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Reducing the dose delivered to major intracranial blood vessels in brain radiotherapy using spot-scanning proton arc therapy.

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Title: Reducing the dose delivered to major intracranial blood vessels in brain radiotherapy using spot-scanning proton arc therapy.
Authors: Liu P; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA.; Medical Physics, School of Medicine, Wayne State University, Detroit, Michigan, USA., Tattenberg S; Laurentian University, Sudbury, Ontario, Canada.; TRIUMF, Vancouver, British Columbia, Canada., Cong X; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA., Chen PY; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA., Ding X; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA.; Corewellhealth William Beaumont University Hospital, Royal Oak, USA., Hammi A; Technical University of Dortmund, Dortmund, Germany.
Source: Journal of applied clinical medical physics [J Appl Clin Med Phys] 2026 Sep; Vol. 27 (9), pp. e70780.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Wiley on behalf of American Association of Physicists in Medicine Country of Publication: United States NLM ID: 101089176 Publication Model: Print Cited Medium: Internet ISSN: 1526-9914 (Electronic) Linking ISSN: 15269914 NLM ISO Abbreviation: J Appl Clin Med Phys Subsets: MEDLINE
Imprint Name(s): Publication: 2017- : Malden, MA : Wiley on behalf of American Association of Physicists in Medicine
Original Publication: Reston, VA : American College of Medical Physics, c2000-
MeSH Terms: Proton Therapy*/methods , Radiotherapy Planning, Computer-Assisted*/methods , Brain Neoplasms*/radiotherapy , Glioblastoma*/radiotherapy , Radiotherapy, Intensity-Modulated*/methods , Organs at Risk*/radiation effects , Blood Vessels*/radiation effects, Humans ; Radiotherapy Dosage ; Linear Energy Transfer ; Prognosis
Abstract: Background: Glioblastoma (GBM) patients have poor clinical prognoses, which may partially be explainable by correlations between radiation-induced killing of circulating blood cells (CBCs) and worse clinical outcomes. Proton radiotherapy is currently delivered via intensity-modulated proton therapy (IMPT), for which the target is irradiated from a few different angles. Spot-scanning proton arc therapy (SPArc), for which the target is irradiated from arc trajectories, is associated with dosimetric benefits, and the first SPArc treatments of head-and-neck cancer patients have now been reported. However, since SPArc increases the low-dose bath, concerns have been raised about potentially higher killing of CBC.
Purpose: This study aims to evaluate and compare blood vessel dose and dose-averaged linear energy transfer (LETd) distributions between IMPT and SPArc, with and without blood vessel sparing, in patients with GBM.
Methods: For 10 GBM patients, patient-specific cerebrovasculature models were developed, and IMPT and SPArc treatment plans were created according to current clinical standards (IMPTConv and SPArcConv) and with sparing of delineated blood vessels (IMPTSparing and SPArcSparing) for every patient. Dose and LETd distributions were then compared across all treatment plans.
Results: While treatment plans maintained comparable target coverage, blood vessel sparing significantly reduced the mean dose to delineated blood vessels, with values of 6.5 ± 2.9 Gy(RBE) for IMPTConv, 5.3 ± 2.3 Gy(RBE) for IMPTSparing, 5.6 ± 2.2 Gy(RBE) for SPArcConv, and 3.8 ± 1.6 Gy(RBE) for SPArcSparing. The dose within the 10% of blood vessel volume receiving the highest dose (D10%) was 29.5 ± 13.4 Gy(RBE) for IMPTConv, 23.2 ± 11.0 Gy(RBE) for IMPTSparing, 24.5 ± 12.6 Gy(RBE) for SPArcConv, and 13.4 ± 8.7 Gy(RBE) for SPArcSparing.
Conclusions: Implementation of blood vessel sparing resulted in successful reductions in blood vessel dose metrics while preserving target coverage, and SPArc further reduced blood vessel dose metrics compared with IMPT, with the potential to reduce radiation-induced lymphopenia and improve clinical outcomes.
