification, and/or TERT promoter (TERTp) mutation. Multiplex ligation-dependent probe amplification (MLPA) can detect copy number alterations with a reasonable cost. The purpose of this study was to find precise and cost-effective method for stratifying the prognosis of IDH-wild-type astrocytomas. Sanger sequencing, MLPA, and quantitative methylation-specific PCR were performed for 42 IDH-wild-type lower-grade astrocytomas surgically treated at Kyoto University Hospital, and overall survival was analyzed for 40 patients. Of the 42 IDH-wild-type astrocytomas, 21 were classified as grade 4 in 2021 WHO classification and all of them had either TERTp mutation or EGFR amplification. Kaplan-Meier analysis confirmed the prognostic significance of 2021 WHO Classification, and WHO grade was also prognostic. Cox regression hazard model identified PTEN loss and PDGFRA amplification as independent significant prognostic indicators (Risk ratio of 9.75, p< 0.001 and 13.9, p=0.002). The classification recommended by 2021 WHO Classification could be completed using Sanger sequencing and MLPA. Survival analysis revealed PTEN and PDGFRA were significant prognostic factors for IDH-wild-type lower-grade astrocytomas.
The ability to write a scientific paper (WASP) is becoming progressively more critical because the “publish or perish” mantra is increasingly valid in today's world where success is judged by number ...of publications and quality of publications based on journals which publish the researcher's work. These metrics are used to gauge applicants in often cut-throat competitions for jobs and/or career advancement. However, the science and art of paper-writing comprise a vast panoply of different skills, from writing a proposal, to ethics and data protection applications, to data collection and analysis, to writing and dealing with editors and authors, and so on. Over the next few issues, Early Human Development will embark on a series of Best Practice Guidelines that will outline and explain the various requisite WASP skills while providing practical guidelines for paper writing. The purpose is to impart the authors' collective experience to trainees in this crucial aspect of career progress. This first set of WASP papers will mainly focus on statistical analysis using Excel™.
Simulation studies are computer experiments that involve creating data by pseudo‐random sampling. A key strength of simulation studies is the ability to understand the behavior of statistical methods ...because some “truth” (usually some parameter/s of interest) is known from the process of generating the data. This allows us to consider properties of methods, such as bias. While widely used, simulation studies are often poorly designed, analyzed, and reported. This tutorial outlines the rationale for using simulation studies and offers guidance for design, execution, analysis, reporting, and presentation. In particular, this tutorial provides a structured approach for planning and reporting simulation studies, which involves defining aims, data‐generating mechanisms, estimands, methods, and performance measures (“ADEMP”); coherent terminology for simulation studies; guidance on coding simulation studies; a critical discussion of key performance measures and their estimation; guidance on structuring tabular and graphical presentation of results; and new graphical presentations. With a view to describing recent practice, we review 100 articles taken from Volume 34 of Statistics in Medicine, which included at least one simulation study and identify areas for improvement.
Researchers and practitioners are typically familiar with descriptive statistics and statistical inference. However, outside of regression techniques, little attention may be given to questions ...around prediction. In the current paper, we introduce prediction intervals using fundamental concepts that are learned in descriptive and inferential statistical training (i.e., sampling error, standard deviation). We walk through an example using simple hand calculations and reference a simple R package that can be used to calculate prediction intervals.Researchers and practitioners are typically familiar with descriptive statistics and statistical inference. However, outside of regression techniques, little attention may be given to questions around prediction. In the current paper, we introduce prediction intervals using fundamental concepts that are learned in descriptive and inferential statistical training (i.e., sampling error, standard deviation). We walk through an example using simple hand calculations and reference a simple R package that can be used to calculate prediction intervals.
Abstract
BACKGROUND
Glioblastoma (GBM) is the most common malignant brain tumor in adults with a slightly higher incidence and shortened survival in males as compared to females in the United States. ...Recently, there has been a focus on specific health disparities between rural versus urban populations. There is growing interest in these disparities as it pertains to CNS tumors. Here, we characterize a rural population of females diagnosed with GBM as part of an ongoing investigation to drive research and further discussion around this important topic.
METHODS
We performed a single institutional retrospective review of patients with GBM in rural Pennsylvania between 2006 and 2019. We collected clinical, demographic, and tumor specific data including chronic comorbid disease, marital status, age at diagnosis, obstetric history, BMI, and tumor location.
RESULTS
Of the 611 patients diagnosed with GBM from 2006–2019, 41% (n= 249) were female with a median overall survival of 9.5 months compared to 10.7 months in males. At diagnoses, 69% (n=173) of females had chronic comorbid allergy/immunology disorders, 41% (n=101) had endocrine disorders, 53% (n=132) had hypertension, and 43% (n=106) had mood disorders. Tumor laterality was predominantly right-sided (58%, n=145) and frequently involved the frontal lobe (38%, n=94). The temporal lobe was the second most commonly involved (32%, n=80). The median age at diagnosis was 65-years-old range, 21–92. Fifty-six percent (n=140) of women were married with an average of 2.27 childbirths. The median body mass index (BMI) was 27.5 range, 16.3–64.9 with 66% of females classified as overweight/obese at diagnosis. Greater than 95% of females were insured.
CONCLUSION
There is a high incidence of chronic comorbid disease and obesity amongst females in this rural population, and females demonstrated a poorer overall survival as compared to males. Further comparisons are needed to characterize rural female GBM populations versus those in urban areas.
Abstract
BACKGROUND
H3 K27M glioblastoma is an aggressive grade IV tumor located in midline structures, added in 2016 by the WHO. Current outcomes are poor. The rarity of these tumors presents a ...challenge for definitive research on developing optimal treatments.
