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.

G. Zahlmann,T. Jaspan,E. Sanchez Aliaga,J. Garcia,J. Grill,R. Calmon,D. Warren,M. Warmuth-Metz,P.S. Morgan,D. Hargrave

doi:10.3174/ajnr.a4782

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.

Highlights

ObjectivesAs part of the HERBY trial, our aims were the following: 1) to evaluate the implementation of the Response Assessment in Neuro-Oncology (RANO) criteria in a phase II trial of pediatric patients with High-grade gliomas (HGGs), 2) to assess the practicality of obtaining multimodal imaging of adequate quality, and 3) to assess the feasibility of including diffusion and perfusion into the response criteria
Tumor diffusion and perfusion imaging have been incorporated to complement the Response Assessment in Neuro-Oncology (RANO) criteria, to investigate whether these tools can enhance the understanding of tumor response to bevacizumab in pediatric patients with High-grade gliomas (HGGs)
DWI was the most prevalent technique used; its value in the context of the RANO criteria is still to be evaluated, but currently it seems that DWI is the most likely to be pragmatically incorporated into the revised RANO criteria for pediatric patients

Summary

Objectives

As part of the HERBY trial, our aims were the following: 1) to evaluate the implementation of the RANO criteria in a phase II trial of pediatric patients with HGG, 2) to assess the practicality of obtaining multimodal imaging of adequate quality, and 3) to assess the feasibility of including diffusion and perfusion into the response criteria

Methods

Findings

Discussion

Conclusion