Newly-diagnosed High-grade Glioma Research Articles

Safety and Feasibility of JAK Inhibitor Ruxolitinib in Newly-Diagnosed High-Grade Gliomas (CRUX): Final Trial Report

INTRODUCTION: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. METHODS: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3 + 3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. Primary study objective was determination of maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. Secondary objective was the determination of safety as assessed using NIH CTCAE scale, overall survival (OS), and progression-free survival (PFS). Exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. RESULTS: 60 patients were enrolled, with median age 60.5 years (range 22-78), 23 (38%) female, and 37 (62%) were male. Amongst 59 evaluable patients, 29 (49%) were MGMT unmethylated and received ruxolitinib with 60Gy radiation over 6 weeks, while 30 (51%) patients were MGMT methylated and received ruxolitinib with 75mg/m2 of temozolomide (TMZ) with 60Gy radiation over 6 weeks. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Median follow-up of patients alive was 34.2 months (range 18-52.2) with outcomes. CONCLUSIONS: Ruxolitinib therapy is safe and therapeutically feasible in combination with TMZ and radiation. A randomized phase 2 trial is planned.

Safety and feasibility of JAK inhibitor ruxolitinib in newly-diagnosed high-grade gliomas (CRUX): Final toxicity report.

2060 Background: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. This concept was explored in a phase I trial (NCT03514069), whose final report on toxicity is presented here. Methods: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3+3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. The primary study objective was the determination of the maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. The secondary objective was the determination of safety, overall survival (OS), and progression-free survival (PFS). The exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. Results: 60 patients were enrolled, with a median age of 60.5 years (range 22-78). 23 (38%) patients were female and 37 (62%) were male. 29 (48%) were MGMT unmethylated and received ruxolitinib with radiation of 60 Gy over 6 weeks. 31 (52%) patients were MGMT methylated and received ruxolitinib with 75 mg/m2 of temozolomide (TMZ) with radiation of 60 Gy over 6 weeks. The 1-year OS rate was 77% for all GBM patients; 62% for arm 1 (unmethylated MGMT) and 93% for arm 2 (methylated MGMT). Median OS for arm 1 was 18.1 months (10.1, NA) and was not reached for arm 2. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Conclusions: Ruxolitinib therapy is safe and feasible in combination with TMZ and radiation. Efficacy of ruxolitinib plus SOC appears promising compared to historical benchmarks for both MGMT methylated and MGMT unmethylated cohorts. A randomized phase 2 trial is planned. Clinical trial information: NCT03514069 .

An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

2043 Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×107 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of >50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .

Clinical application of a functional 3D ex vivo test to predict therapeutic response in patients with HGG: A progression-free survival analysis.