(© 2026 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)
References: Oncotarget. 2017 Dec 14;8(69):114268-114280. (PMID: 29371985)
J Neurooncol. 2019 Jun;143(2):321-328. (PMID: 30982199)
Med Phys. 2013 May;40(5):051711. (PMID: 23635259)
J Appl Clin Med Phys. 2026 Jan;27(1):e70341. (PMID: 41457830)
Phys Imaging Radiat Oncol. 2023 Aug 10;27:100480. (PMID: 37655121)
Front Oncol. 2023 Aug 03;13:1201500. (PMID: 37601664)
Radiat Oncol. 2022 May 7;17(1):87. (PMID: 35525993)
Phys Med Biol. 2023 Jul 12;68(14):. (PMID: 37434549)
Radiother Oncol. 2024 Oct;199:110421. (PMID: 38997093)
Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):1107-1116. (PMID: 27869083)
Phys Med Biol. 2024 Aug 21;69(17):. (PMID: 39084628)
Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):1000-1007. (PMID: 26025775)
Int J Part Ther. 2025 Apr 20;16:100749. (PMID: 40474940)
Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. (PMID: 33293629)
PLoS One. 2016 Mar 31;11(3):e0152477. (PMID: 27030987)
J Neurooncol. 2012 Apr;107(2):359-64. (PMID: 22045118)
Radiother Oncol. 2019 Sep;138:166-172. (PMID: 31302391)
Phys Med Biol. 2024 Jan 05;69(2):. (PMID: 38081067)
Jpn J Radiol. 2023 Oct;41(10):1062-1071. (PMID: 37071249)
Phys Med. 2024 Oct;126:104816. (PMID: 39326286)
Radiother Oncol. 2022 Dec;177:81-94. (PMID: 36334694)
Clin Cancer Res. 2011 Aug 15;17(16):5473-80. (PMID: 21737504)
Phys Med Biol. 2007 May 21;52(10):2755-73. (PMID: 17473350)
Phys Med Biol. 2012 Jun 7;57(11):R99-117. (PMID: 22571913)
J Natl Compr Canc Netw. 2015 Oct;13(10):1225-31. (PMID: 26483062)
Med Phys. 2025 May;52(5):3191-3203. (PMID: 39939287)
Grant Information: R01 CA301448 United States CA NCI NIH HHS; R01CA301448 United States CA NCI NIH HHS
Contributed Indexing: Keywords: blood dose; glioblastoma; lymphopenia; proton arc therapy; proton therapy
Entry Date(s): Date Created: 20260910 Date Completed: 20260910 Latest Revision: 20260915
Update Code: 20260915
PubMed Central ID: PMC13559178
DOI: 10.1002/acm2.70780
PMID: 42717666
Database: MEDLINE
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  Data: Reducing the dose delivered to major intracranial blood vessels in brain radiotherapy using spot-scanning proton arc therapy.
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  Data: <searchLink fieldCode="AU" term="%22Liu+P%22">Liu P</searchLink>; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA.; Medical Physics, School of Medicine, Wayne State University, Detroit, Michigan, USA.<br /><searchLink fieldCode="AU" term="%22Tattenberg+S%22">Tattenberg S</searchLink>; Laurentian University, Sudbury, Ontario, Canada.; TRIUMF, Vancouver, British Columbia, Canada.<br /><searchLink fieldCode="AU" term="%22Cong+X%22">Cong X</searchLink>; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA.<br /><searchLink fieldCode="AU" term="%22Chen+PY%22">Chen PY</searchLink>; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA.<br /><searchLink fieldCode="AU" term="%22Ding+X%22">Ding X</searchLink>; Department of Radiation Oncology, William Beaumont University Hospital, Corewell Health, Royal Oak, Michigan, USA.; Corewellhealth William Beaumont University Hospital, Royal Oak, USA.<br /><searchLink fieldCode="AU" term="%22Hammi+A%22">Hammi A</searchLink>; Technical University of Dortmund, Dortmund, Germany.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Wiley+on+behalf+of+American+Association+of+Physicists+in+Medicine%22">Wiley on behalf of American Association of Physicists in Medicine </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>101089176 <i>Publication Model: </i>Print <i>Cited Medium: </i>Internet <i>ISSN: </i>1526-9914 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2215269914%22">15269914 </searchLink><i>NLM ISO Abbreviation: </i>J Appl Clin Med Phys <i>Subsets: </i>MEDLINE
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  Data: <i>Publication</i>: 2017- : Malden, MA : Wiley on behalf of American Association of Physicists in Medicine<br /><i>Original Publication</i>: Reston, VA : American College of Medical Physics, c2000-
