Morshed, Ramin A.

BACKGROUND: Increases in the extent of resection of both contrast-enhanced (CE) and non–contrast-enhanced (NCE) tissue are associated with substantial survival benefits in patients with isocitrate dehydrogenase wild-type glioblastoma. The fact, however, remains that these lesions exist within the framework of complex neural circuitry subserving cognition, movement, and behavior, all of which affect the ultimate survival outcome. The prognostic significance of the interplay between CE and NCE cytoreduction and neurological morbidity is poorly understood. OBJECTIVE: To identify a clinically homogenous population of 228 patients with newly diagnosed isocitrate dehydrogenase wild-type glioblastoma, all of whom underwent maximal safe resection of CE and NCE tissue and adjuvant chemoradiation. We then set out to delineate the competing interactions between resection of CE and NCE tissue and postoperative neurological impairment with respect to overall survival. METHODS: Nonparametric multivariate models of survival were generated via recursive partitioning to provide a clinically intuitive framework for the prognostication and surgical management of such patients. RESULTS: We demonstrated that the presence of a new postoperative neurological impairment was the key factor in predicting survival outcomes across the entire cohort. Patients older than 60 yr who suffered from at least one new impairment had the worst survival outcome regardless of extent of resection (median of 11.6 mo), whereas those who did not develop a new impairment had the best outcome (median of 28.4 mo) so long as all CE tissue was resected. CONCLUSION: Our data provide novel evidence for management strategies that prioritize safe and complete resection of CE tissue.

Abstract INTRODUCTION The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate the progress made in neuro-oncology in all phase therapeutic clinical trials for neuro-epithelial central nervous system tumors in comparison to their demographic-specific age-adjusted disease incidence and mortality. METHODS Registry study of all published clinical trials for World Health Organization (WHO) defined neuro-epithelial CNS tumors between January 2000 and December 2019. Study participants for trials were obtained from PubMed and ClinicalTrials.gov. Population-based data from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and c2 tests were used to analyze the data. RESULTS Among 662 published clinical trial articles representing 49, 907 accrued participants, 62.5% of study participants were men and 37.5% were women (P< 0.0001) representing a mortality specific over-accrual for men (P= 0.001) and under-accrual for women (P= 0.001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with their US cancer mortality, Blacks (47% of expected mortality, P=.008), Hispanics (17% of expected mortality, P< .001) and Asians (33% of expected mortality, P< .001) were underrepresented compared with Whites (114% of expected mortality, P< .001). CONCLUSIONS Nearly 30 years since the Revitalization Act, minorities and women are consistently underrepresented when compared with their demographic-specific incidence and mortality in therapeutic clinical trials for neuroepithelial tumors. This study provides a framework for investigating cancer clinical trial accrual and offers guidance regarding workforce factors associated with enrollment of vulnerable patients.

Abstract BACKGROUND The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood. METHODS This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS). RESULTS Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5). CONCLUSIONS This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.