title: 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.
abstract: 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.
authors.affiliation: From Nottingham University Hospitals National Health Service Trust (T.J., P.S.M.), Nottingham, UK tjaspan@doctors.org.uk.
authors.forename: T
authors.identifier: 0000-0002-3644-9569
authors.initials: T
authors.lastname: Jaspan
authors.affiliation: From Nottingham University Hospitals National Health Service Trust (T.J., P.S.M.), Nottingham, UK.
authors.forename: P S
authors.identifier: 0000-0002-5870-1446
authors.initials: PS
authors.lastname: Morgan
authors.affiliation: Würzburg University (M.W.-M.), Würzburg, Germany.
authors.forename: M
authors.identifier: 0000-0002-3544-319X
authors.initials: M
authors.lastname: Warmuth-Metz
authors.affiliation: VU University Medical Center (E.S.A.), Amsterdam, the Netherlands.
authors.forename: E
authors.identifier: 0000-0002-7847-3014
authors.initials: E
authors.lastname: Sanchez Aliaga
authors.affiliation: Leeds Teaching Hospital National Health Service Trust (D.W.), Leeds, West Yorkshire, UK.
authors.forename: D
authors.identifier: 0000-0003-4256-3242
authors.initials: D
authors.lastname: Warren
authors.affiliation: Assistance Publique-Hôpitaux de Paris (R.C.), Paris, France.
authors.forename: R
authors.identifier: 0000-0003-2234-6777
authors.initials: R
authors.lastname: Calmon
authors.affiliation: Gustave Roussy and Paris-Sud University (J.Grill), Villejuif, France.
authors.forename: J
authors.identifier: 0000-0003-4773-3001
authors.initials: J
authors.lastname: Grill
authors.affiliation: Great Ormond Street Hospital (D.H.), London, UK.
authors.forename: D
authors.identifier: 0000-0001-8219-9807
authors.initials: D
authors.lastname: Hargrave
authors.affiliation: F. Hoffmann-La Roche (J.Garcia, G.Z.), Basel, Switzerland.
authors.forename: J
authors.identifier: 0000-0002-0849-1698
authors.initials: J
authors.lastname: Garcia
authors.affiliation: F. Hoffmann-La Roche (J.Garcia, G.Z.), Basel, Switzerland.
authors.forename: G
authors.identifier: 0000-0003-4164-4083
authors.initials: G
authors.lastname: Zahlmann
mesh_terms: D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D002648:Child; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab