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Radiation-Induced Contrast Enhancement After Proton Therapy for Paediatric Brain Tumours: Association with Variable Relative Biological Effectiveness and Linear Energy Transfer
by
, , , , , , , , and
Julian Brack
1,2,3,
Valon Gllareva
4,
Bastian von Nettelbladt
1,2,3,5,
Eva Meixner
1,2,5,
Line Hoeltgen
1,2,5,
Laila Koenig
1,2,5,
Hanna Waldsperger
1,2,3,5,
Katharina Kozyra
1,2,3,5,
Habiba Sallem
2,3,
Alexander Neuholz
1,2,3,
Thomas Tessonnier
1,2,3,5,6,
Andrea Mairani
1,2,3,7,8,
Jürgen Debus
1,2,3,5,6,9,
Klaus Herfarth
1,2,3,5 and
Semi B. Harrabi
1,2,3,5,6,*
1
Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
2
Heidelberg Institute for Radiation Oncology (HIRO), 69120 Heidelberg, Germany
3
Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg University Hospital, 69120 Heidelberg, Germany
4
Cantonal Hospital Frauenfeld, Spital Thurgau Ag, Pfaffholzstrasse 4, 8500 Frauenfeld, Switzerland
5
National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
6
Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
7
Translational Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
8
Centro Nazionale di Adroterapia Oncologica (CNAO), 27100 Pavia, Italy
9
German Cancer Consortium (DKTK), Partner Site, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(19), 3243; https://doi.org/10.3390/cancers18193243
Submission received: 11 August 2026
/
Revised: 30 September 2026
/
Accepted: 7 October 2026
/
Published: 8 October 2026
(This article belongs to the Special Issue Radiation Therapy for Pediatric Cancers: Precision Techniques, Late Effects, and Survivorship Strategies)
Simple Summary
Children with brain tumours often survive for many years after treatment, making the prevention of long-term side effects an important goal of modern cancer care. Proton therapy can reduce radiation exposure to healthy tissues compared with conventional radiation techniques, but treatment-related changes in normal brain tissue may still occur. Some of these changes appear on magnetic resonance imaging as contrast-enhancing lesions and can be difficult to distinguish from tumour recurrence. In this study, we investigated the occurrence of these radiation-related imaging changes in children treated with proton therapy for low-grade glioma or ependymoma. We also explored whether biological characteristics of proton radiation, including variations in energy deposition within the brain, may contribute to their development. A better understanding of these mechanisms may help improve treatment planning and further reduce the risk of radiation-induced side effects in paediatric patients.
Abstract
Background/Objectives: Proton therapy is widely used in paediatric neuro-oncology because of its favourable dose distribution and reduced exposure to radiation of healthy tissue. Nevertheless, current knowledge regarding radiation-induced contrast enhancements (RICE) is largely derived from adult proton therapy cohorts, while evidence in paediatric patients remains limited and the underlying biological mechanisms are still incompletely understood. This study investigated the incidence of RICE in paediatric patients with low-grade glioma (LGG) and ependymoma and evaluated potential associations with linear energy transfer (LET) and variable relative biological effectiveness (RBE)-weighted dose distributions. Methods: In this retrospective single-centre study, paediatric patients with LGG or ependymoma were identified from a prospectively maintained institutional registry patients treated with proton therapy at the Heidelberg Ion-Beam Therapy Centre (HIT) between 2010 and 2024. Follow-up magnetic resonance imaging examinations were systematically reviewed for RICE. Lesions were contoured in RayStation and assessed dosimetrically using a fixed RBE of 1.1 and three variable RBE models. LET-weighted dose metrics and Dose(RBE) × LET products were compared between RICE regions and planning target volumes (PTVs). Overall survival and progression-free survival were estimated using Kaplan–Meier method. Results: Seventy-six patients met the inclusion criteria, including 33 patients with LGG and 43 with ependymoma. A total of 724 follow-up magnetic resonance imaging examinations were reviewed. RICE occurred in six patients (7.9%), exclusively in the ependymoma subgroup (14.0%). Higher prescribed radiation dose was significantly associated with RICE occurrence (p = 0.031). Across all variable RBE models, biologically weighted dose estimates and Dose(RBE) × LET products were consistently elevated within RICE regions compared with corresponding PTV regions, particularly at low- and intermediate-dose levels. Five-year overall survival rates were 91.7% for LGG and 86.6% for ependymoma, while corresponding progression-free survival rates were 84.4% and 69.3%, respectively. Conclusions: Variable RBE models identified biologically relevant dose heterogeneities within RICE regions that were not adequately captured by the conventional fixed RBE approach. These findings suggest that LET-associated biological dose escalation may contribute to radiation-related brain tissue changes after proton therapy and support further investigation and prospective validation of LET- and RBE-informed normal-tissue risk assessment in paediatric neuro-oncology.
