Abstract
Background:
Proton beam therapy is increasingly implemented for lower-grade gliomas worldwide, aiming to reduce radiation exposure to healthy tissue and lower treatment related toxicity. However, robust clinical evidence of the benefit of radiotherapy delivered with protons compared to photons is lacking. Importantly, although proton therapy offers potential benefits compared to photon radiotherapy, it is still ionizing radiation and can be associated with severe complications. Emerging concerns include a possible increase of radiotherapy-induced contrast-enhancing lesions.
Case presentation:
A healthy woman in her mid-forties underwent a subtotal resection for an IDH-mutated oligodendroglioma CNS WHO grade 2. She was randomized to proton therapy in the PRO-GLIO trial and received a dose of 54 Gray (Gy) relative biological effectiveness (RBE), followed by chemotherapy. Ten months after completion of radiotherapy, she reported rapid visual deterioration ultimately resulting in blindness. She also developed substantial cognitive deficits, pituitary and hypothalamic failure, and a general decline. MRI showed considerable, progressive radionecrosis in large parts of the irradiated brain. Tragically, the patient passed away 22 months after completing proton therapy.
Conclusion:
This case highlights that although proton beam therapy is considered safe and potentially encumbered with fewer side effects than photon radiotherapy, serious complications may occur. Careful consideration of timing and execution of adjuvant therapy for lower-grade gliomas is essential. Randomized controlled trials are necessary to disclose if proton beam therapy is beneficial or not in lower-grade gliomas.
1 Introduction
Lower-grade isocitrate dehydrogenase (IDH)-mutated gliomas are principally incurable diseases of which four subtypes exist; oligodendroglioma CNS WHO grade 2 and 3 and astrocytoma CNS WHO grade 2 and 3 (). Although incurable, these neoplasms have a slow growth pattern, life expectancy is long and affected patients are relatively young, often diagnosed in their fourth or fifth decade (–). Median overall survival varies from 12.5 years for patients with IDH-mutated astrocytoma grade 3 () to approximately 18 years for individuals with IDH-mutated oligodendroglioma grade 2 (). Anti-neoplastic treatment consists of surgery, radiotherapy, chemotherapy, and IDH-inhibitor (, , –). Although the IDH-inhibitor vorasidenib has been approved for IDH-mutated glioma grade 2 by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), it has not yet received national approval in all countries, including Norway and Sweden. Timing of treatment is important to maximize effect, as well as to postpone treatment-related toxicity. Active surveillance following primary surgery is often chosen for grade 2 neoplasms, although some evidence suggests that early anti-neoplastic treatment is beneficial for tumor control and maintaining health-related quality of life (, ). Higher grade, older patient age (>40–50 years), residual tumor, and persistent neurological deficits all argue for early anti-neoplastic treatment, however, each patient needs to be evaluated individually (, ).
Radiotherapy, although an effective anti-neoplastic treatment, is encumbered with multiple and potentially serious adverse effects (, –). Proton beam therapy (PBT) with its characteristic Bragg peaks enables better sparing of healthy tissue from radiation exposure compared to its photon counterpart, theoretically reducing the risk for treatment-related toxicity (, , ). Clinical evidence of benefit, and its magnitude, is, however, lacking (, , ). Also, PBT is not as available as photon radiotherapy (XRT). For most patients treatment with PBT necessitates time spent away from home, and if the clinical benefit is small or even non-existent this burden results to substantial time toxicity (). Furthermore, in the case of lower-grade gliomas, some but not all reports have raised concerns about radionecrosis, frequently referred to as radiation-induced contrast-enhancing lesions (RICE) following PBT (–).
We present a case of extensive RICE with fatal outcome for a patient following PBT for an IDH-mutated grade 2 oligodendroglioma. The patient presented with a focal epileptic seizure and was otherwise in excellent general condition without neurological deficits. A near gross total resection of her left frontal lobe neoplasm was performed. She was offered and accepted inclusion in the ongoing phase 3 PRO-GLIO trial, one of three trials randomizing patients with IDH-mutated gliomas grade 2 and 3 to proton or photon radiotherapy [NCT03180502, (, )].
2 Case presentation
A previously healthy woman in her mid-forties was admitted to hospital following a focal epileptic seizure. Magnetic resonance imaging (MRI) revealed a diffuse lesion suspicious of an IDH-mutated glioma in the left frontal lobe, Figure 1A. She underwent a subtotal resection, leaving a residual tumor of 10 millimeters, Figure 1B. Histopathology confirmed an IDH-mutated oligodendroglioma grade 2 with a 1p/19q codeletion. Her general condition was excellent with an Eastern Cooperative Oncology Group (ECOG) status of 0 and a Neurologic Assessment in Neuro-Oncology (NANO) score of 0.
