Assessing Neuro-Oncology Disease in Pediatric Clinical Trials

Joseph Pierro and David Raunig | |

Early assessment methods in the field of neuro-oncology relied on generalized adult-based oncology criteria such as the Response Evaluation Criteria in Solid Tumors (RECIST) and Macdonald criteria. Over the past 20 plus years these criteria have been shown to have limitations in the assessment of brain tumors and coupled with the advent of newer oncologic treatments and imaging methods several working groups comprised of international experts were created to provide guidance on appropriate endpoints and assessment recommendations.

The Response Assessment in Neuro-Oncology Working Group (RANO) convened in 2008 to offer guidance initially on gliomas and was subsequently expanded to include brain metastases, meningioma, pediatric tumors, spinal metastases and leptomeningeal disease.1 The RANO group provided guidance on clinical trial endpoints for adult patients and during their work identified specific issues in applying these criteria to pediatric patients. This prompted the formation of the Response Assessment in Pediatric Neuro-Oncology Working Group (RAPNO-WG).

The use of standardized imaging protocols with careful selection of the appropriate radiological and clinical response assessments will improve the robustness of trial data and improve the chances to obtain positive study results.

“The goal of RAPNO is to propose optimal endpoints and study designs, develop a consensus on the radiological assessment for clinical trials involving children with brain tumors, and better define response so that it reflects drug activity. RAPNO has initially targeted the development of response criteria for three tumor subtypes, namely high-grade glioma, low-grade glioma, and diffuse intrinsic pontine glioma, due to the inherent radiographic features of each”.2

The RAPNO recommendations expanded from the original RANO criteria which include:

  • T1 weighted post gadolinium enhancing measurable and non-measurable lesions
  • Non enhancing T2/FLAIR lesion identification
  • New lesion identification
  • Neurological clinical status information and corticosteroid use
  • Standardized imaging protocols3.

Major changes suggested by the working group concentrated on the application and limitations of addressing pediatric brain tumor response across multiple and heterogeneous tumor types, with each representing a distinct disease with variable imaging characteristics1,2.  Key features of the proposed RAPNO-WG recommendations were published in 2018 to also include assessments of MRI-spine, CSF cytology (AFP, βhCG) and extra-CNS disease. As with RANO, all of the criteria must be met in order to determine a subject’s objective response, whereas, progressive disease has been defined when any of the criteria have been met2.

RAPNO addresses the many unique issues in pediatric neuro-oncology which are highlighted below and additional details may be found in the referenced paper:

  • Pediatric brain tumors represent a heterogeneous group of diseases
  • Tumor enhancement is variable, nonspecific, and often not representative of tumor burden
  • Pseudoprogression and pseudoresponse can complicate interpretation of MRI scans
  • Tumor shrinkage does not always correlate with improved survival
  • Tumor identification and measurements are difficult and variable amongst readers due to tumors poorly defined borders, variable contrast enhancement and invasive nature4

As with any clinical trial which includes imaging endpoints to determine efficacy, the use of standardized imaging protocols with the careful selection of the appropriate radiological and clinical response assessments that have been identified to best define post treatment effects (based on tumor characteristics) will improve the robustness of the trial data and improve the chances to obtain positive study results.

Assessment variability occurs despite study protocol design expectations for the sites to evaluate subjects to the same criteria as the central readers. There are many factors which contribute to this variability such as differences in the site read process focused on clinical patient management and further insights may be found in our past blog entitled “Clinical Trial Imaging: A Focus on Reader Agreement” and in  publications from early consortia on best practices.5

Click here to learn how the right technology can significantly improve your clinical trial results.Joseph Pierro is the Medical Director of Imaging at ERT and David Raunig is the Senior Principal Imaging Statistician at ERT.


  1. Chukwueke U, Wen P. Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical trials and clinical practice. CNS Oncol. (2019) 8(1)
  2. Warren EW et al. Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology committee. NeuroOncology 20(1), 13–23, 2018
  3. Japsan 2016 on line table []
  4. Warren K E et al. Challenges With Defining Response to Antitumor Agents in Pediatric Neuro-Oncology: A Report From the Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group. Pediatr Blood Cancer. 2013 September; 60(9): 1397–1401
  5. Ford, R. and P. D. Mozley (2008). “Report of Task Force II: Best Practices in the Use of Medical Imaging Techniques in Clinical Trials.” Drug Information Journal 42(5): 515-523.