2031 Background: High grade gliomas (HGG) including glioblastoma (GBM) are among the most aggressive brain cancers, with patients exhibiting highly variable treatment responses in both newly diagnosed (ND) and recurrent disease. Temozolomide (TMZ) + radiation therapy is the guideline directed standard of care (SOC) in the ND setting; it has remained relatively unchanged for > 15 years, despite variable patient responses. Current available biomarkers do not inform personalized therapy. Functional drug response testing using patient specific tumor cells may have the potential to inform effective therapy selection, thus advancing functional precision oncology. Progression free survival (PFS) is a meaningful surrogate to overall survival (OS) in GBM and therefore, represents a measure of clinical benefit. Methods: The 3D-PREDICT clinical study (NCT03561207) allows enrollment of HGG patients with ECOG ≤ 3, perhaps representing a more accurate real-world population compared to most clinical studies in the same patient cohort. Tumor tissue was prospectively collected during SOC biopsy/resection and analyzed in an ex vivo cell culture test using a panel of agents prescribed as HGG therapeutics. Results: Data pertain to 56 3D-PREDICT patients who had > 6 months of follow up as of December 31, 2021 or experienced progression/death < 6 months post tissue collection. There were 42 3D-PREDICT patients who had IDH wild type ND GBM and received SOC. PFS analysis of these patients showed 3D ex vivo testing was able to prospectively predict TMZ clinical responders vs. non-responders (Kaplan-Meier, p = 0.039; HR 0.516, 95% CI 0.234,1.137). Test predicted TMZ responders had a relative PFS advantage of 3.7 months. Of the 42 patients, 38 had known MGMT methylation status with 23 patients (60%) being unmethylated. Test predicted responders (9) included unmethylated patients; test predicted non-responders (33) included methylated patients. The data suggest ex vivo testing of patient specific tumor tissue may identify ND HGG patients a priori who respond to TMZ, irrespective of MGMT methylation status. Beyond TMZ response prediction, the test assesses tissue response to 11 additional known HGG therapies and therefore may provide a tool to inform potential alternative treatments to TMZ for ND patients. Also evaluated were 14 3D-PREDICT recurrent HGG patients who received test directed salvage therapy; mean PFS after tissue collection from re-resection was 9.0 months (range 2.3 – 24.7 mo) for 9 patients at first recurrence, and 5.7 months (range 1.8 – 11.4 mo) for 5 patients with 2 to 6 recurrences. These examples demonstrate initial test utilization informing salvage therapy selection, correlated with PFS improvements in recurrent HGG. Conclusions: This functional 3D ex vivo cell culture platform provided survival benefit in analyzed ND and recurrent cohorts. Clinical trial information: NCT03561207.

Prospective prediction of clinical drug response in high-grade gliomas using an ex vivo 3D cell culture assay.

BackgroundClinical outcomes in high-grade glioma (HGG) have remained relatively unchanged over the last 3 decades with only modest increases in overall survival. Despite the validation of biomarkers to classify treatment response, most newly diagnosed (ND) patients receive the same treatment regimen. This study aimed to determine whether a prospective functional assay that provides a direct, live tumor cell-based drug response prediction specific for each patient could accurately predict clinical drug response prior to treatment.MethodsA modified 3D cell culture assay was validated to establish baseline parameters including drug concentrations, timing, and reproducibility. Live tumor tissue from HGG patients were tested in the assay to establish response parameters. Clinical correlation was determined between prospective ex vivo response and clinical response in ND HGG patients enrolled in 3D-PREDICT (ClinicalTrials.gov Identifier: NCT03561207). Clinical case studies were examined for relapsed HGG patients enrolled on 3D-PREDICT, prospectively assayed for ex vivo drug response, and monitored for follow-up.ResultsAbsent biomarker stratification, the test accurately predicted clinical response/nonresponse to temozolomide in 17/20 (85%, P = .007) ND patients within 7 days of their surgery, prior to treatment initiation. Test-predicted responders had a median overall survival post-surgery of 11.6 months compared to 5.9 months for test-predicted nonresponders (P = .0376). Case studies provided examples of the clinical utility of the assay predictions and their impact upon treatment decisions resulting in positive clinical outcomes.ConclusionThis study both validates the developed assay analytically and clinically and provides case studies of its implementation in clinical practice.

Sensitivity of the Montreal Cognitive Assessment in screening for cognitive impairment in patients with newly diagnosed high-grade glioma.

