Abstract BACKGROUND Tumor location is known to impact overall survival (OS) in glioblastoma. However, there is a lack of quantitative tools for studying the interplay between tumor location, prognostic variables, and treatments. In the current study we develop a voxel-wise statistical parameter mapping technique using a multivariable Cox regression model to describe the influence of tumor location on treatment effects in newly diagnosed glioblastoma. METHODS 598 newly diagnosed glioblastoma patients from the phase 3 AVAglio trial were studied. Areas of T2/FLAIR hyperintensity and resection cavities on post-surgical MRI scans were segmented and aligned to MNI atlas space. Voxel-wise Cox proportional hazards models for OS were run for each image voxel and included tumor presence in a specific voxel, age, MGMT promoter methylation, baseline tumor volume, and treatment (chemoradiation with or without bevacizumab). Results. After adjusting for other variables, tumor location was an independent predictor of favorable OS for tumors with involvement in the right prefrontal cortex (p<0.05, HR ranging ~0.48–0.65) and a predictor of shorter OS for tumors in the left mesial/basal temporo-occipital areas (p<0.05, HR ~3–6.2) and in the left hemisplenium of the corpus callosum (p<0.05, HR ~2.5–3). Baseline tumor volume (HR ~4–6 x10-6), MGMT status (HR ~0.38–0.41), and age (HR ~1.020–1.025) were significative predictors regardless of location (p<0.05 in all locations). Interestingly, chemoradiation plus bevacizumab treatment showed a favorable OS compared with chemoradiation alone for tumors with involvement in the right corticospinal tract, right motor and sensory cortices, and left hemisplenium of the corpus callosum (p<0.05, HR ~0.82). CONCLUSIONS Tumor involvement in the prefrontal cortex is associated with favorable prognosis, while tumors in mesial/basal temporo-occipital areas or splenium of the corpus callosum are associated with shorter OS. Chemoradiation plus bevacizumab may improve OS for tumors involving eloquent motor areas and the corticospinal tract.

AbstractPurpose: Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy. Experimental Design: N = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival. Results: Optimized thresholds occurred at g = 0.07 months−1 (phase II: HR = 0.2579, P = 5 × 10−20; phase III: HR = 0.2197, P = 5 × 10−5); d = 0.11 months−1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10−17; HR = 0.2061, P = 2 × 10−5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth. Conclusions: Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.

Supplementary Table 1 from Molecular Study of Malignant Gliomas Treated with Epidermal Growth Factor Receptor Inhibitors: Tissue Analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01

Supplementary Data 1 ELIGIBILITY CRITERIA. Supplementary Data 2 HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY PLANNING. Supplementary Data 3 MRI ACQUISITION PARAMETERS AND PROCESSING. Supplementary Data 4 Nanostring-based Tissue Correlates Methods. Supplementary Data 5 Number of patients experiencing Grades 3-5 treatment-related toxicities. Supplementary Data 6 Univariate analysis of DSC MR perfusion and diffusion MRI. Supplementary Data 7 NEUROPSYCHOLOGICAL TEST Z-SCORES, QUALITY OF LIFE, DEPRESSION AND FATIGUE SCORES OVER TIME.

Supplementary Table Legend from Molecular Study of Malignant Gliomas Treated with Epidermal Growth Factor Receptor Inhibitors: Tissue Analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01

