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Med. Biol."],"published-print":{"date-parts":[[2026,2,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Objective.<\/jats:italic>\n                    The LET trilemma\u2014an inherent conflict between target dose homogeneity, range robustness, and high dose-averaged linear energy transfer (LET\n                    <jats:sub>d<\/jats:sub>\n                    )\u2014poses 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\n                    <jats:sub>d<\/jats:sub>\n                    -optimized treatment plans and explored strategies to overcome this trilemma, framed within the phase I LET\n                    <jats:sub>d<\/jats:sub>\n                    escalation trial for head and neck cancers.\n                    <jats:italic>Approach.<\/jats:italic>\n                    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\n                    <jats:sub>d<\/jats:sub>\n                    of 90 keV \u03bcm\n                    <jats:sup>\u22121<\/jats:sup>\n                    (the final LET\n                    <jats:sub>d<\/jats:sub>\n                    level of the phase I trial). These plans were recalculated to incorporate systematic range uncertainty (\u00b12.5%) 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\n                    <jats:sub>d<\/jats:sub>\n                    distributions 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.\n                    <jats:italic>Main Results.<\/jats:italic>\n                    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\n                    <jats:sub>d<\/jats:sub>\n                    variations were approximately 3 keV \u03bcm\n                    <jats:sup>\u22121<\/jats:sup>\n                    . The most effective mitigation strategy involved replacing the original carbon\u2013oxygen combination with oxygen ions for two beam ports, reducing dose inhomogeneity by more than 7% while maintaining normal tissue sparing adjacent to the target.\n                    <jats:italic>Significance.<\/jats:italic>\n                    Optimization toward achieving higher LET\n                    <jats:sub>d<\/jats:sub>\n                    makes 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\n                    <jats:sub>d<\/jats:sub>\n                    while sparing normal tissues. These findings provide a key rationale for ion selection in the design of robust multi-ion therapy.\n                  <\/jats:p>","DOI":"10.1088\/1361-6560\/ae387b","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T22:54:40Z","timestamp":1768431280000},"page":"035016","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Robustness of LET\n                    <sub>d<\/sub>\n                    -optimized multi-ion therapy against range and setup uncertainties: evaluation and enhancement with carbon-, oxygen-, and neon-ion beams"],"prefix":"10.1088","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9648-764X","authenticated-orcid":true,"given":"Takamitsu","family":"Masuda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1081-1136","authenticated-orcid":false,"given":"Hiroaki","family":"Ikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3556-2164","authenticated-orcid":false,"given":"Makoto","family":"Shinoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2872-6570","authenticated-orcid":false,"given":"Masashi","family":"Koto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4927-0901","authenticated-orcid":true,"given":"Koki","family":"Kasamatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2180-568X","authenticated-orcid":true,"given":"Yusuke","family":"Nomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2534-9933","authenticated-orcid":true,"given":"Nobuyuki","family":"Kanematsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2967-4004","authenticated-orcid":true,"given":"Taku","family":"Inaniwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"pmbae387bbib1","doi-asserted-by":"publisher","DOI":"10.1088\/1361-6560\/ad7cbd","type":"journal-article","article-title":"First clinical implementation of a highly efficient daily online adapted proton therapy (DAPT) workflow","volume":"69","author":"Albertini","year":"2024","journal-title":"Phys. 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