Figure 1
Active surveillance or initiation of further anti-neoplastic therapy were considered. Following discussions in the multidisciplinary team and with the patient, a decision to initiate adjuvant therapy was made. The patient consented to participation in the PRO-GLIO trial and a pre-radiation neuropsychological evaluation revealed only minor cognitive difficulties (variable attention function and lightly reduced psychomotor speed), and otherwise average to high average cognitive functioning. She was randomized to PBT and received 1.8 Gray (Gy) relative biological effect (RBE) × 30, which was well tolerated except for a localized skin rash. Chemotherapy with procarbazine, lomustine, and vincristine (PCV) was initiated four weeks after completion of radiotherapy, and a total of five courses were administered. The patient experienced fatigue common terminology criteria for adverse events (CTCAE) grade 2 and bone marrow suppression grade 2–3 during chemotherapy.
Ten months following completion of PBT, the patient reported reduced vision. Ophthalmologic examination revealed right-sided homonymous hemianopsia and papilledema in the left eye. MRI was first described as unchanged, however, subtle contrast enhancement was seen retrospectively, Figure 1C. One month later, MRI showed radiological changes in optic nerves, chiasm, optic tracts, and hypothalamic region, Figure 1D. High-dose methylprednisolone (64 milligrams daily) was initiated without clinical improvement. As vision continued to deteriorate, bevacizumab (7.5 milligrams/kilogram) was initiated one week later but was discontinued after two courses due to malignant hypertension and proteinuria requiring hospitalization. Temozolomide was also attempted as neoplastic progression could not be fully ruled out, however, discontinued after two cycles due to consolidation of the RICE diagnosis using MRI perfusion and diffusion. Amino acid positron emission tomography (PET) is not routinely used at OUS. The next MRI scan showed transient radiological improvement likely related to the administered bevacizumab, but visual deterioration continued and the patient was functionally blind seven months after symptom onset. Subsequent MRI scans revealed progressive RICE, Figures 1E–I. The patient exhibited marked cognitive decline, accompanied by loss of functional independence and delirium, leading to need for institutionalization. At this stage, she lacked the capacity to undergo formal neuropsychological assessment. In few months the patient developed general deterioration and pituitary and hypothalamic failure resulting in diabetes insipidus, hypernatremia, and appetite dysregulation. She was treated with desmopressin, levothyroxine, and corticosteroid replacement therapy. Nonetheless, clinical deterioration progressed and the patient passed away 12 months from debut of her visual symptoms. Autopsy revealed extensive radionecrosis involving large regions of the brain, concluded to be the primary cause of death. The patient’s medical journey is outlined in Figure 2.
Figure 2
Admission to Department of Neurology for second opinion was performed twice, first two months after onset of visual symptoms and again four months later. Apart from slightly elevated protein levels in the cerebrospinal fluid, likely related to the radionecrosis process, no pathological findings were detected. Genetic testing using a Next-Generation Sequencing (NGS) gene panel for hereditary cancer revealed a mosaic TP53-mutation of uncertain clinical significance, but no known radiotherapy vulnerability predisposing syndrome. The patient’s family was offered genetic counselling following the results from the genetic testing.
Based on the unexpected and severe treatment-related toxicity, hospital legal authorities and relevant governmental bodies were notified. The PBT plan underwent extensive scrutinization in the PRO-GLIO study group, national governmental bodies, and also in two independent PBT institutions outside Norway and Sweden. All evaluations concluded that PBT had been administered according to current standards, with appropriate target coverage and OARs sparing, and without dosimetric hot spots. PBT had been delivered with three fields aiming for optimal angulation to achieve a conformal and homogenous dose distribution, Figure 3C. Robust evaluation was performed according to the PRO-GLIO protocol and standard clinical practice, using +/- 3 millimeters and a range of +/- 3.5%. Doses to OARs were within constraints defined by the European Particle Therapy Network (EPTN) consensus (), Table 1. The clinical target volume (CTV) was 77.3 cubic centimeters. The CARE Checklist was applied when writing this case report, see Supplementary Material.
Figure 3
Table 1
| Structure (metric) | Dose (Gy(RBE)) | EQD2 dose (α/β=2 Gy) (Gy(RBE)) | EPTN consensus based EQD2 dose constraints (Gy) |
|---|---|---|---|
| Left hippocampus(D40%) | 1.8 | 0.9 | ≤7.3 |
| Right hippocampus (D40%) | 0.0 | 0.0 | ≤7.3 |
| Optic chiasm (D0.03cc) | 53.4 | 50.5 | ≤55 |
| Left optic nerve (D0.03cc) | 53.7 | 50.9 | ≤55 |
| Right optic nerve (D0.03cc) | 44.3 | 38.5 | ≤55 |
| Body (patient contour), (D0.03cc) | 56.8 | 55.2 | NA |
Doses to key structures.
