Robustness of LETd-optimized multi-ion therapy against range and setup uncertainties: evaluation and enhancement with carbon-, oxygen-, and neon-ion beams.

Objective.The LET trilemma-an inherent conflict between target dose homogeneity, range robustness, and high dose-averaged linear energy transfer (LETd)-poses a major challenge in treatment optimization. To ensure accurate beam delivery in multi-ion therapy, this study evaluated the effects of range and setup uncertainties on LETd-optimized treatment plans and explored strategies to overcome this trilemma, framed within the phase I LETdescalation trial for head and neck cancers.Approach.Six head and neck cancer patients representing diverse tumors were selected. Multi-ion therapy plans using carbon-, oxygen-, and neon-ion beams were optimized to achieve a target LETdof 90 keV μm-1(the final LETdlevel of the phase I trial). These plans were recalculated to incorporate systematic range uncertainty (±2.5%) and random daily setup variations (mean, 0.45 mm; standard deviation, 0.23 mm) across the 16 fractions, and their combined effects on the dose and LETddistributions were evaluated. Additionally, to explore strategies to enhance plan robustness, five modified plans were evaluated for one patient identified as particularly susceptible to these uncertainties.Main Results.Range uncertainty was the dominant contributor to degraded plan quality, substantially outweighing setup uncertainty. A small, centrally located tumor was most susceptible, exhibiting dose inhomogeneity of approximately 11%, while LETdvariations were approximately 3 keV μm-1. The most effective mitigation strategy involved replacing the original carbon-oxygen combination with oxygen ions for two beam ports, reducing dose inhomogeneity by more than 7% while maintaining normal tissue sparing adjacent to the target.Significance.Optimization toward achieving higher LETdmakes treatment plans susceptible to range uncertainty, leading to dose degradation within small, deep-seated tumors. Employing heavier ions is an effective strategy to overcome this challenge, enabling robust target coverage by leveraging their inherently higher LETdwhile sparing normal tissues. These findings provide a key rationale for ion selection in the design of robust multi-ion therapy.