Cognitive impairment is frequent in patients with high-grade glioma and requires cognitive follow-up. Cognitive screening tools such as the Montreal Cognitive Assessment (MoCA) have been used to assess cognition in these patients. Here we assessed the sensitivity of the MoCA in screening for cognitive impairment in a cohort of 156 patients with newly-diagnosed high-grade glioma, after surgery and before radiochemotherapy. We assessed cognitive performance with the MoCA and a neuropsychological battery. Cognitive scores were analyzed in terms of a previously validated framework designed to control false positives and data for 1003 control participants from the GRECOGVASC study. After comparison of performance on the tests, we used stepwise logistic regression to produce a cognitive summary score from the neuropsychological battery. Then we analyzed sensitivity and specificity of the MoCA with receiver operator characteristic (ROC) curve analysis. Both raw and adjusted MoCA scores showed only moderate sensitivity. The area under the ROC curve was 0.759 (95% CI 0.703-0.815) for the raw score and 0.788 (95% CI 0.734-0.842) for the adjusted score. Optimal discrimination was obtained with a raw score ≤ 25 (sensitivity: 0.526; specificity: 0.832; positive predictive value: 0.2; negative predictive value: 0.96) and an adjusted score - 0.603 (sensitivity: 0.716; specificity: 0.768; positive predictive value: 0.24; negative predictive value: 0.96). The moderate sensitivity of MoCA indicates that it is not a suitable screening tool for detecting cognitive impairment in patients with newly-diagnosed high-grade glioma.

P08.05 Cognitive impairment in patients with newly-diagnosed high-grade gliomas

Abstract BACKGROUND Cognitive dysfunction is frequent in patients with primary brain tumor, impairing attention, memory and executive function. It compromises functional independence, decision making capacity and psycho-social well-being. Cognitive functioning is highly correlated to disease progression and quality of survival, thus cognitive follow-up is essential in the management of the disease. Cognitive screening tools are often used, since a comprehensive battery may be time consuming and challenging for patients. The objective of this study was to identify a pattern of cognitive dysfunction in patients with newly-diagnosed high-grade gliomas and evaluate the sensitivity and specificity of the MoCA (Montreal Cognitive Assessment) as a cognitive screening tool in the clinical practice. MATERIAL AND METHODS We compared performances in tests of memory, action speed, visuospatial ability and executive function of 156 patients with newly-diagnosed WHO Grade III and IV gliomas, after surgery and prior to radiochemotherapy, to those of a group of healthy controls (n=1003). Relatives assessed behavior through a questionnaire of behavioral dysexecutive syndrome. A stepwise logistic regression was performed to select cognitive domains better discriminating patients from healthy controls and we tested the sensitivity and specificity of the MOCA using ROC curve analysis. RESULTS The stepwise logistic regression analysis identified the 3 following factors better discriminating patients from controls: TMT-B completion time (OR: 0.673; 95% CI: 0.511–0.886; p=0.0005), a verbal memory index (OR:0.507; 95% CI: 0.358–0.718; p=0.0001) and a behavioral dysexecutive score (OR:0.616; 95% CI: 0.468–0.812, p=0.001). Prevalence of cognitive-behavioral impairment was of 35.94%; 95% CI: 28.3 - 43.5. The ROC curve analysis for the assessment of the MoCA sensitivity and specificity in detecting impairment yielded 0.795 (95%CI: 0.714–0.875) for the MoCA raw score, and 0.804 (95%CI: 0.727 - 0.881) for the adjusted z score. The optimal discrimination was obtained for a raw score ≤ 25 (sensitivity of 0.526; specificity of 0.832). For the adjusted score, optimal discrimination value was observed with a -0.603 z score (sensitivity of 0.716; specificity of 0.768). CONCLUSION Cognitive impairment and behavioral dysexecutive syndrome is frequent in patients with newly-diagnosed high-grade glioma. The MoCA lacks sensitivity in screening cognitive impairment to discriminate patients from healthy controls in this setting, and a comprehensive neuropsychological assessment is still recommended.