α/β, alfa/beta; CTV, clinical target volume; D0.03cc, maximum dose; D40%, dose to 40%; EPTN, European Particle Therapy Network; EQD2, equivalent dose in 2 Gy fractions; Gy, Gray; RBE, relative biological effect. All doses are nominal.
3 Discussion
Following PBT, a previously healthy woman with an IDH-mutated oligodendroglioma grade 2 experienced extensive RICE. This led to blindness, hypothalamic and pituitary failure, cognitive decline, and ultimately death. The case blatantly highlights that also PBT, although with diminished radiation exposure of normal tissue compared to photon radiotherapy, nonetheless is encumbered with a risk of severe treatment-related toxicity analogous to photon radiotherapy.
Radiotherapy is an effective anti-neoplastic treatment modality in diffuse gliomas (, ), and is extensively used in IDH-mutated grade 2 gliomas. A major caveat with radiotherapy, however, is the risk of unwanted effects including potentially severe late sequelae (–). As patients with IDH-mutated grade 2 gliomas are young and with a favorable prognosis, reduction of unwanted late effects is a high priority. PBT has inherent properties enabling better sparing of healthy tissue from radiation exposure when compared to XRT (, , ). Dosimetrically, it looks evident that PBT is superior to XRT for lower-grade gliomas (, , ). However, there are no high-quality data supporting this position (, ), and several arguments could be made against such a perspective. The diffuse infiltration of glioma cells into seemingly normal brain tissue suggests that PBT might lead to undercoverage of neoplastic cells (, ), and there are still uncertainties associated with PBT. Internationally, as well in this case, RBE is typically fixed at 1.1. However, the RBE is not invariant and depends on factors such as the linear energy transfer (LET). LET increases toward the distal end of the Bragg peak, so using a fixed RBE of 1.1 in these areas might underestimate the biological dose. Regions characterized by high LET, and consequently increased biological dose, are associated with an elevated risk of toxicity, including RICE (, ). Several reports on unpredictable toxicity in patients with lower-grade gliomas following PBT remind us of this and is of concern (, , ).
However, the reports on unexpected toxicity are based on retrospective data, and RICE occurs after both PBT and XRT. For lower-grade gliomas, RICE is reported in 12-34% of cases following PBT (, , –) and in 10-28% of cases following XRT (–). Most RICE cases are mild and asymptomatic (), usually appear within the radiotherapy target volume (, , ), and the periventricular zone (PVZ) seems to be a predilection site (). For our patient, the first RICE lesion appeared within the optic apparatus and was located outside of both the target volume and the PVZ. Later RICE changes occurred, however, within the PVZ. Most studies do not report higher toxicity from RICE than CTCAE grade 3 (, , , , ), however, a few higher grades of RICE have been reported (). The fatal outcome of our patient is exceptional, and to the best of our knowledge not previously reported following standard dose PBT for an IDH-mutated grade 2 glioma. The risk of RICE correlates with radiation dose and irradiated brain volume, and some studies link older age, grade 2 histology, and re-irradiation to higher risk of RICE (, –). Our patient harbored a 1p/19q codeletion, which in some but not all reports is associated with an increased risk of RICE (, –).
In our patient, RICE appeared 10 months following radiotherapy and mainly outside the target volume. RICE increased and the patient developed blindness (RION – radiation induced optic neuropathy), cognitive decline and ultimately had a fatal outcome. The PBT plan had OAR doses well below constraints, and independent second and third opinions obtained on the treatment plan identified no flaws. We decided to perform retrospective analyses on LET-weighted dose, using the formula Dbiological = Dphysical × RBE = Dphysical × (1 + LETd × c), where LETd is the dose-averaged LET. The c is a scaling factor defined as c = 0,055 µm/keV published by McMahon et al. (). The LETd was calculated in water for primary and secondary protons using Monte Carlo in RayStation® version 2024A SP1. The analyses of our case showed an elevated LET-weighted dose with a maximum (dose to 0.03 cubic centimeters D0.03cc)) of 59.1 Gy(RBE) in the area where RICE first appeared, acknowledging the fact that these analyses are based on models and parameters with considerable uncertainties. Nevertheless, this might explain parts of the clinical picture, as the calculated LET-weighted dose is significantly higher than the nominal RBE 1.1 dose. The RICE lesion appeared predominantly outside the target volume, however, with an increased LET-weighted dose in this area. Elevated LET combined with high doses within the locations where RICE occurs are similar to findings from others (, , ). Genetic analyses and autopsy revealed no explanation for the extensive tissue damage, leaving only speculation about an unknown genetic vulnerability. Although the patient only had a mosaic TP53 mutation, Li-Fraumeni syndrome harboring germline pathogenic variants in TP53 might potentially lead to higher radiosensitivity, including an increased risk of radiation-induced malignancies and therefore likely benefiting from PBT because of the dosimetric advantages (). Our patient was offered combined radiotherapy and chemotherapy which prolonged median overall survival from 7.8 to 13.3 years in patients with IDH-mutated grade 2 glioma in a previous study (). This effect needs to be weighed against unwanted side effects which may be devastating. It was, though, impossible to anticipate that this patient would develop severe RICE. PBT reports indicate similar dose constraints for RION as XRT (), and we believe it is probable that the patient would have developed RICE also if she had received XRT.
