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Clinical trials utilizing positron emission tomography (PET) to image tumor hypoxia and escalate the prescription dose in hypoxic sub\u2010volumes are being pursued in response, with current clinical prescription doses of 70 Gy generally escalated to 77\u201378 Gy. Instead utilizing magnetic resonance imaging (MRI) for hypoxia\u2010based prescription dose escalation would be associated with a variety of advantages, including not requiring an additional imaging\u2010related radiation dose to be delivered to the patient and allowing for a variety of other functional maps to be extracted from the same patient imaging session, in addition to tumor hypoxia information.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>The purpose of this study is to investigate the benefits of MRI\u2010informed hypoxia\u2010based radiotherapy dose escalation for head\u2010and\u2010neck cancer patients treated with proton radiotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Ten patients with head\u2010and\u2010neck cancer scheduled to undergo photon therapy underwent a multi\u2010parametric MRI protocol based on which tumor hypoxia maps were computed for every patient using a quantitative blood oxygenation level dependent (BOLD) approach. Four proton therapy treatment plans were then created for each patient, consisting of intensity\u2010modulated proton therapy (IMPT) and proton arc therapy (PAT) treatment planning performed according to current clinical standards (IMPT\n                      <jats:sub>Conv<\/jats:sub>\n                      and PAT\n                      <jats:sub>Conv<\/jats:sub>\n                      ) or with a 10% prescription dose escalation to the hypoxic sub\u2010volumes of the low\u2010 and high\u2010risk target structures (IMPT\n                      <jats:sub>Esc<\/jats:sub>\n                      and PAT\n                      <jats:sub>Esc<\/jats:sub>\n                      ). The generated treatment plans were then analyzed with respect to target and organ\u2010at\u2010risk (OAR) doses and normal tissue complication probabilities (NTCPs) as well as tumor control probabilities (TCPs) calculated according to conventional models (TCP\n                      <jats:sub>Conv<\/jats:sub>\n                      ) or with consideration of hypoxia\u2010induced radioresistance (TCP\n                      <jats:sub>Hyp<\/jats:sub>\n                      ). Statistical significance (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.05) of different TCP or mean OAR dose distributions was determined using the Wilcoxon signed\u2010rank test.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      During IMPT, radiotherapy prescription dose escalation increased TCP\n                      <jats:sub>Conv<\/jats:sub>\n                      in the nominal scenario by (5.9 \u00b1 6.3) percentage points (pp) in the normoxic (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) and (5.2 \u00b1 9.0) pp in the hypoxic target volumes (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.006). In the worst\u2010case scenario, TCP\n                      <jats:sub>Conv<\/jats:sub>\n                      was increased by (5.6 \u00b1 4.5) pp (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) and (5.3 \u00b1 6.4) pp (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.003). Dose escalation during PAT improved TCP\n                      <jats:sub>Conv<\/jats:sub>\n                      by (3.1 \u00b1 3.3) pp (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) and (2.1 \u00b1 5.4) pp (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.015) in the nominal scenario and (3.3 \u00b1 3.1) pp (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) and (3.3 \u00b1 4.4) pp (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) in the worst\u2010case scenario. When hypoxia\u2010induced radioresistance was considered, dose escalation elevated TCP\n                      <jats:sub>Hyp<\/jats:sub>\n                      in the nominal scenario by (7.6 \u00b1 4.5) pp (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt; 0.001) during IMPT and (6.4 \u00b1 4.1) pp (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) during PAT and TCP\n                      <jats:sub>Hyp<\/jats:sub>\n                      in the worst\u2010case scenario by (6.3 \u00b1 3.8) pp (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) during IMPT and (6.3 \u00b1 3.1) pp (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001) during PAT. Compared to the patients\u2019 clinical photon therapy treatment plans in the nominal scenario, mean OAR doses were reduced by (13.5 \u00b1 9.3)Gy RBE by IMPT\n                      <jats:sub>Conv<\/jats:sub>\n                      , (14.3 \u00b1 10.5)Gy RBE by PAT\n                      <jats:sub>Conv<\/jats:sub>\n                      , (9.8 \u00b1 10.5)Gy RBE by IMPT\n                      <jats:sub>Esc<\/jats:sub>\n                      , and (10.4 \u00b1 12.8)Gy RBE by PAT\n                      <jats:sub>Esc<\/jats:sub>\n                      (all\n                      <jats:italic>p<\/jats:italic>\n                      = 0.002).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MRI\u2010based hypoxia\u2010informed radiotherapy prescription dose escalation during both IMPT and PAT significantly increased calculated TCPs while significantly reducing doses delivered to nearby healthy organs compared to the patients\u2019 clinical photon therapy treatment plans. MRI\u2010based hypoxia\u2010informed prescription dose escalation is therefore considered feasible and may help partially address hypoxia\u2010induced radioresistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mp.70480","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:35:21Z","timestamp":1778736921000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MRI\u2010informed hypoxia\u2010based proton radiotherapy dose escalation for head\u2010and\u2010neck cancer\u2014a proof\u2010of\u2010concept"],"prefix":"10.1002","volume":"53","author":[{"given":"Sebastian","family":"Tattenberg","sequence":"first","affiliation":[{"name":"CREATIS UMR 5220, U1294 CNRS, Inserm, INSA\u2010Lyon, Universite Claude Bernard Lyon 1  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Tanneau","sequence":"additional","affiliation":[{"name":"CREATIS 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