Direct medical costs of treatment in newly-diagnosed high-grade glioma among commercially insured US patients

Aim: This analysis assessed the direct medical costs of newly-diagnosed, temozolomide (TMZ)-treated glioblastoma (GBM) from the perspective of a US commercial setting.Materials and methods: The analysis included subjects identified from the IMS PharMetrics LifeLink Plus™ claims database from January 1, 2008 to August 31, 2014 who were ≥18 years of age, had ≥1 malignant brain cancer diagnosis, had brain surgery ≤90 days prior to TMZ initiation, had TMZ treatment, and were continuously enrolled for ≥12 months pre-diagnosis and ≥1 month post-diagnosis. Per-patient per-month (PPPM) and cumulative costs from 3 months pre-diagnosis to various post-diagnosis follow-up time points were calculated. Multivariable analyses were used to estimate adjusted mean cost and identify contributors of cost.Results: The study included 2,921 subjects (median age = 56 years; 60% male). After diagnosis, the median (interquartile range, IQR) number of inpatient, emergency department, and outpatient visits were 2 (1–4), 1 (1–3), and 19 (13–27); median (IQR) length of stay per hospitalization was 5 (3–9) days. Mean total cumulative costs per patient from 3 months pre-diagnosis to 12 months and to 5 years post-diagnosis were $201,749 (197,490–206,024) and $268,031 (262,877–274,416). Mean (SD) PPPM costs were $818 (1,128) and $7,394 (8,676) pre- and post-GBM diagnosis, respectively. The variables most predictive of cumulative costs included radiation therapy (+$81,732), ≥2 weeks of hospitalization (+$49,629), and ≥7 MRI scans (+$40,105).Conclusions: The direct medical costs of newly-diagnosed, TMZ-treated GBM in commercially insured patients are substantial, with estimated total cumulative costs of $268,031.

ATPS-33EVIDENCE OF ABSENCE FOR CYTOMEGALOVIRUS IN PATIENTS WITH GLIOBLASTOMAS AND OTHER HIGH-GRADE GLIOMAS BY REAL-TIME PCR FOR DNA, IMMUNOHISTOCHEMISTRY FOR PROTEIN ANDIN-SITUHYBRIDIZATION FOR mRNA

BACKGROUND: Several groups have suggested a potential causative role of cytomegalovirus (CMV) in the development of high-grade gliomas (HGG), while others have not found any evidence of CMV in these cancers. We used 3 different molecular technologies to assay for the presence of CMV DNA, mRNA and protein in tumor tissue and blood samples of patients with HGG. METHODS: Part A: Fresh-frozen tissues from 27 glioblastomas (GBM) were analyzed for CMV by real-time PCR of US17. Part B: Prospective study of patients with newly-diagnosed HGG (grades III or IV) who underwent standard chemoradiation. Plasma and serum were collected at baseline, and plasma at follow-up visits. FFPE tumor tissue was analyzed for CMV proteins by genetically validated immunohistochemistry (IHC), in-situ hybridization assays targeting 1E1/2 and pp65, and by real-time PCR for US17 (tissue and plasma). RESULTS: Part A: CMV was detected in 0/27 fresh-frozen GBM tissue samples using real-time PCR. Part B: Eighteen patients with HGG (12 grade IV, 6 grade III) were enrolled. CMV tissue testing was negative in all samples by both probes for in-situ hybridization, both antibodies for IHC (n = 11 available samples), and CMV US17 real-time PCR (PCR successful in 8/14 samples). Serum CMV IgG avidity index was positive (0.55-0.82) in 8/15 cases, consistent with rates in the general population. CMV was detected in baseline plasma samples of 3/16 patients and in 1 single follow-up sample. All other plasma samples were negative for CMV (n = 34). CONCLUSION: CMV was not detected in any HGG tissue. Half of the patients with HGG did not have an exposure to CMV prior to their diagnosis, and viremia was rare at presentation and follow-up. An independent, unbiased investigation of CMV positivity rates using a central reference laboratory with standardized tissue samples and controls is warranted before further consideration of CMV-targeted therapy in HGG.

Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis.

Carmustine wafers (CW; Gliadel® wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction (P = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols.

