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.