Journal Article Towards more Diversity in Neuro-oncology Leadership—the DivINe Initiative Get access Sylvia C Kurz, Sylvia C Kurz Department of Neurology & Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University of Tübingen, Tübingen, GermanyCenter for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital Tübingen, Germany Corresponding Author: Sylvia Kurz, MD PhD, Department of Neurology & Interdisciplinary Neuro-Oncology, Eberhard-Karls-University Tübingen, Hoppe-Seyler-Str. 3 72076 Tübingen, Germany (sylvia.kurz@med.uni-tuebingen.de) https://orcid.org/0000-0002-5247-5636 Search for other works by this author on: Oxford Academic PubMed Google Scholar Anja Stammberger, Anja Stammberger Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Steffen K Rosahl, Steffen K Rosahl Health and Medical University, Campus Helios Erfurt, Erfurt, GermanyDepartment of Neurosurgery, Friedrich-Schiller-University Jena, Jena, Germany https://orcid.org/0000-0002-0589-618X Search for other works by this author on: Oxford Academic PubMed Google Scholar Lauren E Abrey, Lauren E Abrey InCephalo Therapeutics, Allschwil, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar Nathalie L Albert, Nathalie L Albert Department of Nuclear Medicine, LMU University Hospital, Ludwig-Maximilians-University, Munich, Germany https://orcid.org/0000-0003-0953-7624 Search for other works by this author on: Oxford Academic PubMed Google Scholar Louisa von Baumgarten, Louisa von Baumgarten Department of Neurology, LMU University Hospital, Ludwig-Maximilians-University, Munich, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Jens Gempt, Jens Gempt Department of Neurosurgery, University Hospital Hamburg Eppendorf, Hamburg, Germany https://orcid.org/0000-0003-4123-4690 Search for other works by this author on: Oxford Academic PubMed Google Scholar Anca-L Grosu, Anca-L Grosu Department of Radiation Oncology, Medical Center, Medical Faculty, Albert-Ludwigs-University Freiburg, Germany https://orcid.org/0000-0003-2255-2255 Search for other works by this author on: Oxford Academic PubMed Google Scholar Verena Leidgens, Verena Leidgens Novocure GmbH, Munich, Germany https://orcid.org/0000-0002-3977-0796 Search for other works by this author on: Oxford Academic PubMed Google Scholar Anna McLean, Anna McLean Department of Neurosurgery, Jena University Hospital, Jena, Germany https://orcid.org/0000-0002-3146-4241 Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Mirjam Renovanz, Mirjam Renovanz Department of Neurology & Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University of Tübingen, Tübingen, GermanyCenter for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital Tübingen, GermanyDepartment of Neurosurgery, Eberhard Karls University Tübingen, Germany https://orcid.org/0000-0002-2824-3720 Search for other works by this author on: Oxford Academic PubMed Google Scholar Julia Schwarzenberger, Julia Schwarzenberger Novocure GmbH, Munich, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Lisa Sevenich, Lisa Sevenich Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany https://orcid.org/0000-0002-6543-6273 Search for other works by this author on: Oxford Academic PubMed Google Scholar Tadeja Urbanic Purkart, Tadeja Urbanic Purkart Department of Neurology and Department of Radiology—Division of Neuroradiology, Vascular and Interventional Neuroradiology, Medical University of Graz, Graz, Austria https://orcid.org/0000-0001-5101-868X Search for other works by this author on: Oxford Academic PubMed Google Scholar Stephanie E Combs, Stephanie E Combs Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, GermanyHelmholtz Zentrum München (HMGU), Oberschleißheim, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Ghazaleh Tabatabai, Ghazaleh Tabatabai Department of Neurology & Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University of Tübingen, Tübingen, GermanyCenter for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital Tübingen, Germany https://orcid.org/0000-0002-3542-8782 Search for other works by this author on: Oxford Academic PubMed Google Scholar Monika Hegi, Monika Hegi Laboratory of Brain Tumour Biology and Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland https://orcid.org/0000-0003-0855-6495 Search for other works by this author on: Oxford Academic PubMed Google Scholar Martha Nowosielski Martha Nowosielski Department of Neurology, Medical University Innsbruck, Innsbruck, Austria https://orcid.org/0000-0002-8068-315X Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 12, December 2023, Pages 2302–2304, https://doi.org/10.1093/neuonc/noad157 Published: 21 September 2023 Article history Corrected and typeset: 21 September 2023 Published: 21 September 2023

Purpose Pseudoprogression (PsP) remains an elusive and clinically important, yet ill-defined, phenomena that, generally, involves a period of early radiographic progression (enhancement) followed by a period of radiographic stability or regression. In the current study, we utilized data from the control arm of a phase III clinical trial in newly-diagnosed glioblastoma to explore imaging characteristics of "clinically-defined PsP", or early radiographic progression (PFS < 6 months from chemoradiation) followed by a long post-progression residual overall survival (ROS > 12 months). Methods One hundred sixty-nine patients with newly-diagnosed GBM from the control arm of the AVAglio trial (NCT00943826) who presented with early radiographic progressive disease (PD) (< 6 months) were included. Clinical characteristics, topographical patterns, and radiomic features were compared between newly-diagnosed GBM exhibiting early PD and early death (< 12-month ROS, "true PD") with those exhibiting early PD and a long residual survival (> 12-month ROS, "clinically-defined PsP"). Results "Clinically-defined PsP" occurred to 38.5% of patients with early PD, and was more associated with MGMT methylation (P = 0.02), younger age (P = 0.003), better neurological performance (P = 0.01), and lower contrast-enhancing tumor volume (P = 0.002) at baseline. GBM showing "true PD" occurred more frequently in the right internal capsule, thalamus, lentiform nucleus, and temporal lobe than those with "clinical PsP". Radiomic analysis predicted "clinical PsP" with > 70% accuracy on the validation dataset. Conclusion Patients with early PD that eventually exhibit "clinically-defined PsP" have distinct clinical, molecular, and MRI characteristics. This information may be useful for treating clinicians to better understand the potential risks and outcome in patients exhibiting early radiographic changes following chemoradiation.

Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma.

Abstract Purpose Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well‐tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti‐tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. Methods Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. Results We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose‐limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). Conclusion Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

BackgroundReceptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.MethodsPatients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).ResultsSixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.ConclusionThis study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.

Introduction The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to reduce neurotoxicity, including reduced-dose WBRT (rdWBRT) or high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT). In this study, we characterized cognitive functions in PCNSL patients achieving long-term remission following rdWBRT or HDC-ASCT. Methods PCNSL patients completed cognitive evaluations at diagnosis, post-induction chemotherapy, and yearly up to 5 years following rdWBRT or HDC-ASCT. Quality of life (QoL), white matter (WM) disease, and cortical atrophy (CA) on MRI were assessed at similar intervals. Results Performance was impaired on most cognitive tests at diagnosis. Linear mixed model analyses in each group showed statistically significant improvement from baseline up to year 3 in attention/executive functions, graphomotor speed, and memory; however, there was a decline in attention/executive functions and memory after year 3 in both groups. WM abnormalities increased over time in both groups, but more patients treated with rdWBRT developed CA and WM changes. There were no significant longitudinal group differences in cognitive performance or QoL. Conclusions Results indicated improvement in cognitive function up to 3 years post-treatment, but a decline at later time points and an increase in brain structure abnormalities in both groups. The findings suggest that rdWBRT and HDC-ASCT may be associated with delayed neurotoxicity in progression-free patients and underscore the need for long-term follow-up to characterize cognitive dysfunction in PCNSL patients.

Purpose Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM). Methods We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort. Results Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14). Conclusions PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.

Background. In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS). Methods. Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O-6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS. Results. A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status. Conclusion. Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

BACKGROUND:The efficacy of bevacizumab (BEV) in elderly patients with glioblastoma remains unclear. We evaluated the effect of BEV on survival in this patient population using the Survival, Epidemiology, and End Results (SEER)-Medicare database. METHODS:This retrospective, cohort study analyzed SEER-Medicare data for patients (aged ≥66 years) diagnosed with glioblastoma from 2006 to 2011. Two cohorts were constructed: one comprised patients who had received BEV (BEV cohort); the other comprised patients who had received any anticancer treatment other than BEV (NBEV cohort). The primary analysis used a multivariate Cox proportional hazards model to compare overall survival in the BEV and NBEV cohorts with initiation of BEV as a time-dependent variable, adjusting for potential confounders (age, gender, Charlson comorbidity index, region, race, radiotherapy after initial surgery, and diagnosis of coronary artery disease). Sensitivity analyses were conducted using landmark survival, propensity score modeling, and the impact of poor Karnofsky Performance Status. RESULTS:We identified 2603 patients (BEV, n = 597; NBEV, n = 2006). In the BEV cohort, most patients were Caucasian males and were younger with fewer comorbidities and more initial resections. In the primary analysis, the BEV cohort showed a lower risk of death compared with the NBEV cohort (hazard ratio, 0.80; 95% confidence interval, 0.72-0.89; P < .01). The survival benefit of BEV appeared independent of the number of temozolomide cycles or frontline treatment with radiotherapy and temozolomide. CONCLUSION:BEV exposure was associated with a lower risk of death, providing evidence that there might be a potential benefit of BEV in elderly patients with glioblastoma.

Background. In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods. Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had > 4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results. A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions. The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

