Technical Considerations on Proton Therapy in NRG's Multi-Institutional Clinical Trials

Integrating proton therapy into multi-institutional clinical trials introduces distinct physical and biological complexities. Modern pencil beam scanning enables highly conformal dose delivery but increases sensitivity to setup and range uncertainties, patient motion, interfractional anatomic changes, and variability in relative biological effectiveness. These factors complicate treatment standardization and outcome interpretation across institutions.

Under the leadership of NRG Oncology, current proton therapy clinical trial protocols were reviewed to identify technical challenges. Key issues examined included robustness evaluation, motion management, adaptive planning considerations, treatment reporting, and limitations in dosimetric and biological data collection. Recommendations were developed based on contemporary proton therapy practice and multi-institutional clinical trial experience.

This guideline establishes a harmonized framework for proton therapy in cooperative group clinical trials and provides practical recommendations for robustness evaluation, motion management, treatment reporting, and standardized data collection. Specifically, we recommend evaluating plan robustness directly on the clinical target volume using worst-case scenarios, rather than relying on conventional photon-based geometric expansions (planning target volume). Guidance is also provided for uncertainty parameters and minimum uncertainty scenario sets. In addition, expansion of centralized data collection through the Imaging and Radiation Oncology Core is recommended to include beam model parameters and linear energy transfer information to support independent dose reconstruction, cross-validation, and future retrospective radiobiological analyses as clinical relative biological effectiveness models evolve.

This unified framework aims to improve treatment consistency, outcome reliability, and harmonized proton therapy implementation across cooperative group clinical trials while supporting future investigation of biological dose-response relationships.