AT-32A PHASE I DOSE-ESCALATION STUDY OF GEMCITABINE PLUS STANDARD RADIATION THERAPY FOR MALIGNANT HIGH GRADE GLIOMAS

BACKGROUND: Based on preclinical data that gemcitabine (GEM) is an effective radiosensitizer in a mouse glioma model, a phase I study was undertaken assessing the feasibility of administering GEM during radiation therapy (RT) in patients with newly-diagnosed high-grade gliomas. METHODS: Adult patients with pathologically confirmed WHO grade III-IV supratentorial gliomas were eligible. Five dose levels of weekly GEM were tested starting the last 2 weeks of RT and advancing stepwise into earlier weeks (500 mg/m2 weeks 5,6; 1000 mg/m2 weeks 5,6; 1000 mg/m2 weeks 4,5,6; 750 mg/m2 weeks 3,4,5,6 and 1000 mg/m2 weeks 3,4,5,6). All patients received 60 Gy in 30 fractions. Primary objective was to determine the maximum tolerated dose (MTD) associated with DLT (any ≥grade 4 hematologic or ≥grade 3 non-hematologic toxicity) in 20% of patients within 90 days from start RT. Secondary objectives included estimates of ≥grade 3 toxicity, progression-free (PFS) and overall survival (OS). RESULTS: Between 2004-2012, 29 patients were enrolled (6 oligodendroglioma, 10 oligoastrocytoma, 9 astrocytoma and 4 glioblastoma), with 24 evaluable for toxicity. With median follow-up of 35.7 months (IQR, 36.6-58.6), OS for 22 evaluable patients with grade III tumors was 48.0 months (95% CI 26.2-inestimable), and PFS was 26.0 months (95% CI 11.7-48.5). MTD was 750 mg/m2/week given the last 4 weeks of RT. DLT events (grade 3 nausea, venous thromboembolism and syncope at dose levels 3-5) occurred in 4 patients, and three patients had biopsy-confirmed radiation necrosis (1 at dose level 1, 2 at dose level 5). No grade 5 toxicities related to therapy were observed. CONCLUSIONS: Among patients with high-grade gliomas, the MTD of GEM delivered with 60 Gy in 30 fractions was 750 mg/m2/week given the last 4 weeks of RT in this study. The combination of GEM and RT was well-tolerated, and preliminary estimates of efficacy are promising.

Central neurotoxicity of standard treatment in patients with newly-diagnosed high-grade glioma: a prospective longitudinal study

Following tumor resection, the majority of high-grade glioma (HGG) patients are treated with a combined modality regimen of radiotherapy and temozolomide. As a result of the tumor itself or as treatment-related neurotoxic side-effects, these patients may experience cognitive deficits. Additionally, radiological abnormalities expressed as white matter hyperintensities (WMH) and cerebral atrophy (CA) can develop. In this study, these functional and morphological parameters are evaluated, and their relation is investigated. After surgery, HGG patients underwent chemo-irradiation for six weeks, followed by six cycles of temozolomide. Assessments were performed before chemo-irradiation, post-concomitantly, after the third and sixth adjuvant cycle, and 3 and 7 months after treatment. Degree of WMH and CA was scored on MRI. Patients' neuropsychological performance was compared to healthy matched controls, yielding six cognitive domain z-scores. Development or progression of pre-existing WMH and CA during follow-up was observed in 36 and 45 % of the patients (n = 39) respectively. Cognitive functioning remained stable or improved in 70 % of the patients and deteriorated in 30 % of the patients (n = 33). Of the cognitive decliners, 80 % had tumor progression within 4 months thereafter. No clear association between cognitive functioning and WMH or CA was found. Central neurotoxic effects of combined modality treatment in HGG patients expressed by radiological abnormalities are encountered in approximately 40 % of patients. However, functional impact as indexed by cognitive functioning was found to be limited. Furthermore, development or progression of pre-existing WMH and CA does not consistently result in functional impairment as measured by cognitive tests.

