Introduction:
Survival rates in pediatric cancers continue to improve, with 5-year survival rates ranging from 68% to 86% 1. However, a consequence of improving survival outcomes is the increased long-term morbidity of treatment toxicities 2–4. Radiation therapy is necessary for childhood cancer types and has evolved with the growing awareness of long-term sequelae following treatment5. This is of particular concern among children and adolescents for whom irradiation of actively developing tissues impairs growth and maturation. Accordingly, radiation exposure can cause neurocognitive, growth, and reproductive deficits, as well as organ dysfunction and risk of subsequent malignancies 6–12. Modern radiation techniques, with improved imaging modalities, comprise one such effort to reduce late adverse effects. While these advanced techniques deliver highly uniform and conformal dose distributions to the target volumes, incidental irradiation of surrounding normal tissues, referred to as organs at risk (OARs), are more variable and depend on their proximity to the target volume, the prescribed tumor dose, the radiation technique, and the permitted dose-volume constraints used during treatment planning 13.
Evidence-based dose-volume risk guidelines and consensus constraints are essential to provide optimal tumor control in a safe and effective manner that minimizes toxicity. Clinical trials requiring radiotherapy rely on the current state of knowledge about normal organ dose-response to inform the choice of dose constraints in protocols. However, organ-specific constraints specified in adult protocols have been shown to be highly variable 14. To counter this, task forces have formed to evaluate normal tissue tolerances and propose corresponding dose-volume constraints, with notable collaborations being Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) and Pediatric Normal Tissue Effects in the Clinic (PENTEC) in adults and children, respectively 13,15. This study provides a survey of the dose-volume constraints from closed clinical trials in the Children’s Oncology Group (COG) as well as others outside of the United States (US), in an effort to describe the heterogeneity in OAR-specific dose constraints in contemporary and historic protocols. Such variations undermine the clinical trial paradigm of consistency and motivate an organized effort to redefine and standardize OAR dose constraints across clinical trials. To our knowledge, an evaluation of dose constraint variability for pediatric trials has not been previously documented.