{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:18:55Z","timestamp":1778779135279,"version":"3.51.4"},"reference-count":23,"publisher":"IOP Publishing","issue":"4","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/iop-standard\/v1"},{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/iopscience.iop.org\/info\/page\/text-and-data-mining"}],"content-domain":{"domain":["iopscience.iop.org"],"crossmark-restriction":false},"short-container-title":["Phys. Med. Biol."],"published-print":{"date-parts":[[2022,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Objective.<\/jats:italic>\n                    In intensity modulated particle therapy (IMPT), the adoption of spatially and temporally heterogeneous dose distributions allows to decouple the fractionation scheme from the patient anatomy, so that an hypofractionated schedule can be selectively created inside the tumour, while simultaneously exploiting the fractionation effect in the healthy tissues. In this paper, the authors show the reproducibility of the method on a set of prostate patients, quantifying the dependencies of the achievable benefit with respect to conventional and hypofractionated schemes and the sensitivity of the method to setup errors and range uncertainty.\n                    <jats:italic>Approach.<\/jats:italic>\n                    On a cohort of 9 patients, non-uniform IMPT plans were optimised and compared to conventional and hypofractionated schedules. For each patient, the comparison of the three strategies has been based on the output of the cost function used to optimise the treatments. The analysis has been repeated considering different\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \/\n                    <jats:italic>\u03b2<\/jats:italic>\n                    ratios for the tumour, namely 1.5, 3 and 4.5 Gy. For a single patient, setup errors and beam range uncertainty have been analysed: the plans, for each optimisation strategy, have been iteratively forward planned 500 times with randomly varying the patient position in each fraction, and 200 times for systematic range shift.\n                    <jats:italic>Main results.<\/jats:italic>\n                    An average 10% benefit has been shown for the lowest\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \/\n                    <jats:italic>\u03b2<\/jats:italic>\n                    ratio considered for the tumour, where the non-uniform schedule generally converges to hypofractionation; the benefit decreases to 5%\u20137% for higher\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \/\n                    <jats:italic>\u03b2<\/jats:italic>\n                    ratios, for which the non-uniform schedule always showed better outcomes with respect to the other fractionation schedules. An increased sensitivity to uncertainty, especially for setup errors, has been shown, which can be associated to the spatial non-uniformity of the dose distributions peculiar of the spatiotemporal plans.\n                    <jats:italic>Significance.<\/jats:italic>\n                    This work represents the first investigation of spatiotemporal fractionation for prostate cancer and the beginning of further investigations before clinical implementation can be considered.\n                  <\/jats:p>","DOI":"10.1088\/1361-6560\/ac4fa2","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T17:26:02Z","timestamp":1643304362000},"page":"045005","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Spatiotemporal optimisation of prostate intensity modulated proton therapy (IMPT) treatments"],"prefix":"10.1088","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4755-1638","authenticated-orcid":true,"given":"L","family":"Manganaro","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital (MGH), Massachusetts,"},{"name":"Harvard Medical School, Massachusetts,"},{"name":"Universit\u00e0 degli studi di Torino (UniTO)"},{"name":"Istituto Nazionale di Fisica Nucleare (INFN) Sezione di Torino"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Attili","sequence":"additional","affiliation":[{"name":"Istituto Nazionale di Fisica Nucleare (INFN) Sezione di Torino"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Bortfeld","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital (MGH), Massachusetts,"},{"name":"Harvard Medical School, Massachusetts,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Paganetti","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital (MGH), Massachusetts,"},{"name":"Harvard Medical School, Massachusetts,"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"266","published-online":{"date-parts":[[2022,2,10]]},"reference":[{"key":"pmbac4fa2bib1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1007\/s11912-017-0584-7","type":"journal-article","article-title":"The role of hypofractionated radiotherapy in prostate cancer","volume":"19","author":"Benjamin","year":"2017","journal-title":"Curr. Oncol. Rep."