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Non-squamous cell carcinomas exhibit relatively low radiosensitivity, limiting the efficacy of conventional photon RT. Carbon-ion (C-ion) RT, characterised by high linear energy transfer (LET) and high relative biological effectiveness (RBE), has shown promising outcomes in treating radioresistant head and neck cancers. However, local recurrences still occur, and further improvements in treatment outcomes are needed. To enhance the local control rate, an increase in dose-averaged LET (LETd) to the tumour was considered.<\/jats:p>\n                    <jats:p>Following a simulation study, a clinical trial was conducted to optimise LETd using only C-ion therapy, and its safety was confirmed. However, in this clinical trial, LETd could only be increased to approximately 70 keV\/\u03bcm. To further escalate LETd, multi-ion therapy using ions heavier than carbon was developed. Simulation studies demonstrated that multi-ion therapy incorporating carbon, oxygen and neon ions could increase LETd up to 90 keV\/\u03bcm, regardless of tumour size, while maintaining high-dose uniformity within the tumour. Based on these results, a clinical study was planned to evaluate the safety of escalating LETd from 70 keV\/\u03bcm to 90 keV\/\u03bcm using multi-ion therapy. The primary objective of this study is to evaluate the safety of escalating LETd to the tumour using multi-ion therapy for head and neck cancer, with the secondary goal of identifying the maximum tolerated LETd.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This is a non-randomised, open-label, phase 1 study focused on LETd escalation. A maximum of 18 patients with histologically confirmed inoperable head and neck malignancies will be enrolled. All patients will receive multi-ion therapy using helium, carbon, oxygen or neon ions, either alone or in combination, at an RBE-weighted dose ranging from 57.6 to 70.4\u2009Gy, delivered in 16 fractions (4 fractions per week) over 4 weeks. The specific dose will be determined according to histology. LETd escalation will begin at 70 keV\/\u03bcm and will increase by 10 keV\/\u03bcm increments, reaching a maximum of 90 keV\/\u03bcm. The safety of multi-ion therapy will be assessed based on the frequency and severity of dose-limiting toxicities, monitored up to 90 days after the initial irradiation. Patients will be followed up according to the protocol for 180 days after the initial multi-ion therapy irradiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study protocol has been approved by the National Institutes for Quantum Science and Technology Certified Review Board (#L24-002). The results will be published in a peer-reviewed journal and presented at a scientific conference.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>jRCTs032240451.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-098151","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T09:00:44Z","timestamp":1760605244000},"page":"e098151","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Dose-averaged LET escalation with multi-ion therapy for head and neck cancers: a phase I study protocol for a prospective, open-label, single-arm, single-centre trial (MULTI-ION-HN-I)"],"prefix":"10.1136","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1081-1136","authenticated-orcid":false,"given":"Hiroaki","family":"Ikawa","sequence":"first","affiliation":[{"name":"QST Hospital, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Shinoto","sequence":"additional","affiliation":[{"name":"QST Hospital, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Koto","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Faculty of Medicine, Yamagata University, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takamitsu","family":"Masuda","sequence":"additional","affiliation":[{"name":"Department of Accelerator and Medical Physics, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Inaniwa","sequence":"additional","affiliation":[{"name":"Department of Accelerator and Medical Physics, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotoshi","family":"Takiyama","sequence":"additional","affiliation":[{"name":"QST Hospital, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Isozaki","sequence":"additional","affiliation":[{"name":"QST Hospital, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Yamada","sequence":"additional","affiliation":[{"name":"QST Hospital, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"QST Hospital, National Institutes for Quantum Science and Technology (QST), Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"2025120415073603000_15.10.e098151.1","unstructured":"National comprehensive cancer network practice guidelines in oncology, version 1.2023, pp. or-1 to or-3. 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