Independent prognostic value of pre-treatment 18-FDG-PET in high-grade gliomas

The prognostic value of PET with (18F)-fluoro-2-deoxy-D: -glucose (FDG) has been shown in high-grade gliomas (HGG), but not compared with consensual prognostic factors. We sought to evaluate the independent predictive value of pre-treatment FDG-PET on overall (OS) and event-free survival (EFS). We retrospectively analyzed 41 patients with histologically-confirmed HGG (31 glioblastomas and 10 anaplastic gliomas). The pre-treatment uptake of FDG was assessed qualitatively by five-step visual metabolic grading, and quantitatively by the ratio between the tumor and contralateral maximal standardized uptake value (T/CL). EFS and OS following PET were compared with FDG uptake by univariate analysis, and by two multivariate analyses: one including main consensual prognostic factors (age, KPS, extent of surgery and histological grade), and the other including the classification system of the Radiation Therapy Oncology Group (Recursive Partitioning Analysis, RPA). Median OS and EFS were 13.8 and 7.4 months, respectively, for glioblastomas, and over 25.8 and 12 months, respectively, for anaplastic gliomas (P = 0.040 and P = 0.027). The T/CL ratio predicted OS in the entire group [P = 0.003; Hazard Ratio (HR) = 2.3] and in the glioblastoma subgroup (P = 0.018; HR = 2), independently of age, Karnofsky performance status, histological grade, and surgery, and independently of RPA classification. T/CL ratio tended to predict EFS in the whole group (P = 0.052). The prognostic value of visual metabolic grade on OS was less significant than T/CL ratio, both in the entire group and in the glioblastoma subgroup (P = 0.077 and P = 0.059). Quantitative evaluation of the ratio between the maximal tumor and contralateral uptake in pre-treatment FDG-PET provides significant additional prognostic information in newly-diagnosed HGG, independently of consensual prognostic factors.

Radiotherapy and temozolomide for newly diagnosed glioblastoma and anaplastic astrocytoma: validation of Radiation Therapy Oncology Group-Recursive Partitioning Analysis in the IMRT and temozolomide era

Since the development of the Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) risk classes for high-grade glioma, radiation therapy in combination with temozolomide (TMZ) has become standard care. While this combination has improved survival, the prognosis remains poor in the majority of patients. Therefore, strong interest in high-grade gliomas from basic research to clinical trials persists. We sought to evaluate whether the current RTOG-RPA retains prognostic significance in the TMZ era or alternatively, if modifications better prognosticate the optimal selection of patients with similar baseline prognosis for future clinical protocols. The records of 159 patients with newly-diagnosed glioblastoma (GBM, WHO grade IV) or anaplastic astrocytoma (AA, WHO grade III) were reviewed. Patients were treated with intensity-modulated radiation therapy (IMRT) and concurrent followed by adjuvant TMZ (n = 154) or adjuvant TMZ only (n = 5). The primary endpoint was overall survival. Three separate analyses were performed: (1) application of RTOG-RPA to the study cohort and calculation of subsequent survival curves, (2) fit a new tree model with the same predictors in RTOG-RPA, and (3) fit a new tree model with an expanded predictor set. All analyses used a regression tree analysis with a survival outcome fit to formulate new risk classes. Overall median survival was 14.9 months. Using the RTOG-RPA, the six classes retained their relative prognostic significance and overall ordering, with the corresponding survival distributions significantly different from each other (P < 0.01, χ2 statistic = 70). New recursive partitioning limited to the predictors in RTOG-RPA defined four risk groups based on Karnofsky Performance Status (KPS), histology, age, length of neurologic symptoms, and mental status. Analysis across the expanded predictors defined six risk classes, including the same five variables plus tumor location, tobacco use, and hospitalization during radiation therapy. Patients with excellent functional status, AA, and frontal lobe tumors had the best prognosis. For patients with newly-diagnosed high-grade gliomas, RTOG-RPA classes retained prognostic significance in patients treated with TMZ and IMRT. In contrast to RTOG-RPA, in our modified RPA model, KPS rather than age represented the initial split. New recursive partitioning identified potential modifications to RTOG-RPA that should be further explored with a larger data set.