},{"key":"pmbac4fa2bib2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/s0360-3016(01)02664-5","type":"journal-article","article-title":"Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha\/beta ratio), similar to late-responding normal tissue","volume":"52","author":"Brenner","year":"2002","journal-title":"Int. J. Radiat. Oncol.*Biol.*Phys."},{"key":"pmbac4fa2bib3","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.ijrobp.2016.07.033","type":"journal-article","article-title":"The price of target dose uniformity","volume":"96","author":"Craft","year":"2016","journal-title":"Int. J. Radiat. Oncol.*Biol.*Phys."},{"key":"pmbac4fa2bib4","author":"Efron","year":"1994","edition":"Ist edn","type":"book"},{"key":"pmbac4fa2bib5","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1259\/bjr\/31372149","type":"journal-article","article-title":"21 years of biologically effective dose","volume":"83","author":"Fowler","year":"2010","journal-title":"Br. J. Radiol."},{"key":"pmbac4fa2bib6","doi-asserted-by":"publisher","first-page":"2988","DOI":"10.1002\/mp.13593","type":"journal-article","article-title":"Robust spatiotemporal fractionation schemes in the presence of patient setup uncertainty","volume":"46","author":"Gaddy","year":"2019","journal-title":"Med. Phys."},{"key":"pmbac4fa2bib7","doi-asserted-by":"publisher","DOI":"10.1088\/1361-6560\/aa9975","type":"journal-article","article-title":"Optimization of spatiotemporally fractionated radiotherapy treatments with bounds on the achievable benefit","volume":"63","author":"Gaddy","year":"2018","journal-title":"Phys. Med. Biol."},{"key":"pmbac4fa2bib8","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1186\/s13014-014-0275-6","type":"journal-article","article-title":"Hypofractionated radiotherapy for prostate cancer","volume":"9","author":"Hegemann","year":"2014","journal-title":"Radiat. Oncol."},{"key":"pmbac4fa2bib9","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1016\/j.ijrobp.2010.12.040","type":"journal-article","article-title":"Later outcomes and alpha\/beta estimate from hypofractionated conformal three-dimensional radiotherapy versus standard fractionation for localized prostate cancer","volume":"82","author":"Leborgne","year":"2012","journal-title":"Int. J. Radiat. Oncol.*Biol.*Phys."},{"key":"pmbac4fa2bib10","doi-asserted-by":"publisher","DOI":"10.1118\/1.4892601","type":"journal-article","article-title":"The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions","volume":"41","author":"Liebl","year":"2014","journal-title":"Med. Phys."},{"key":"pmbac4fa2bib11","article-title":"Dose delivery time structure effects in particle therapy: development of a time-resolved microdosimetric-kinetic model and implementation of spatiotemporal treatment plan optimisation","author":"Manganaro","year":"2019","type":"other"},{"key":"pmbac4fa2bib12","doi-asserted-by":"publisher","first-page":"S69","DOI":"10.1016\/S0167-8140(16)30141-4","type":"journal-article","article-title":"Investigation of the use of inhomogeneous fractional dose distributions in IMPT to improve the therapeutic index","volume":"118","author":"Manganaro","year":"2016","journal-title":"Radiother. Oncol."},{"key":"pmbac4fa2bib13","doi-asserted-by":"publisher","first-page":"R419","DOI":"10.1088\/0031-9155\/59\/22\/R419","type":"journal-article","article-title":"Relative biological effectiveness (RBE) values for proton beam therapy. variations as a function of biological endpoint, dose, and linear energy transfer","volume":"59","author":"Paganetti","year":"2014","journal-title":"Phys. Med. Biol."},{"key":"pmbac4fa2bib14","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1088\/0031-9155\/61\/1\/183","type":"journal-article","article-title":"A novel algorithm for the calculation of physical and biological irradiation quantities in scanned ion beam therapy: the beamlet superposition approach","volume":"61","author":"Russo","year":"2016","journal-title":"Phys. Med. Biol."