Imaging Assessment of Radiation Therapy-Related Normal Tissue Injury in Children: A PENTEC Visionary Statement

Abstract

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium has made significant contributions to understanding and mitigating the adverse effects of childhood cancer therapy. This review addresses the role of diagnostic imaging in detecting, screening, and comprehending radiation therapy-related late effects in children, drawing insights from individual organ-specific PENTEC reports. We further explore how the development of imaging biomarkers for key organ systems, alongside technical advancements and translational imaging approaches, may enhance the systematic application of imaging evaluations in childhood cancer survivors. Moreover, the review critically examines knowledge gaps and identifies technical and practical limitations of existing imaging modalities in the pediatric population. Addressing these challenges may expand access to, minimize the risk of, and optimize the real-world application of, new imaging techniques. The PENTEC team envisions this document as a roadmap for the future development of imaging strategies in childhood cancer survivors, with the overarching goal of improving long-term health outcomes and quality of life for this vulnerable population.

Figures 1:. Paradigms for Imaging Biomarker Development.

Imaging Biomarker development begins with selection of a model in vitro and/or in vivo system which can be paired with an imaging technique or tracer. After establishing key metrics for each organ disease state and functional corollaries, both tracer and/or technique tolerability and/or toxicity parameters can be assessed. Early clinical assessments usually take place in healthy volunteers and may not involve children in the first round of evaluations. During this time, key practical and technical concerns are addressed. Either concurrently or following initial demonstration of the technique and or tracer’s potential utility in the clinical setting in clinical trials, it may be necessary to compare the new technique/tracer to existing means of assessing end organ function or other disease states. This may occur in silico through cost-benefit analyses with healthcare economists or by examining existing healthcare policies and their impact on reimbursement strategies in the healthcare system. In what is anticipated to be many years after the initial phase of development, clinical application may proceed.

Figure 2.. Experimental Imaging/Modality Tracer Development.

Representative Treatment schema for experimental imaging modalities and tracers undergoing active development with supporting literature on example model systems. Please see manuscript text for references for each organ system.

Figure 3.. Real-time fMRI-based Neurofeedback system.

Developing imaging modalities have the potential to facilitate functional changes which may be therapeutic in select subsets of childhood cancer survivors. Real time fMRI neurofeedback has the potential to facilitate behavioral or cognitive conditioning strategies to mitigate some of the neurologic late effects of cancer therapy.