Comparative proton and photon treatment plans in children treated for neuroblastoma
DOI:
https://doi.org/10.2340/1651-226X.2025.43865Keywords:
neuroblastoma, radiotherapy, protons, photons, adverse effects, Paediatric cancerAbstract
Background and purpose: Neuroblastoma is the most common extracranial solid tumour in children. Radiotherapy is commonly part of the multimodal treatment for high-risk patients. The aim of this study is to analyse doses to organs at risk (OAR) in comparative proton and photon treatment plans for children treated for neuroblastoma and report side effects.
Patient/material and methods: All children in Sweden treated with curative intent radiotherapy for abdominal neuroblastoma in 2017–2024 with comparative proton and photon treatment plans were retrospectively identified through a national registry (RADTOX), where data on side effects were collected. Doses to OAR were compared in each patient’s proton and photon treatment plans.
Results: A total of 30 children with a median age of 45 months (range 11–150) were included. The low-dose spread was significantly lower in the proton compared to the photon treatment plans measured as Body V5Gy and V10Gy (p < 0.001). Furthermore, the mean doses to the bowel bag, kidneys, liver, pancreas, and spleen were significantly lower in the proton plans. The median follow-up was 14 months (1–61), and the 2-year overall survival was 75.3%. While acute radiotherapy related grade ≥ 2 side effects were experienced by 12 patients (40%), late side effects were experienced by 7 patients (13%). The most common side effects were haematological and from the upper gastrointestinal tract.
Interpretation: In selected cases, proton treatment can offer lower doses to OAR and less low-dose exposure compared to photon treatment in children treated for abdominal neuroblastoma. Whether this translates into a clinical benefit is currently unclear and should be evaluated in future studies.
Downloads
References
Barncancerregistret S. Årsrapport 2023 Svenska Barncancerregistret [Internet]. 2023. Available from: https://cceg.ki.se/documents/Arsrapport_SBCR_2023.pdf. [Cited date: 22 April 2025]
Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, et al. Neuroblastoma. Nat Rev Dis Primers. 2016;2:16078.
https://doi.org/10.1038/nrdp.2016.78 DOI: https://doi.org/10.1038/nrdp.2016.78
Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F, et al. International incidence of childhood cancer, 2001–10: a population-based registry study. Lancet Oncol. 2017;18(6):719–31.
https://doi.org/10.1016/S1470-2045(17)30186-9 DOI: https://doi.org/10.1016/S1470-2045(17)30186-9
Chung C, Boterberg T, Lucas J, Panoff J, Valteau-Couanet D, Hero B, et al. Neuroblastoma. Pediatr Blood Cancer. 2021;68(Suppl 2):e28473.
https://doi.org/10.1002/pbc.28473 DOI: https://doi.org/10.1002/pbc.28473
Laverdiere C, Liu Q, Yasui Y, Nathan PC, Gurney JG, Stovall M, et al. Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2009;101(16):1131–40.
https://doi.org/10.1093/jnci/djp230 DOI: https://doi.org/10.1093/jnci/djp230
Casey DL, Vogelius IR, Brodin NP, Roberts KB, Avanzo M, Moni J, et al. Risk of subsequent neoplasms in childhood cancer survivors after radiation therapy: a comprehensive PENTEC review. Int J Radiat Oncol Biol Phys. 2023.
https://doi.org/10.1016/j.ijrobp.2023.07.025 DOI: https://doi.org/10.1016/j.ijrobp.2023.07.025
Constine LS, Marks LB, Milano MT, Ronckers CM, Jackson A, Hudson MM, et al. A user’s guide and summary of pediatric normal tissue effects in the clinic (PENTEC): radiation dose-volume response for adverse effects after childhood cancer therapy and future directions. Int J Radiat Oncol Biol Phys. 2024;119(2):321–37.
https://doi.org/10.1016/j.ijrobp.2023.09.005 DOI: https://doi.org/10.1016/j.ijrobp.2023.09.005
Greenberger BA, Yock TI. The role of proton therapy in pediatric malignancies: recent advances and future directions. Semin Oncol. 2020;47(1):8–22.
https://doi.org/10.1053/j.seminoncol.2020.02.002 DOI: https://doi.org/10.1053/j.seminoncol.2020.02.002
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341–6.
https://doi.org/10.1016/0360-3016(95)00060-C DOI: https://doi.org/10.1016/0360-3016(95)00060-C
Ladenstein R, Potschger U, Pearson ADJ, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18(4):500–14.
https://doi.org/10.1016/S1470-2045(17)30070-0 DOI: https://doi.org/10.1016/S1470-2045(17)30070-0
von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495–9.
https://doi.org/10.1016/j.ijsu.2014.07.013 DOI: https://doi.org/10.1016/j.ijsu.2014.07.013
Mirandola A, Colombo F, Cavagnetto F, Cavallo A, Gusinu M, Molinelli S, et al. Dosimetric comparison between proton and photon radiation therapies for pediatric neuroblastoma. Int J Part Ther. 2024;12:100100.
https://doi.org/10.1016/j.ijpt.2024.100100 DOI: https://doi.org/10.1016/j.ijpt.2024.100100
Poppe MM, Tai A, Li XA, Miften M, Olch A, Marks LB, et al. Kidney disease in childhood cancer survivors treated with radiation therapy: a comprehensive PENTEC genitourinary review. Int J Radiat Oncol Biol Phys. 2024;119(2):560–74.
