Intensity Modulated PrOton Therapy in Pediatric BRain Tumors (IMPORT)

Benign and low-grade primary brain tumors constitute a substantial proportion of pediatric central nervous system tumors and are associated with excellent long-term survival when managed with multimodality therapy. Despite favorable tumor control rates, survivors are at significant risk of treatment-related late effects, particularly following radiation therapy, which can adversely impact neurocognitive function, endocrine health, auditory function, and overall quality of life. Given the prolonged life expectancy of this population, minimizing radiation-induced toxicity while maintaining effective disease control is a major therapeutic priority.

Radiation therapy remains an essential curative modality for children with unresectable, residual, progressive, or recurrent benign and low-grade brain tumors. Advances in high-precision photon-based techniques such as intensity-modulated radiation therapy (IMRT) have improved dose conformality; however, photon therapy continues to expose large volumes of normal brain tissue to low and intermediate radiation doses. This exposure may lead to white matter injury, neuroinflammation, microvascular damage, and subsequent neurocognitive, endocrine, and auditory dysfunction, particularly in younger patients with developing brains.

Proton beam therapy offers a potential dosimetric advantage over photon therapy due to its physical depth-dose characteristics, allowing reduced integral dose to surrounding normal tissues. Intensity-modulated proton therapy (IMPT), delivered using pencil beam scanning, enables highly conformal dose distributions with improved sparing of organs at risk and may allow for reduction in treatment margins through enhanced image guidance and dose painting capabilities. These properties suggest a potential for meaningful reduction in late radiation-related toxicity in pediatric patients, while preserving tumor control.

While dosimetric and retrospective clinical data suggest advantages of proton therapy in reducing radiation exposure to critical neural structures, robust prospective randomized evidence demonstrating clinically meaningful benefits remains limited. Furthermore, the higher cost and limited availability of proton therapy necessitate careful evaluation of its value relative to advanced photon techniques, particularly in resource-constrained healthcare systems. Generating high-level evidence to guide patient selection and policy decisions is therefore essential.

The IMPORT trial is a prospective, randomized, open-label, phase III superiority study designed to compare IMPT with IMRT in children with benign and low-grade primary brain tumors treated with curative intent radiotherapy. The trial focuses on outcomes that are particularly relevant to long-term pediatric survivorship, including neurocognitive function, endocrine and auditory toxicity, and quality of life, while ensuring comparable tumor control.

The study introduces the concept of Qualified Overall Survival (qOS) as a composite primary endpoint that integrates survival, disease control, and clinically significant treatment-related morbidity. This composite endpoint is intended to capture outcomes that reflect both oncologic efficacy and functional preservation, thereby providing a patient-centered assessment of treatment benefit.

Participants will be randomized to receive either IMPT or IMRT, with radiation dose, fractionation, and target volumes determined by tumor type, location, and standard clinical practice. Tumor response and disease progression will be assessed using contemporary imaging-based criteria, while functional outcomes will be evaluated using standardized neurocognitive testing, endocrine assessments, audiological evaluations, and patient-reported quality-of-life instruments.

By directly comparing IMPT and IMRT in a randomized setting, the IMPORT trial aims to determine whether the dosimetric advantages of proton therapy translate into superior long-term functional outcomes and improved qualified survival, thereby informing evidence-based clinical decision-making and health policy for pediatric brain tumor management.