We argue that randomized studies need to be carried out to shed light on the hitherto unquantified possible benefit of proton, or photon, radiotherapy compared to the other modality in patients with lower-grade gliomas. One such study has completed enrollment and two are ongoing [NCT03180502, (, )]. It is of course very important not to endanger patients and protective measures such as dose lowering, LET evaluation, and extra caution to avoid high radiotherapy doses in the PVZ and other critical organs need to be discussed. Further studies are necessary to evaluate biological and clinical uncertainties related to PBT; is the magnitude of a potential benefit enough to avoid time and financial toxicity for patients, caregivers, and society (, ).
In conclusion, our patient developed extensive symptomatic RICE and tragically passed away 22 months after completion of PBT. This case underscores that, although hopefully encumbered with fewer and less severe unwanted side effects, PBT is – as is photon radiotherapy - ionizing radiation with a risk of grave complications. Randomized studies should be executed to reveal if and to what extent PBT is beneficial, particularly in lower-grade gliomas. Careful consideration of timing of adjuvant therapy for lower-grade gliomas is also essential. In addition, we advocate that LET and RBE considerations should be incorporated into PBT planning, although existing models remain associated with considerable uncertainty.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by Regional Committee for Medical and Health Research Ethics, South East Norway, Section C: reference number: 265626 and The Swedish Ethical Review Authority, Västra Götaland: reference number: Dnr 2021-04239 and Dnr 2022-01305-02. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was provided by the patient's next of kin prior to manuscript preparation and publication.
Author contributions
LH: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft. LF: Formal analysis, Investigation, Writing – review & editing. FG: Writing – review & editing. IB: Writing – review & editing. HB: Writing – review & editing. TPH: Writing – review & editing. CS: Writing – review & editing. KK: Writing – review & editing. HR: Writing – review & editing. TH: Writing – review & editing. MG: Writing – review & editing. KW: Funding acquisition, Writing – review & editing. MB: Funding acquisition, Writing – review & editing. PB: Conceptualization, Funding acquisition, Investigation, Project administration, Supervision, Writing – original draft.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This patient was included in the PRO-GLIO trial, which has received financial support from the South-Eastern Norway Regional Health Authority (Project number: 2021081), the Norwegian Cancer Society (Project number: 216158), Network in Radiation Oncology (NIRO), the Swedish Society of Medicine (SLS-890541), the Gothenburg Society of Medicine (GLS-887961), Jubileumsklinikens Cancerfond and Lions Cancer Research Fund of Western Sweden.
Acknowledgments
We are grateful to the patient´s family for allowing us to publish this case report, as it brings valuable knowledge regarding severe RICE following proton beam therapy for an IDH-mutant oligodendroglioma CNS WHO grade 2. We are deeply sorry for the patient who experienced this fatal treatment outcome and we express our deepest sympathy to her family.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2026.1803943/full#supplementary-material
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Summary
Keywords
case report, IDH-mutated glioma, oligodendroglioma, proton therapy, radionecrosis, RICE
Citation
Heggebø LC, Fjæra LF, Garrote FLB, Borgen IMH, Blakstad H, Hellebust TP, Saxhaug C, Knutstad K, Rylander H, Henry T, Gustafsson M, Werlenius K, Blomstrand M and Brandal P (2026) Case Report: Proton beam therapy – friend or foe for patients with IDH-mutated WHO grade 2 and 3 gliomas?. Front. Oncol. 16:1803943. doi: 10.3389/fonc.2026.1803943
Received
04 February 2026
Revised
27 March 2026
Accepted
21 April 2026
Published
08 May 2026
Volume
16 - 2026
Edited by
Eric Chi-ching Ko, Beth Israel Deaconess Medical Center Cancer Center, United States
Reviewed by
Surekha Yadav, University of California, San Francisco, United States
Konstantin Gordon, Federal State Budget Institution National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation (FSBI NMRRC), Russia
Camilla Skinnerup Byskov, Aarhus University Hospital, Denmark
Updates
Copyright
© 2026 Heggebø, Fjæra, Garrote, Borgen, Blakstad, Hellebust, Saxhaug, Knutstad, Rylander, Henry, Gustafsson, Werlenius, Blomstrand and Brandal.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Liv Cathrine Heggebø, licahe@ous-hf.no
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.