https://doi.org/10.1016/j.ijrobp.2023.02.040 DOI: https://doi.org/10.1016/j.ijrobp.2023.02.040
Hall MD, Howell RM, Jackson A, Owens CA, Hernandez S, Castellino SM, et al. Liver late effects in childhood cancer survivors treated with radiation therapy: a PENTEC comprehensive review. Int J Radiat Oncol Biol Phys. 2024;119(2):575–87.
https://doi.org/10.1016/j.ijrobp.2023.06.002 DOI: https://doi.org/10.1016/j.ijrobp.2023.06.002
Meacham LR, Sklar CA, Li S, Liu Q, Gimpel N, Yasui Y, et al. Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the childhood cancer survivor study. Arch Intern Med. 2009;169(15):1381–8.
https://doi.org/10.1001/archinternmed.2009.209 DOI: https://doi.org/10.1001/archinternmed.2009.209
Hessels AC, Langendijk JA, Gawryszuk A, Heersters M, van der Salm NLM, Tissing WJE, et al. Review – late toxicity of abdominal and pelvic radiotherapy for childhood cancer. Radiother Oncol. 2022;170:27–36.
https://doi.org/10.1016/j.radonc.2022.02.029 DOI: https://doi.org/10.1016/j.radonc.2022.02.029
Arunagiri N, Kelly SM, Dunlea C, Dixon O, Cantwell J, Bhudia P, et al. The spleen as an organ at risk in paediatric radiotherapy: a SIOP-Europe Radiation Oncology Working Group report. Eur J Cancer. 2021;143:1–10.
https://doi.org/10.1016/j.ejca.2020.10.025 DOI: https://doi.org/10.1016/j.ejca.2020.10.025
Friedman DN, Henderson TO. Late effects and survivorship issues in patients with neuroblastoma. Children (Basel). 2018;5(8):107.
https://doi.org/10.3390/children5080107 DOI: https://doi.org/10.3390/children5080107
Yeung V, Gabriel M, Padhye BD. Late effects and treatment related morbidity associated with treatment of neuroblastoma patients in a tertiary paediatric centre. Cancer Rep (Hoboken). 2023;6(3):e1738.
https://doi.org/10.1002/cnr2.1738 DOI: https://doi.org/10.1002/cnr2.1738
Tan J, McLoone JK, Wakefield CE, Nassar N, Cohn RJ, Signorelli C. Neuroblastoma survivors’ self-reported late effects, quality of life, health-care use, and risk perceptions. Palliat Support Care. 2024;22(2):296–305.
https://doi.org/10.1017/S1478951523000615 DOI: https://doi.org/10.1017/S1478951523000615
Taylor S, Lim P, Ahmad R, Alhadi A, Harris W, Rompokos V, et al. Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma. Phys Imaging Radiat Oncol. 2021;19:45–52.
https://doi.org/10.1016/j.phro.2021.06.003 DOI: https://doi.org/10.1016/j.phro.2021.06.003
Jazmati D, Butzer S, Hero B, Ahmad Khalil D, Merta J, Baumer C, et al. Proton beam therapy for children with neuroblastoma: experiences from the prospective KiProReg registry. Front Oncol. 2020;10:617506.
https://doi.org/10.3389/fonc.2020.617506 DOI: https://doi.org/10.3389/fonc.2020.617506
Hill-Kayser CE, Tochner Z, Li Y, Kurtz G, Lustig RA, James P, et al. Outcomes after proton therapy for treatment of pediatric high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2019;104(2):401–8.
https://doi.org/10.1016/j.ijrobp.2019.01.095 DOI: https://doi.org/10.1016/j.ijrobp.2019.01.095
Flaadt T, Rehm J, Simon T, Hero B, Ladenstein RL, Lode HN, et al. Long-term outcomes and quality of life of high-risk neuroblastoma patients treated with a multimodal treatment including anti-GD2 immunotherapy: a retrospective cohort study. Cancers (Basel). 2025;17(1):149.
https://doi.org/10.3390/cancers17010149 DOI: https://doi.org/10.3390/cancers17010149
Hoeben BA, Carrie C, Timmermann B, Mandeville HC, Gandola L, Dieckmann K, et al. Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group. Lancet Oncol. 2019;20(3):e155–66.
https://doi.org/10.1016/S1470-2045(19)30034-8 DOI: https://doi.org/10.1016/S1470-2045(19)30034-8
Lim PS, Pica A, Hrbacek J, Bachtiary B, Walser M, Lomax AJ, et al. Pencil beam scanning proton therapy for paediatric neuroblastoma with motion mitigation strategy for moving target volumes. Clin Oncol (R Coll Radiol). 2020;32(7):467–76.
https://doi.org/10.1016/j.clon.2020.02.002 DOI: https://doi.org/10.1016/j.clon.2020.02.002
Samim A, Littooij AS, Peters M, de Keizer B, van der Steeg AFW, Fajardo RD, et al. Locoregional control in high-risk neuroblastoma using highly-conformal image-guided radiotherapy, with reduced margins and a boost dose for residual lesions. Radiother Oncol. 2025;202:110604.
https://doi.org/10.1016/j.radonc.2024.110604 DOI: https://doi.org/10.1016/j.radonc.2024.110604
Additional Files
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2025 Anna Embring, Ingrid Kristensen, Martin P. Nilsson, Jacob Engellau, Malin Blomstrand, Charlotta Fröjd, Måns Agrup, Anna Flejmer, Anna-Maja Svärd, Anna Asklid

This work is licensed under a Creative Commons Attribution 4.0 International License.
