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Neurocognition and mean radiotherapy dose to vulnerable brain structures: new organs at risk?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects.
Uppsala Univ Hosp, Dept Hematol & Oncol, Uppsala, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
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2023 (English)In: Radiation Oncology, E-ISSN 1748-717X, Vol. 18, article id 132Article in journal (Refereed) Published
Abstract [en]

Background: Children with brain tumors are at high risk of neurocognitive decline after radiotherapy (RT). However, there is a lack of studies on how RT doses to organs at risk (OARs) impacts neurocognition. The aim of this study was to examine dose-risk relationships for mean RT dose to different brain structures important for neurocognitive networks. We explored previously established OARs and potentially new OARs.

Methods: A sample of 44 pediatric brain tumor survivors who had received proton and/or photon RT were included. Correlations between mean RT doses to OARs and IQ were analyzed. Previously established OARs were cochleae, optic chiasm, optic nerve, pituitary gland, hypothalamus, hippocampus and pons. Potential new OARs for RT-induced neurocognitive decline were cerebellum, vermis and thalamus.

Results: Mean RT dose to different OARs correlated with several IQ subtests. Higher mean RT dose to cochleae, optic nerve, cerebellum, vermis and pons was correlated with lower performance on particularly full-scale IQ (FIQ), Perceptual Reasoning (PRI), Working Memory (WMI) and Processing Speed Index (PSI). Higher mean RT dose to hippocampus correlated with lower performance on processing speed and working memory. For those receiving whole brain RT (WBRT), higher mean RT dose to the pituitary gland correlated with lower performance on working memory.

Conclusion: A high dose-risk correlation was found between IQ subtests and mean RT dose in established and potential new OARs. Thus, in the lack of validated dose constraints for vulnerable brain structures, a parsimonious approach in RT planning should be considered to preserve neurocognitive networks.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023. Vol. 18, article id 132
Keywords [en]
Pediatric brain tumor, Neurocognition, Radiotherapy doses, Organs at risk
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-510636DOI: 10.1186/s13014-023-02324-2ISI: 001048687800001PubMedID: 37568180OAI: oai:DiVA.org:uu-510636DiVA, id: diva2:1794014
Funder
Uppsala UniversitySwedish Childhood Cancer Foundation, PR2018-0042Swedish Childhood Cancer Foundation, TJ2018-0046Available from: 2023-09-04 Created: 2023-09-04 Last updated: 2026-01-27Bibliographically approved
In thesis
1. Pediatric Brain Tumor Survivors after Radiotherapy: Long-Term Neurocognitive Outcomes, Oculomotor Function, and Arousal
Open this publication in new window or tab >>Pediatric Brain Tumor Survivors after Radiotherapy: Long-Term Neurocognitive Outcomes, Oculomotor Function, and Arousal
2026 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pediatric brain tumor survivors (PBTS) are at increased risk of long-term neurocognitive late effects, particularly following radiotherapy (RT), with processing speed being one of the domains most commonly impaired. The developing brain is particularly vulnerable to RT, and long-term neuropsychological follow-up is therefore recommended. Most studies addressing this topic have primarily focused on prescribed dose, planning target volume (PTV), and whole-brain radiotherapy (WBRT) dose, whereas the association between mean radiation dose to organs at risk (OAR) and neurocognitive outcomes remains insufficiently explored. Although neurocognitive functioning is routinely assessed through standardized neuropsychological testing, eye-tracking measures—including eye movements and pupillometry—may serve as sensitive complementary indicators of attention, processing speed, arousal, and executive functioning.

This thesis investigated neurocognitive outcomes in relation to different RT dose measures, including PTV dose and mean RT dose to established and potential new OAR, using both neuropsychological assessment and eye-tracking metrics. Additional clinical risk factors were also explored. Both retrospective and prospective studies of PBTS treated with RT between 2003-2015 were included. Neurocognitive function was assessed before, after, and 8–20 years post-RT. Long-term outcomes were related to RT dose parameters, and eye-tracking and fatigue were compared with age-matched controls.

Neurocognitive impairments were present prior to RT and became more prevalent with increasing time after treatment. Higher PTV dose was associated with lower working memory performance. Higher mean RT doses to several established and potential new OAR were associated with lower intelligence quotient and processing speed, as well as impaired oculomotor performance, altered pupil responses, and higher fatigue. WBRT and larger tumor size were also linked to poorer outcomes. 

In conclusion, the findings from this thesis show that PBTS are at elevated risk of long-term neurocognitive, oculomotor, and arousal-related difficulties following RT. Mean RT dose to OAR provides valuable information on radiation-related impairment beyond PTV dose. These findings underscore the need of structured neuropsychological follow-up. They further demonstrate the value of mean RT dose metrics an eye-tracking measures in evaluating radiation-related neurocognitive outcomes and guiding targeted treatment and rehabilitation strategies.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2026. p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2229
Keywords
Pediatric brain tumor, radiotherapy, organs at risk, mean dose, neurocognition, processing speed, fatigue, eye-tracking, pupillometry
National Category
Pediatrics Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-577656 (URN)978-91-513-2726-6 (ISBN)
Public defence
2026-03-13, Universitetshuset, sal IV, Biskopsgatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Funder
Swedish Childhood Cancer Foundation, PR2013-0062,PR2018-0042, TJ2018-0046
Available from: 2026-02-19 Created: 2026-01-27 Last updated: 2026-02-20

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Söderström, HelenaMartinsson, UllaIsacsson, UlfBrocki, Karin C.Ljungman, Gustaf

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