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

<i>Objective.</i>The LET trilemma-an inherent conflict between target dose homogeneity, range robustness, and high dose-averaged linear energy transfer (LET_d)-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 LET_d-optimized treatment plans and explored strategies to overcome this trilemma, framed within the phase I LET_descalation trial for head and neck cancers.<i>Approach.</i>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 LET_dof 90 keV μm^-1(the final LET_dlevel 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 LET_ddistributions 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.<i>Main Results.</i>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 LET_dvariations 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.<i>Significance.</i>Optimization toward achieving higher LET_dmakes 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 LET_dwhile sparing normal tissues. These findings provide a key rationale for ion selection in the design of robust multi-ion therapy.