Feasibility of reduced setup uncertainty in intensity-modulated proton therapy for mediastinal lymphoma

Background and purpose: Mediastinal lymphoma patients are typically young and are at risk of long-term radiation-induced adverse events, making organ of interest (OOI) sparing a key objective of radiotherapy. This study investigated whether reducing setup uncertainty during robust intensity-modulated proton therapy (IMPT) planning is feasible without compromising target coverage and delivered dose robustness. Materials and methods: Ten consecutive mediastinal lymphoma patients treated with IMPT were retrospectively analyzed. Treatment plans were generated on the four-dimensional average computed tomography (4DCT) using a 5 mm setup uncertainty (clinical standard). Additional plans with 4 and 3 mm setup uncertainties were created using a dose-mimicking optimization approach while maintaining identical clinical priorities. Robustness was evaluated using a three-dimensional robustness evaluation method (3DREM) and a longitudinal four-dimensional robustness evaluation method (4DREM), incorporating setup and range variations, machine uncertainties, respiratory motion, and weekly anatomical changes. Results: All plans achieved adequate target coverage in the 3D-nominal and 4DREM voxel-wise mean dose distributions (V95 % > 99.6 %). The voxel-wise minimum dose distributions from 4DREM confirmed robust target coverage (V95 % > 98 %, D98 % > 95 % of prescription dose) for all setup uncertainties, with one clinically accepted exception. Reducing setup uncertainty resulted in statistically significant reductions in organs of interest doses (p < 0.01), corresponding to median reductions in predicted lifetime acute coronary event risk of 0.17 % and 0.32 % for 4 mm and 3 mm setup uncertainties, respectively (p < 0.01). Conclusion: Reducing setup uncertainty during robust IMPT planning for mediastinal lymphoma patients was feasible and improved OOI sparing without compromising delivered dose robustness.