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Jointly optimized combined proton\u2013photon treatments may serve as a means to redistribute LET and avoid high\u2010LET regions in organs at risk (OARs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To mitigate LET\u2010related toxicity in OARs, this work leverages combined treatments by direct integration of LET in the joint optimization process. To this end, LET\u2010modifying objective functions and variable RBE models are used within a joint optimization framework for combined proton\u2013photon treatments. This approach combines the properties of both modalities to achieve LET\u2010shaping and satisfy biological dose objectives in the target and\u00a0OAR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      LET\u2010modifying objective (LMO) functions based on the dose\u2010weighted LET (LETxDose) and on\n                      <jats:italic>dirty dose<\/jats:italic>\n                      \u2014defined as high\u2010LET dose above a defined LET\u2010threshold\u2014 were integrated into joint optimization within the open source toolkit\n                      <jats:italic>matRad<\/jats:italic>\n                      (v2.10.1). Treatment plans with phantom and clinical test cases were optimized and evaluated, consistently using the same dose objectives in each plan. The compared plans use the following: (1) constant RBE model, (2) variable RBE models, (3)\n                      <jats:italic>dirty dose<\/jats:italic>\n                      objectives, (4) LETxDose (LxD) objectives. Furthermore, sensitivity analysis was performed for various penalty weights, different proton beam angles and \u2013 ratios. The plans were assessed for target coverage, dose conformity, and LET reduction in OARs, combining five proton fractions with 25 photon\u00a0fractions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LET\u2010modifying objectives enabled localized reduction of high\u2010LET exposition in OARs by redistributing dose contributions of both modalities. Protons provided superior tumor\u2010targeted dose delivery and reduced integral dose, while photons mitigated high\u2010LET at the distal edge without compromising dose conformity in the tumor. Beam alignment had a greater influence on enhancing the LMO effect than the number of proton beams. The\n                      <jats:italic>dirty dose<\/jats:italic>\n                      to  of brain stem volume was reduced when using joint LET optimization approaches. LET\u2010modifying squared underdosing objectives increased the\n                      <jats:italic>dirty dose<\/jats:italic>\n                      in the GTV by up to  compared with the reference joint plan, whereas squared overdosing objectives reduced the\n                      <jats:italic>dirty dose<\/jats:italic>\n                      in the brain stem by . Their combination achieved a  increase of\n                      <jats:italic>dirty dose<\/jats:italic>\n                      in the GTV with a corresponding reduction in the brain stem. Despite  per fraction, the proton\u2010only plan resulted with a  times higher\n                      <jats:italic>dirty dose<\/jats:italic>\n                      per fraction in a joint optimized plan using\n                      <jats:italic>dirty dose<\/jats:italic>\n                      objectives, approximately  locally per fraction. Using LETxDose objectives, it was  times higher.\n                      <jats:italic>Dirty dose<\/jats:italic>\n                      objectives provided more explicit LET control than LETxDose, with minimal compromise in target coverage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Integrating LET\u2010based objectives into a jointly optimized proton\u2013photon system allows for direct steering of the combined LET, improving dose conformity and reducing high\u2010LET exposure in critical regions. This approach leverages modality\u2010specific strengths and offers a practical route toward LET\u2010optimized multimodality radiotherapy for safer, more effective\u00a0treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mp.70478","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:57:20Z","timestamp":1779944240000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Impact of LET\u2010modifying planning objectives on the optimization of mixed\u2010modality proton\u2013photon treatments"],"prefix":"10.1002","volume":"53","author":[{"given":"Lisa","family":"Seckler","sequence":"first","affiliation":[{"name":"Division of Medical Physics in Radiation Oncology German Cancer Research Center\u2014DKFZ Heidelberg Germany"},{"name":"University of Applied Sciences (THM) Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit Ben Antony","family":"Bennan","sequence":"additional","affiliation":[{"name":"Division of Medical Physics in Radiation Oncology German Cancer Research Center\u2014DKFZ Heidelberg Germany"},{"name":"Heidelberg Institute for Radiation Oncology and National Center for Radiation Research in Oncology Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Wahl","sequence":"additional","affiliation":[{"name":"Division of Medical Physics in Radiation Oncology German Cancer Research Center\u2014DKFZ Heidelberg Germany"},{"name":"Heidelberg Institute for Radiation Oncology and National Center for Radiation Research in Oncology Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1088\/1361\u20106560\/aad9db"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1088\/0031\u20109155\/60\/21\/8399"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mp.13390"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/mp.13911"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.adro.2021.100776"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13014\u2010016\u20100642\u20106"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2013.05.013"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.14338\/IJPT\u201020\u201000049.1"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15174268"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/mp.13347"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1088\/1361\u20106560\/aae8a5"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.01.013"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1088\/1361\u20106560\/aa9a2e"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2016.08.038"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2018.10.031"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3109\/0284186X.2013.832835"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2019.10.008"},{"key":"e_1_2_8_19_1","doi-asserted-by":"crossref","unstructured":"UnkelbachJ FabianoS BennanABA MuellerS BangertM.Joint optimization of radiotherapy treatments involving multiple radiation modalities.IEEE Trans Radiat Plasma Med Sci.\u00a02021;6(3):294\u2010303 doi:10.1109\/TRPMS.2021.3092423","DOI":"10.1109\/TRPMS.2021.3092423"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2021.05.126"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2019.12.013"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.04.029"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2017.12.031"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1088\/1361\u20106560\/ad5d48"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1088\/1361\u20106560\/ac36a3"},{"key":"e_1_2_8_26_1","unstructured":"BennanABA.Combined photon\u2010carbon ion radiotherapy treatment planning. 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