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  Data: <searchLink fieldCode="MM" term="%22Proton+Therapy%22">Proton Therapy*</searchLink>/<searchLink fieldCode="MM" term="%22Proton+Therapy+methods%22">methods</searchLink> <br /><searchLink fieldCode="MM" term="%22Radiotherapy+Planning%2C+Computer-Assisted%22">Radiotherapy Planning, Computer-Assisted*</searchLink>/<searchLink fieldCode="MM" term="%22Radiotherapy+Planning%2C+Computer-Assisted+methods%22">methods</searchLink> <br /><searchLink fieldCode="MM" term="%22Brain+Neoplasms%22">Brain Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+Neoplasms+radiotherapy%22">radiotherapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Glioblastoma%22">Glioblastoma*</searchLink>/<searchLink fieldCode="MM" term="%22Glioblastoma+radiotherapy%22">radiotherapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Radiotherapy%2C+Intensity-Modulated%22">Radiotherapy, Intensity-Modulated*</searchLink>/<searchLink fieldCode="MM" term="%22Radiotherapy%2C+Intensity-Modulated+methods%22">methods</searchLink> <br /><searchLink fieldCode="MM" term="%22Organs+at+Risk%22">Organs at Risk*</searchLink>/<searchLink fieldCode="MM" term="%22Organs+at+Risk+radiation+effects%22">radiation effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Blood+Vessels%22">Blood Vessels*</searchLink>/<searchLink fieldCode="MM" term="%22Blood+Vessels+radiation+effects%22">radiation effects</searchLink><br /><searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Radiotherapy+Dosage%22">Radiotherapy Dosage</searchLink> ; <searchLink fieldCode="MH" term="%22Linear+Energy+Transfer%22">Linear Energy Transfer</searchLink> ; <searchLink fieldCode="MH" term="%22Prognosis%22">Prognosis</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Background: Glioblastoma (GBM) patients have poor clinical prognoses, which may partially be explainable by correlations between radiation-induced killing of circulating blood cells (CBCs) and worse clinical outcomes. Proton radiotherapy is currently delivered via intensity-modulated proton therapy (IMPT), for which the target is irradiated from a few different angles. Spot-scanning proton arc therapy (SPArc), for which the target is irradiated from arc trajectories, is associated with dosimetric benefits, and the first SPArc treatments of head-and-neck cancer patients have now been reported. However, since SPArc increases the low-dose bath, concerns have been raised about potentially higher killing of CBC.<br />Purpose: This study aims to evaluate and compare blood vessel dose and dose-averaged linear energy transfer (LET<subscript>d</subscript>) distributions between IMPT and SPArc, with and without blood vessel sparing, in patients with GBM.<br />Methods: For 10 GBM patients, patient-specific cerebrovasculature models were developed, and IMPT and SPArc treatment plans were created according to current clinical standards (IMPT<subscript>Conv</subscript> and SPArc<subscript>Conv</subscript>) and with sparing of delineated blood vessels (IMPT<subscript>Sparing</subscript> and SPArc<subscript>Sparing</subscript>) for every patient. Dose and LET<subscript>d</subscript> distributions were then compared across all treatment plans.<br />Results: While treatment plans maintained comparable target coverage, blood vessel sparing significantly reduced the mean dose to delineated blood vessels, with values of 6.5 ± 2.9 Gy(RBE) for IMPT<subscript>Conv</subscript>, 5.3 ± 2.3 Gy(RBE) for IMPT<subscript>Sparing</subscript>, 5.6 ± 2.2 Gy(RBE) for SPArc<subscript>Conv</subscript>, and 3.8 ± 1.6 Gy(RBE) for SPArc<subscript>Sparing</subscript>. The dose within the 10% of blood vessel volume receiving the highest dose (D<subscript>10%</subscript>) was 29.5 ± 13.4 Gy(RBE) for IMPT<subscript>Conv</subscript>, 23.2 ± 11.0 Gy(RBE) for IMPT<subscript>Sparing</subscript>, 24.5 ± 12.6 Gy(RBE) for SPArc<subscript>Conv</subscript>, and 13.4 ± 8.7 Gy(RBE) for SPArc<subscript>Sparing</subscript>.<br />Conclusions: Implementation of blood vessel sparing resulted in successful reductions in blood vessel dose metrics while preserving target coverage, and SPArc further reduced blood vessel dose metrics compared with IMPT, with the potential to reduce radiation-induced lymphopenia and improve clinical outcomes.<br /> (© 2026 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)
