{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:51:12Z","timestamp":1791352272169,"version":"4.3.1"},"reference-count":21,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["aapm.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Applied Clin Med Phys"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Large hepatocellular carcinoma (HCC) adjacent to gastrointestinal (GI) organs presents a constrained radiotherapy problem because dose escalation is limited by both hepatic reserve and serial\u2010organ tolerance. Although intensity\u2010modulated proton therapy (IMPT) can reduce uninvolved liver irradiation, its achievable advantage over volumetric modulated arc therapy (VMAT) may depend on baseline liver function and robustness to treatment uncertainties.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To present and demonstrate a robust isotoxic dose\u2010escalation framework for evaluating IMPT and VMAT in large HCC adjacent to GI organs while accounting for baseline liver function and treatment uncertainty.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Thirteen patients with HCC (equivalent tumor diameter, 3.0\u201320.9\u00a0cm) underwent comparative IMPT and VMAT treatment planning. Robust optimization incorporated 5\u2010mm setup uncertainty for both modalities and 3% range uncertainty for IMPT. Dose escalation was performed using a fixed dose per fraction of 3.87\u00a0Gy while varying the maximum acceptable number of fractions,\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      , under non\u2010cirrhotic, Child\u2010Pugh A (CP\u2010A), and Child\u2010Pugh B (CP\u2010B) liver\u2010function assumptions. Liver mean dose constraints were evaluated on nominal dose, while serial\u2010organ constraints were assessed using both nominal dose and voxel\u2010wise maximum dose across uncertainty scenarios. Unirradiated liver volume normalized to standard liver volume (ULV\/SLV) was used to estimate the relative hazard of radiation\u2010induced liver disease (RILD).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the nominal\u2010dose analysis, IMPT achieved a higher\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      than VMAT in 5 of 13, 8 of 13, and 8 of 13 patients under non\u2010cirrhotic, CP\u2010A, and CP\u2010B assumptions, respectively, with mean \u0394\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      values of 0.38, 1.23, and 1.69 fractions. Similar trends were observed in the voxel\u2010wise maximum\u2010dose analysis, where mean \u0394\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      values were 0.00, 1.08, and 1.77 fractions, respectively. VMAT dose escalation was predominantly limited by mean liver dose, whereas IMPT was more frequently constrained by GI maximum\u2010dose limits, indicating a shift from liver reserve to serial\u2010organ tolerance as the primary limiting factor. Among patients with an IMPT dose\u2010escalation advantage, IMPT maintained higher ULV\/SLV and correspondingly lower estimated RILD hazard despite treatment escalation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>IMPT provides greater isotoxic dose\u2010escalation potential than VMAT for selected patients with large HCC, particularly when impaired baseline liver function causes photon therapy to be limited by mean liver dose. The proton advantage is ultimately constrained by robust GI organ\u2010at\u2010risk tolerances, emphasizing the importance of integrating baseline liver function, liver reserve, and uncertainty\u2010aware serial\u2010organ evaluation into modality selection and treatment planning.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acm2.70846","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:29:10Z","timestamp":1791350950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Potential of isotoxic dose escalation with robustly optimized VMAT and IMPT for large hepatocellular carcinoma according to baseline liver function"],"prefix":"10.1002","volume":"27","author":[{"given":"Elise","family":"Cherek","sequence":"first","affiliation":[{"name":"Physics Department University of Nebraska Lincoln  Lincoln Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Ka Heng","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Schott","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"issue":"3","key":"e_1_2_12_2_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung H","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"10","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s41575-019-0186-y","article-title":"A global view of hepatocellular carcinoma: trends, risk, prevention and management","volume":"16","author":"Yang JD","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"7","key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1111\/j.1445-2197.2012.06079.x","article-title":"Surgical treatment for large hepatocellular carcinoma: does size matter?","volume":"82","author":"Tsoulfas G","year":"2012","journal-title":"ANZ J Surg"},{"issue":"1","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.prro.2021.09.004","article-title":"External beam radiation therapy for primary liver cancers: an ASTRO clinical practice guideline","volume":"12","author":"Apisarnthanarax S","year":"2022","journal-title":"Pract Radiat Oncol"},{"issue":"1","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ijrobp.2019.02.032","article-title":"Predictors of radiation\u2010induced liver disease in eastern and western patients with hepatocellular carcinoma undergoing proton beam therapy","volume":"105","author":"Hsieh CE","year":"2019","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"9","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0203854","article-title":"How small is too small? 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