A Survey of Pediatric Clinical Trial Radiotherapy Dose Constraints

Abstract

<h3>Purpose/Objective(s)</h3> Radiation therapy normal tissue dose constraints are critical when treating children with cancer due to the vulnerability of developing organs to toxicity and the many years over which these effects can evolve. Guidelines in international clinical trials have been instrumental in shaping how treatment plans are designed; however, consistency among organs at risk (OARs) constraints has not been previously evaluated. In this study we identify the variations in OAR-specific dose constraints within pediatric trials both in the United States (US) and in Europe. <h3>Materials/Methods</h3> All US pediatric trials from the COG website were included up until 1/1/2020 along with a sampling of European trials accessible in the Netherlands. Dose constraints were identified and built into an interactive web application with filters to display data by OAR, protocol, dose, volume, and fractionation scheme. Dose constraints were compared between pediatric US and European trials by graphical intercomparison and by comparing high dose constraints (maximum dose [Dmax] or dose to a volume ≤ 20%) and by dose metrics that were commonly used across protocols. <h3>Results</h3> Sixty-five trials were included with the US trials (53) represented by the COG/CCG/POG and the European trials (12) represented by the SIOP, EURAMOS, GPOH, DCOG, and EpSSG. Thirty-three separate OARs were found with high variability within the trials for each OAR, ranging from different maximum tolerable doses to variations of volumetric dose constraints. Seven organs had 10 to 18 different constraints and included serial organs such as the spinal cord, optic chiasm, optic nerves, and brainstem as well as parallel organs including the lungs, liver, and heart. An example of dose variability can be seen with the spinal cord Dmax constraint ranging from 50 Gy to V59 < 10%, the optic nerves constraint ranging from a Dmax of 45 Gy to 60 Gy, the heart V30 constraint ranging from 40-100%, and the kidney D50% constraint ranging from 8-24 Gy. When comparing high dose tolerances between US and European trials, US constraints were higher for four OARs—bladder (V70 < 20% vs Dmax < 60), lungs (V20 < 20% vs Dmax < 18), mandible (V77 < 1cc vs Dmax < 60), and spinal cord (V57 < 10% vs Dmax < 54); lower for four OARs—brainstem (V63 < 10% vs V64 < 10%), heart (Dmax < 30 vs Dmax < 30.6), kidneys (Dmax < 15 vs Dmax < 19.8), and liver (Dmax < 15 vs Dmax < 23.4); and identical in four OARs—brain, optic chiasm, optic nerves, and bowel. <h3>Conclusion</h3> Review of pediatric dose-volume constraints in clinical trials showed substantial variability for all OARs. Continued focus on standardization of OAR dose constraints and risk profiles are essential to improving clinical trial consistency and improving understanding of dose-response in the pediatric population.