METHODS
We conducted a case series of 12 patients at the Barrow Neurological Institute who were diagnosed with biopsy-proven H3 K27M glioblastoma. The clinical status of these patients was followed from dates of first and last contact. Factors included first line treatment, best response to first line treatment, recurrences, second line treatments, response assessment criteria for all treatment rounds, any discovered metastases, and vital status by date of last contact.
RESULTS
Of the initial 12 patients, 5 were lost to follow-up before meaningful clinical outcomes could be recorded. Of the remaining 7, all underwent temozolomide and radiation as components of first-line treatment. After first-line treatment, 1/7 (14.2%) had partial response, 3/7 (42.8%) had stable disease, and 3/7 (42.8%) had progressive disease. 4 patients elected to undergo second line treatment: 2 underwent bevacizumab with lomustine, 1 underwent bevacizumab and irinotecan, and 1 underwent surgery with carmustine. Of the 2 who underwent bevacizumab and lomustine, 1 (50%) improved from progressive to stable disease and 1 (50%) stayed at stable disease. Of the 1 patient who underwent bevacizumab and lomustine, outcome worsened from stable to progressive disease. Of the 1 patient who underwent surgery and carmustine, outcome improved from progressive to stable disease.
CONCLUSIONS
H3 K27M is a highly aggressive tumor with poor outcomes. This case series demonstrates that multiple treatment rounds with chemotherapy and radiation therapy may benefit patients, with bevacizumab/lomustine and surgery/carmustine appearing to lead to promising outcomes. Further research is needed to establish evidence-based protocols so quality of life and survival time in these patients may improve.
Abstract
INTRODUCTION
Primary central nervous system (CNS) sarcomas are rare mesenchymal non-meningothelial tumors accounting for less than 0.2% of intracranial lesions. Diagnosis and management are ...challenging due to the current lack of substantive clinical, histological and molecular data.
METHODS
We retrospectively identified all patients with diagnosis of primary CNS sarcoma at the Hospital Fundación Pediatrico la Misericordia (HOMI) in Bogota, Colombia. We collected patient demographics, disease characteristics, and outcomes for analysis.
RESULTS
Between 2008 and 2020, twenty-four consecutive patients were diagnosed at the HOMI representing 6% of all CNS tumors diagnosed over the same time period. The median age at presentation was 9.48 years (range:1.6–13.4). The median time of symptoms prior to diagnosis was 2 weeks (0.1–24). The most common presentation was headache (21/24- 89%) and vomiting (19/24- 79%). The frontal lobe was involved in 63% of patients (15/24) and only one patient presented with a cerebellar lesion. Histologically, these tumors were characterized by a pleomorphic spindle cell architecture and high mitotic activity. All samples lacked immunoreactivity to GFAP, CD34, EMA, and S100 and all samples had strong nuclear immunopositivity for TLE-1; BCL-2 was reactive in eighteen cases. Gross total resection was attained in fifteen patients, most patients received focal radiation therapy and ICE chemotherapy. Progression-free survival at 12 and 24 months was 57% and 31% respectively. Overall survival was 77% at 12 months and 39% at 24 months. Thirteen patients relapsed, 11 presented with local failures, and 2 with intracranial recurrences outside of the radiation field.
CONCLUSION
Our study identifies TLE-1 as a diagnostic marker of primary CNS sarcoma, a highly malignant supratentorial tumor of childhood. Further molecular studies are urgently needed to elucidate the biology of this disease and the unusually high incidence observed in the Colombian pediatric population.
Abstract
OBJECTIVES
To investigate the impact of biopsy preceding resection compared to upfront resection in glioblastoma overall survival (OS) and post-operative outcomes using the National Cancer ...Database (NCDB).
METHODS
A total of 17,334 GBM patients diagnosed between 2010 and 2014 were derived from the NCDB. Patients were categorized into two groups: “upfront resection” versus “biopsy followed by resection”. Primary outcome was OS. Post-operative outcomes including 30-day readmission/mortality, 90-day mortality, and prolonged length of inpatient hospital stay (LOS) were secondary endpoints. Kaplan-Meier methods and accelerated failure time (AFT) models with gamma distribution were applied for survival analysis. Multivariable binary logistic regression models were performed to compare differences in the post-operative outcomes between these groups.
RESULTS
Patients undergoing “upfront resection” experienced superior survival compared to those undergoing “biopsy followed by resection” (median OS: 12.4 versus 11.1 months, log-rank test: P=0.001). In multivariable AFT models, significant survival benefits were observed among patients undergoing “upfront resection” (time ratio TR: 0.83, 95% CI: 0.75–0.93, P=0.001). Patients undergoing upfront GTR had the longest survival compared to upfront STR, GTR following STR, or GTR and STR following an initial biopsy (14.4 vs. 10.3, 13.5, 13.3, and 9.1, months), respectively (TR: 1.00 Ref., 0.75, 0.82, 0.88, and 0.67). Recent years of diagnosis, higher income and treatment at academic facilities were significantly associated with the likelihood of undergoing upfront resection after adjusting the covariates. Multivariable logistic regression revealed that 30-day mortality and 90-day mortality were decreased by 73% and 44% for patients undergoing “upfront resection” over “biopsy followed by resection”, respectively (both p < 0.001).
CONCLUSIONS
Pre-operative biopsies for surgically accessible tumors with characteristic imaging features of Glioblastoma lead to worse survival despite subsequent resection compared to patients undergoing upfront resection.
PDF