– Name: Ref
  Label: References
  Group: RefInfo
  Data: Oncotarget. 2017 Dec 14;8(69):114268-114280. (PMID: <searchLink fieldCode="PM" term="%2229371985%22">29371985)</searchLink><br />J Neurooncol. 2019 Jun;143(2):321-328. (PMID: <searchLink fieldCode="PM" term="%2230982199%22">30982199)</searchLink><br />Med Phys. 2013 May;40(5):051711. (PMID: <searchLink fieldCode="PM" term="%2223635259%22">23635259)</searchLink><br />J Appl Clin Med Phys. 2026 Jan;27(1):e70341. (PMID: <searchLink fieldCode="PM" term="%2241457830%22">41457830)</searchLink><br />Phys Imaging Radiat Oncol. 2023 Aug 10;27:100480. (PMID: <searchLink fieldCode="PM" term="%2237655121%22">37655121)</searchLink><br />Front Oncol. 2023 Aug 03;13:1201500. (PMID: <searchLink fieldCode="PM" term="%2237601664%22">37601664)</searchLink><br />Radiat Oncol. 2022 May 7;17(1):87. (PMID: <searchLink fieldCode="PM" term="%2235525993%22">35525993)</searchLink><br />Phys Med Biol. 2023 Jul 12;68(14):. (PMID: <searchLink fieldCode="PM" term="%2237434549%22">37434549)</searchLink><br />Radiother Oncol. 2024 Oct;199:110421. (PMID: <searchLink fieldCode="PM" term="%2238997093%22">38997093)</searchLink><br />Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):1107-1116. (PMID: <searchLink fieldCode="PM" term="%2227869083%22">27869083)</searchLink><br />Phys Med Biol. 2024 Aug 21;69(17):. (PMID: <searchLink fieldCode="PM" term="%2239084628%22">39084628)</searchLink><br />Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):1000-1007. (PMID: <searchLink fieldCode="PM" term="%2226025775%22">26025775)</searchLink><br />Int J Part Ther. 2025 Apr 20;16:100749. (PMID: <searchLink fieldCode="PM" term="%2240474940%22">40474940)</searchLink><br />Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. (PMID: <searchLink fieldCode="PM" term="%2233293629%22">33293629)</searchLink><br />PLoS One. 2016 Mar 31;11(3):e0152477. (PMID: <searchLink fieldCode="PM" term="%2227030987%22">27030987)</searchLink><br />J Neurooncol. 2012 Apr;107(2):359-64. (PMID: <searchLink fieldCode="PM" term="%2222045118%22">22045118)</searchLink><br />Radiother Oncol. 2019 Sep;138:166-172. (PMID: <searchLink fieldCode="PM" term="%2231302391%22">31302391)</searchLink><br />Phys Med Biol. 2024 Jan 05;69(2):. (PMID: <searchLink fieldCode="PM" term="%2238081067%22">38081067)</searchLink><br />Jpn J Radiol. 2023 Oct;41(10):1062-1071. (PMID: <searchLink fieldCode="PM" term="%2237071249%22">37071249)</searchLink><br />Phys Med. 2024 Oct;126:104816. (PMID: <searchLink fieldCode="PM" term="%2239326286%22">39326286)</searchLink><br />Radiother Oncol. 2022 Dec;177:81-94. (PMID: <searchLink fieldCode="PM" term="%2236334694%22">36334694)</searchLink><br />Clin Cancer Res. 2011 Aug 15;17(16):5473-80. (PMID: <searchLink fieldCode="PM" term="%2221737504%22">21737504)</searchLink><br />Phys Med Biol. 2007 May 21;52(10):2755-73. (PMID: <searchLink fieldCode="PM" term="%2217473350%22">17473350)</searchLink><br />Phys Med Biol. 2012 Jun 7;57(11):R99-117. (PMID: <searchLink fieldCode="PM" term="%2222571913%22">22571913)</searchLink><br />J Natl Compr Canc Netw. 2015 Oct;13(10):1225-31. (PMID: <searchLink fieldCode="PM" term="%2226483062%22">26483062)</searchLink><br />Med Phys. 2025 May;52(5):3191-3203. (PMID: <searchLink fieldCode="PM" term="%2239939287%22">39939287)</searchLink>
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  Data: R01 CA301448 United States CA NCI NIH HHS; R01CA301448 United States CA NCI NIH HHS
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  Data: <i>Keywords: </i>blood dose; glioblastoma; lymphopenia; proton arc therapy; proton therapy
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        Type: general
      – SubjectFull: Radiotherapy Dosage
        Type: general
      – SubjectFull: Linear Energy Transfer
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      – SubjectFull: Blood Vessels radiation effects
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      – TitleFull: Reducing the dose delivered to major intracranial blood vessels in brain radiotherapy using spot-scanning proton arc therapy.
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