Josep Garcia

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

PURPOSE The AVAglio (Avastin in Glioblastoma) and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy plus temozolomide. To establish whether certain patient subgroups derived an OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy was assessed for each patient subgroup. PATIENTS AND METHODS A total of 349 pretreatment specimens (bevacizumab arm, n = 171; placebo arm, n = 178) from AVAglio patients (total, N = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype. RESULTS A multivariable analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the proneural subtype biomarker and treatment arm (P = .023). The group of patients with mesenchymal and proneural tumors derived a PFS benefit from bevacizumab compared with placebo; however, this translated to an OS benefit in the proneural subset only. CONCLUSION Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type proneural glioblastoma may derive an OS benefit from first-line bevacizumab treatment. The predictive value of the proneural subtype observed in AVAglio should be validated in an independent data set.

Response Assessment in Pediatric Neuro-Oncology: Implementation and Expansion of the RANO Criteria in a Randomized Phase II Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas

SUMMARY: Determination of tumor response to treatment in neuro-oncology is challenging, particularly when antiangiogenic agents are considered. Nontumoral factors (eg, blood-brain barrier disruption, edema, and necrosis) can alter contrast enhancement independent of true tumor response/progression. Furthermore, gliomas are often infiltrative, with nonenhancing components. In adults, the Response Assessment in Neuro-Oncology (RANO) criteria attempted to address these issues. No such guidelines exist yet for children. The ongoing randomized phase II trial, A Study of Avastin (bevacizumab) in Combination With Temolozomide (TMZ) and Radiotherapy in Paediatric and Adolescent Patients With High-Grade Glioma (HERBY), will establish the efficacy and safety of the antiangiogenic agent bevacizumab for the first-line treatment of newly diagnosed high-grade glioma in children (n = 121 patients, enrollment complete). The primary end point is event-free survival (tumor progression/recurrence by central review, second primary malignancy, or death). Determination of progression or response is based on predefined clinical and radiographic criteria, modeled on the RANO criteria and supported by expert pseudoprogression review and the use of standardized imaging protocols. The HERBY trial will also compare conventional MR imaging (T1-weighted and T2/fluid-attenuated inversion recovery sequences) with conventional MR imaging plus diffusion/perfusion imaging for response assessment. It is anticipated that HERBY will provide new insights into antiangiogenic-treated pediatric brain tumors. HERBY will also investigate the practicality of obtaining adequate quality diffusion/perfusion scans in a trial setting, and the feasibility of implementing standard imaging protocols across multiple sites. To date, 61/73 (83.6%) patients with available data have completed diffusion-weighted imaging (uptake of other nonconventional techniques has been limited). Harmonization of imaging protocols and techniques may improve the robustness of pediatric neuro-oncology studies and aid future trial comparability.

Phase II, Open-Label, Randomized, Multicenter Trial (HERBY) of Bevacizumab in Pediatric Patients With Newly Diagnosed High-Grade Glioma

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.

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

Summary The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term “HGG” in the pediatric population.

Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma

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, O6-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.

Post-chemoradiation volumetric response predicts survival in newly diagnosed glioblastoma treated with radiation, temozolomide, and bevacizumab or placebo.

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.

Efficacy and biomarker findings from AVaglio, a phase III trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma

WCN 2013 No: 1207 Topic: 36 — Other topic Efficacy and biomarker findings from AVaglio, a phase III trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma W. Wick, T. Cloughesy, W. Mason, R. Henriksson, F. Saran, R. Nishikawa, M. Hilton, J. Garcia, C. Pallaud, O. Chinot. University Medical Centre, Heidelberg, Germany; University of California, Los Angeles, CA, USA; Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada; Regional Cancer Center Stockholm, Stockholm, Sweden; Umea University, Umea, Sweden; The Royal Marsden NHS Foundation Trust, Surrey, UK; International Medical Center, Saitama Medical University, Saitama, Japan; F. Hoffmann-La Roche, Basel, Switzerland; Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France Background: Glioblastoma has a high disease burden and poor prognosis. AVAgliowas the first double-blind, placebo-controlled phase III study evaluating bevacizumab in newly diagnosed glioblastoma. Objectives: To evaluate efficacy, safety and potential biomarkers (plasma VEGF-A/VEGFR-2 prioritised). Patients and methods: Patients received single-agent bevacizumab or placebo plus standard-of-care treatment (radiotherapy plus temozolomide) until progression/unacceptable toxicity. Co-primary endpoints were investigator-assessed PFS and OS. Secondary endpoints included health-related quality of life (HRQoL). Exploratory endpoints included correlative biomarker analysis, KPS, corticosteroid use. Results: Baseline characteristics were balanced for intent-to-treat (n = 921) and biomarker-evaluable (n = 571) populations. Bevacizumab significantly prolonged PFS (HR = 0.64, 95% CI 0.55– 0.74, p b 0.0001; median 10.6 vs 6.2 months) and delayed HRQoL time to definitive deterioration (p b 0.0001). Interim OS did not cross the threshold for significance (HR = 0.89, 95% CI 0.75–1.07, p = 0.2135). Functional independence (KPS ≥ 70%) was maintained during PFS in both arms (median bevacizumab vs placebo: 9 vs 6 months). Patients treated with bevacizumab had a diminished corticosteroid requirement. Patients with low and high baseline plasma VEGF-A concentrations derived similar PFS benefit with bevacizumab (p = 0.610): low VEGF-A (HR = 0.64, 95% CI 0.48– 0.84) versus high (HR = 0.59, 95% CI 0.45–0.78). Similarly, PFS benefit in patients with low and high baseline VEGFR-2 levels was comparable (p = 0.736): low VEGFR-2 (HR = 0.54, 95% CI 0.41– 0.71) versus high (HR = 0.66, 95% CI 0.50–0.87). Conclusion: Addition of bevacizumab to standard-of-care therapy provided a significant clinically meaningful PFS improvement with stable/improved HRQoL/KPS and reduced corticosteroid requirement. NoVEGF-A/VEGFR-2 predictive/prognostic effectwas observed. Interim OS analysis did not cross the threshold for significance. doi:10.1016/j.jns.2013.07.2268 Abstract — WCN 2013 No: 2103 Topic: 36 — Other topic Flow cytometric analysis of cerebrospinal fluid is low diagnostic yield without atypical morphology or prior history of hematologic malignancy WCN 2013 No: 2103 Topic: 36 — Other topic Flow cytometric analysis of cerebrospinal fluid is low diagnostic yield without atypical morphology or prior history of hematologic malignancy G.H.J. Stevens, A.M.B. Collie, B.T. Hill, K. Fenner, E. Gazdick, L.A. Rybicki, E.H. Hsi. Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA; Pathology, Cleveland Clinic, Cleveland, OH, USA; Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA; Quality Health Science, Cleveland Clinic, Cleveland, OH, USA Background: Flow cytometric analysis (FCA) of cerebrospinal fluid (CSF) has utility in detecting central nervous system (CNS) involvement by hematologic malignancies. Yet, the majority of samples are negative by FCA. Objective: Identify pre-test characteristics of CSF specimens that will allow the rational use of FCA in the diagnosis of hematologic malignancy in CSF. Design: Retrospective data was collected from the medical record and flow cytometric reports for all CSF samples submitted for FCA between 2007 and 2009. Patients: 423 patients for whom 501 CSF samples were submitted for FCA. Results: A positive diagnosis of a hematologic malignancy was made in 41 specimens (8.2%). The FCA-positive specimens showed atypical morphology, either blasts or atypical lymphocytes, in 98% of Abstracts / Journal of the Neurological Sciences e629 (2013) e629–e678 e654