Purpose Bevacizumab (BEV) is approved in more than 60 countries for use in adults with recurrent glioblastoma. We evaluated the addition of BEV to radiotherapy plus temozolomide (RT+TMZ) in pediatric patients with newly diagnosed high-grade glioma (HGG). Methods The randomized, parallel group, multicenter, open-label HERBY trial ( ClinicalTrials.gov identifier: NCT01390948) enrolled patients age ≥ 3 years to ≤ 18 years with localized, centrally neuropathology-confirmed, nonbrainstem HGG. Eligible patients were randomly assigned to receive RT + TMZ (RT: 1.8 Gy, 5 days per week, and TMZ: 75 mg/m2 per day for 6 weeks; 4-week treatment break; then up to 12 × 28-day cycles of TMZ [cycle 1: 150 mg/m2 per day, days 1 to 5; cycles 2 to 12: 200 mg/m2 per day, days 1 to 5]) with or without BEV (10 mg/kg every 2 weeks). The primary end point was event-free survival (EFS) as assessed by a central radiology review committee that was blinded to treatment. We report findings of EFS at 12 months after the enrollment of the last patient. Results One hundred twenty-one patients were enrolled (RT+TMZ [n = 59]; BEV plus RT+TMZ [n = 62]). Central radiology review committee-assessed median EFS did not differ significantly between treatment groups (RT+TMZ, 11.8 months; 95% CI, 7.9 to 16.4 months; BEV plus RT+TMZ, 8.2 months; 95% CI, 7.8 to 12.7 months; hazard ratio, 1.44; P = .13 [stratified log-rank test]). In the overall survival analysis, the addition of BEV did not reduce the risk of death (hazard ratio, 1.23; 95% CI, 0.72 to 2.09). More patients in the BEV plus RT+TMZ group versus the RT+TMZ group experienced one or more serious adverse events (n = 35 [58%] v n = 27 [48%]), and more patients who received BEV discontinued study treatment as a result of adverse events (n = 13 [22%] v n = 3 [5%]). Conclusion Adding BEV to RT+TMZ did not improve EFS in pediatric patients with newly diagnosed HGG. Our findings were not comparable to those of previous adult trials, which highlights the importance of performing pediatric-specific studies.

Background:In this exploratory analysis of AVAglio, a randomized phase III clinical study that investigated the addition of bevacizumab (Bev) to radiotherapy/temozolomide in newly diagnosed glioblastoma, we aim to radiologically characterize glioblastoma on therapy until progression and investigate whether the type of radiologic progression differs between treatment arms and is related to survival and molecular data.Methods:Five progression types (PTs) were categorized using an adapted algorithm according to MRI contrast enhancement behavior in T1- and T2-weighted images in 621 patients (Bev, n = 299; placebo, n = 322). Frequencies of PTs (designated as classic T1, cT1 relapse, T2 diffuse, T2 circumscribed, and primary nonresponder), time to progression (PFS), and overall survival (OS) were assessed within each treatment arm and compared with molecular subtypes and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status.Results:PT frequencies differed between the Bev and placebo arms, except for "T2 diffuse" (12.4% and 7.1%, respectively). PTs showed differences in PFS and OS; with "T2 diffuse" being associated with longest survival. Complete disappearance of contrast enhancement during treatment ("cT1 relapse") showed longer survival than only partial contrast enhancement decrease ("classic T1"). "T2 diffuse" was more commonly MGMT hypermethylated. Only weak correlations to molecular subtypes from primary tissue were detected.Conclusions:Progression of glioblastoma under therapy can be characterized radiologically. These radiologic phenotypes are influenced by treatment and develop differently over time with differential outcomes. Complete resolution of contrast enhancement during treatment is a favorable factor for outcome.

The prognostic significance of residual contrast enhancing tumor volume after initial surgery to predict OS in newly diagnosed GBM remains poorly understood and not controlled for in prospective clinical trials. In the current study we pooled imaging data in >1,400 newly diagnosed GBM patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums identify relationships between clinical parameters, MGMT methylation status, treatment, and residual enhancing tumor volume on OS. Data from 1,458 newly diagnosed GBM patients from 3 sources (2 for training and 1 for validation) were included in our imaging database: 1) a single institution database from UCLA (N=398; Training Set 1); 2) patients treated within the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Consortium (N=262 from 8 centers; Training Set 2); and 3) AVAglio – an international phase III trial comparing chemoradiation plus bevacizumab (N=404) vs. placebo (N=394) used as a validation set. Post-surgical, residual enhancing disease was isolated from blood products and quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, MGMT status, and residual tumor volume on OS. Results confirmed that post-surgical, residual enhancing tumor volume is a strong prognostic factor for OS (P<0.0001), regardless of therapy, age, and MGMT status. Pre-surgical tumor volume and extent of resection as continuous variables were not significant prognostic factors, but patients with an extent of resection greater than 98% had a significant survival advantage (P<0.01). Influence of residual non-enhancing disease and other imaging factors will also be discussed. Results support the hypotheses that post-surgical, residual contrast-enhancing disease significantly influences survival in patients with newly diagnosed glioblastoma, regardless of treatment.