},{"key":"pmbac4fa2bib15","article-title":"Isotoxic dose escalation by increasing tumor dose variance","author":"Steneker","year":"2010","type":"book"},{"key":"pmbac4fa2bib16","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.ijrobp.2017.06.017","type":"journal-article","article-title":"Superiority in robustness of multifield optimization over single-field optimization for pencil-beam proton therapy for oropharynx carcinoma: An enhanced robustness analysis","volume":"99","author":"St\u00fctzer","year":"2017","journal-title":"Int. J. Radiat. Oncol.*Biol.*Phys."},{"key":"pmbac4fa2bib17","doi-asserted-by":"publisher","DOI":"10.1088\/1361-6560\/abbb75","type":"journal-article","article-title":"Probing spatiotemporal fractionation on the preclinical level","volume":"65","author":"Telarovic","year":"2020","journal-title":"Phys. Med. Biol."},{"key":"pmbac4fa2bib18","doi-asserted-by":"publisher","first-page":"2779","DOI":"10.1088\/0031-9155\/50\/12\/004","type":"journal-article","article-title":"Temporo-spatial IMRT optimization: concepts, implementation and initial results","volume":"50","author":"Trofimov","year":"2005","journal-title":"Phys. Med. Biol."},{"key":"pmbac4fa2bib19","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1016\/j.ijrobp.2016.02.001","type":"journal-article","article-title":"Spatiotemporal fractionation schemes for irradiating large cerebral arteriovenous malformations","volume":"95","author":"Unkelbach","year":"2016","journal-title":"Int. J. Radiat. Oncol.*Biol.*Phys."},{"key":"pmbac4fa2bib20","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1118\/1.4916684","type":"journal-article","article-title":"The emergence of nonuniform spatiotemporal fractionation schemes within the standard BED model","volume":"42","author":"Unkelbach","year":"2015","journal-title":"Med. Phys."},{"key":"pmbac4fa2bib21","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.radonc.2017.09.003","type":"journal-article","article-title":"Spatiotemporal fractionation schemes for liver stereotactic body radiotherapy","volume":"125","author":"Unkelbach","year":"2017","journal-title":"Radiother. Oncol."},{"key":"pmbac4fa2bib22","doi-asserted-by":"publisher","DOI":"10.1118\/1.4816658","type":"journal-article","article-title":"Simultaneous optimization of dose distributions and fractionation schemes in particle radiotherapy","volume":"40","author":"Unkelbach","year":"2013","journal-title":"Med. Phys."},{"key":"pmbac4fa2bib23","doi-asserted-by":"publisher","DOI":"10.1118\/1.4801897","type":"journal-article","article-title":"Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions","volume":"40","author":"Zeng","year":"2013","journal-title":"Med. Phys."}],"container-title":["Physics in Medicine &amp; Biology"],"original-title":[],"link":[{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2","content-type":"text\/html","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"similarity-checking"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:00:54Z","timestamp":1778778054000},"score":1,"resource":{"primary":{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ac4fa2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,10]]},"references-count":23,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2,10]]},"published-print":{"date-parts":[[2022,2,21]]}},"URL":"https:\/\/doi.org\/10.1088\/1361-6560\/ac4fa2","relation":{},"ISSN":["0031-9155","1361-6560"],"issn-type":[{"value":"0031-9155","type":"print"},{"value":"1361-6560","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,10]]},"assertion":[{"value":"Spatiotemporal optimisation of prostate intensity modulated proton therapy (IMPT) treatments","name":"article_title","label":"Article Title"},{"value":"Physics in Medicine & Biology","name":"journal_title","label":"Journal Title"},{"value":"paper","name":"article_type","label":"Article Type"},{"value":"\u00a9 2022 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.","name":"copyright_information","label":"Copyright Information"},{"value":"2021-11-09","name":"date_received","label":"Date Received","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2022-01-27","name":"date_accepted","label":"Date Accepted","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2022-02-10","name":"date_epub","label":"Online publication date","group":{"name":"publication_dates","label":"Publication dates"}}]}}