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

Abstract

BACKGROUND AND PURPOSE: HERBY was a Phase II multicenter trial setup to establish the efficacy and safety of adding bevacizumab to radiation therapy and temozolomide in pediatric patients with newly diagnosed non-brain stem high-grade gliomas. This study evaluates the implementation of the radiologic aspects of HERBY. MATERIALS AND METHODS: We analyzed multimodal imaging compliance rates and scan quality for participating sites, adjudication rates and reading times for the central review process, the influence of different Response Assessment in Neuro-Oncology criteria in the final response, the incidence of pseudoprogression, and the benefit of incorporating multimodal imaging into the decision process. RESULTS: Multimodal imaging compliance rates were the following: diffusion, 82%; perfusion, 60%; and spectroscopy, 48%. Neuroradiologists' responses differed for 50% of scans, requiring adjudication, with a total average reading time per patient of approximately 3 hours. Pseudoprogression occurred in 10/116 (9%) cases, 8 in the radiation therapy/temozolomide arm and 2 in the bevacizumab arm (P Ͻ .01). Increased target enhancing lesion diameter was a reason for progression in 8/86 cases (9.3%) but never the only radiologic or clinical reason. Event-free survival was predicted earlier in 5/86 (5.8%) patients by multimodal imaging (diffusion, n ϭ 4; perfusion, n ϭ 1). CONCLUSIONS: The addition of multimodal imaging to the response criteria modified the assessment in a small number of cases, determining progression earlier than structural imaging alone. Increased target lesion diameter, accounting for a large proportion of reading time, was never the only reason to designate disease progression. ABBREVIATIONS: BEV ϭ bevacizumab; CRRC ϭ Centralized Radiologic Review Committee; EFS ϭ event-free survival; HGG ϭ high-grade glioma; MM ϭ multimodal; RANO ϭ Response Assessment in Neuro-Oncology; RT ϭ radiotherapy; TMZ ϭ temolozomide T he recent Avastin in Glioblastoma (AVAglio) clinical trial investigated the use of bevacizumab (BEV) plus radiation therapy (RT) and temozolomide (TMZ) compared with a placebo plus RT-TMZ in adult patients with newly diagnosed glioblastoma. 1 This was subsequently investigated in a pediatric patient population. The Study of Bevacizumab (Avastin) in Combination with Temozolomide and Radiotherapy in Paediatric and Adolescent Participants with High-Grade Glioma (HERBY) (BO25041; clinicaltrials.gov NCT01390948) was a Phase II, open-label, randomized, multicenter, comparator study set up to establish the efficacy and safety of the addition of BEV to RT and TMZ in patients between 3 and 18 years of age with newly diagnosed non-brain stem high-grade glioma (HGG). 2 The radiologic aspects of the HERBY trial were expanded compared with AVAglio in a number of aspects. In HERBY, the

Response assessment in paediatric high-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group

“…Furthermore, some sequence acquisition recommendations are inconsistent across studies, and may or may not include advanced imaging. 14 For baseline scans in newly diagnosed disease, Ellingson et al challenged the use of postoperative MRI in adult glioblastoma clinical trials 10 due to the propensity to develop pseudoprogression within the first 12 weeks of chemoradiotherapy. In adult glioblastoma, it is now recommended to use the first post chemoradiotherapy MRI as the baseline scan, as opposed to the first post-operative MRI 10 to reduce the challenges posed by blood products, increased vascular permeability, imaging variation secondary to surgical complexity, and perisurgical steroid use.…”

“…Furthermore, contrast enhancement in pHGG is almost never the sole determinant used to determine progression in pHGG and generally is accompanied by non-enhancing tumor growth on T2/FLAIR and/or clinical decline. 14 Given these findings, changes in non-enhancing tumor are important to characterize in pHGG response assessment.…”

“…34 Pseudoprogression occurs most frequently within the first 3 months after chemoradiotherapy, limiting the evaluation for PD during this initial time period and occurs in approximately 7-12% of pHGG. [13][14][15] Other treatment-related changes that may raise concern for pseudoprogression include increased enhancement such as treatment-related inflammation, radiation effects, seizure activity, postsurgical changes, and radiation necrosis. 11 Pseudoprogression highlights an additional challenge encountered in pHGG radiologic assessment.…”

“…[10][11][12][13] Using RANO, the HERBY study required a high adjudication rate for the expert panel radiological read, resulted in notable differences in date of progression comparing local to central review, and increased read times per patient, in part, due to inconsistent lesion diameter measurements, highlighting the need for consensus criteria. 14 There are several differences between pediatric and adult HGGs with regard to tumor biology, tumor location, higher likelihood of leptomeningeal dissemination, and an increased frequency of non-enhancing tumors. 15 These differences and the use of a variety of response assessments for pHGG across different studies have led herein to the development of standardized response assessment criteria from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.…”

Radiological Evaluation of Newly Diagnosed Non-Brainstem Pediatric High-Grade Glioma in the HERBY Phase II Trial

“…Tumor response evaluation was undertaken according to the Response Assessment in Neuro-Oncology (RANO) criteria 13 by a panel of 5 experienced pediatric Neuroradiologists for each timepoint 14 .…”