Change in pattern of relapse in newly diagnosed high-grade glioma following bevacizumab therapy.

2020 Background: Local recurrence (LR) accounts for > 90% at the time of relapse in newly diagnosed high-grade glioma (HGG) following conventional therapy. Use of bevacizumab has shown impressive radiologic and clinical responses in both newly diagnosed and recurrent HGG. However, an apparent increase in diffuse invasive relapse (DIR) following therapy necessitated a detailed analysis of the pattern of recurrence. Methods: Seventy five patients with newly-diagnosed HGG were treated with radiation therapy and concomitant temozolomide (75 mg/m2 daily for 42 days) with bevacizumab (10 mg/kg every 2 weeks), 29 days following surgery, followed by 6 cycles of adjuvant TMZ (150 mg/m2 × 7d, q28 with bevacizumab at 10 mg/kg days 8 and 22 of each 28 day cycle. Recurrence was defined according to MacDonald Criteria. Pattern of recurrence and time to relapse were the primary aims of this study. DIR was defined as involvement of multiple lobes ± crossing the midline. Results: With a mean follow-up of 6.0 months (range 1-20), 40 patients have relapsed with 26 patients failing as DIR (65%). Seven patients who presented with multicentric HGG relapsed as DIR. The median progression-free survival (PFS) and overall survival (OS) were 8 (range 1-21 months) and 15 months (range 1-24 months) respectively for the entire group. The median OS for the patients who failed as DIR was 12 months vs. 4 months for patients with LR alone (p = 0.651). While the hazard risk for LR remained linear over time (R2 = 0.53), the risk of DR increased exponentially (R2 = 0.933). Biopsies done on five of these patients at the time of recurrence showed decreased expression of Olig-2 in 4 and increased expression of SDF-1 in 4 patients. No change in expression of HIF-1, p53, PDGF or CD163 was seen. Conclusions: Invasion remains a dominant process in newly diagnosed HGG treated with bevacizumab therapy. Unopposed angiogenic blockade resulting in increased invasiveness needs to be addressed in future clinical trials. No significant financial relationships to disclose.

Prognosis in patients with anaplastic oligoastrocytoma is associated with histologic grade

Anaplastic oligoastrocytomas (AOA) are relatively uncommon high-grade gliomas. While oligodendroglial elements are thought to be associated with better outcomes, the magnitude of the difference is not clear. Between 1980 and 1999, Mayo Clinic and the NCCTG conducted 10 trials of radiation therapy and chemotherapy in adults with newly-diagnosed high-grade gliomas. All pathology slides were reviewed by one of the authors (BWS or CG). We grouped patients by cell type and grade, compared survival distributions by the log-rank statistic, and performed multiple variable analyses. Of 1368 patients, 68 (5%) had AOA, including 21 Grade 3 (OA3) and 47 grade 4 (OA4), 153 (11%) had anaplastic astrocytoma (AA), and 1147 (84%) had glioblastoma multiforme (GBM). Patients with OA3 survived significantly longer than those with OA4 (P=0.0001) or AA (P=0.0044). Patients with OA4 lived significantly longer than those with GBM (P=0.0005). The same differences were noted for PFS. Prognostic factors for survival identified by multiple variable analysis were histology, age, ECOG performance score, and extent of surgical resection, but not treatment administered. Patients with anaplastic oligoastrocytoma have distinct outcomes based upon grade (OA3 vs. OA4) and in comparison with pure astrocytoma (AA or GBM). Future trials which include more than one histologic entity need to report results by cell type and grade and account for the varying prognoses in interpreting treatment outcomes.

Temozolomide (TMZ) in radio-chemotherapy combined schedule for treatment of newly-diagnosed high-grade gliomas (HGG)

1578 Background: Temozolomide (TMZ) is an oral alkylating agent known to cross the blood-brain barrier with efficacy against HGG and a favourable safety profile compared to conventional chemotherap...