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.

Consensus recommendations on standardized magnetic resonance imaging protocols for multicenter canine brain tumor clinical trials

“…Criteria for high grade gliomas include the RECIST criteria, the Macdonald method, and the Response Assessment in Neuro‐Oncology criteria . There are additional published Response Assessment in Neuro‐Oncology criteria for diffused low grade glial tumors, pediatric high grade gliomas, brain metastasis, and spinal metastasis, as well as specific response assessments guidelines for immunotherapeutic trials . Criteria for meningioma, despite it being one of the more common brain tumor histologies seen, are not yet available, although they are being developed .…”

Radiological pseudoprogression post‐radiotherapy in a child with pineal germ cell tumour

“…Pseudoprogression has been reported in various paediatric and adult brain tumours and it is also increasingly being reported in clinical trials 7,9,10,14 . Notwithstanding, to our knowledge this is the first reported case of pseudoprogression post‐radiotherapy in a child with intracranial GCT.…”

Evaluation of the Implementation of the Response Assessment in Neuro-Oncology Criteria in the HERBY Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas

“…On completing the structural MR imaging review, the same central reviewers performed an additional evaluation combining diffusion and perfusion MR imaging findings (when available) with the structural assessment to determine whether they would alter the structural MR imaging review response. The incorporation of the multimodal imaging into the RANO assessment followed that proposed previously, both with respect to the evaluation of the multimodal data (Supplementary Material in Jaspan et al, 2016, 5 ) and its incorporation into the overall response decision (Fig 3). This article evaluates the implementation of the radiologic aspects of HERBY, summarized above.…”

“…MR imaging was requested following a standardized protocol (which can be accessed in the Supplementary Materials Section of Jaspan et al 5 ). Images were provided by the sites to the contract research organization of the trial, ICON Medical Imaging, and all radiologic reviews were conducted using their MIRA platform (ICON Medical Imaging, Dublin, Ireland).…”