Proton therapy is a powerful tool enabling oncologists to spare normal tissue around the target for irradiation much better than what can be achieved with photon irradiation. The infiltrative nature of IDH-mutated grade II and III diffuse glioma, however, renders proton therapy a potential problem. A randomized controlled trial (RCT) is the only option when trying to ensure that chances of long-term survival are not impaired seeking to reduce unwanted late treatment effects. Non-inferiority of proton therapy compared to photon irradiation is the primary endpoint of the RCT.

Hence, PRO-GLIO has two main objectives. First, PRO-GLIO will evaluate if proton therapy is safe in patients with IDH-mutated grade II and III diffuse glioma, showing that survival figures at 2 years from radiotherapy are not poorer in the proton arm than in the photon arm. Second, we want to find the true number of patients in need of rehabilitation in both arms, and evaluate if proton therapy conveys a higher QoL than photon irradiation at 2 years from radiotherapy.

PRO-GLIO aims at establishing proton irradiation as standard radiotherapy for IDH-positive diffuse glioma grade II and III patients. First, PRO-GLIO will show that proton therapy is safe, despite the infiltrative nature of these tumors. Second, the HRQOL and neuropsychological investigating part of PRO-GLIO will show that patients irradiated with protons have a better outcome in this regard than those irradiated with photons. Inclusion criteria are a diagnosis of grade II or grade III IDH-mutated diffuse glioma, good performance status, indication for radiotherapy and age between 18 and 65 years.

Patients will be randomized to proton or photon radiotherapy and the study work will be divided in three work packages (WP).

1. In WP1, survival data will be the main focus, but the estimation of QALY will also be an important part - concentrating on differences between the two study arms. If there is truly no difference between the proton and photon radiotherapy on the probability of FIFS after two years, then 224 randomized patients (112 in each treatment group) are required to be 80% certain that the upper limit of a two-sided 95% confidence interval will exclude a difference in favor of the photon radiotherapy of more than 15%. This assumes a 0.8 probability of FIFS in the control arm, and no drop-outs.
2. In WP2, a battery of validated neuropsychological tests will be used to test the cognive abilities of the patients. All patients will be testes using an internet-based test (Cog-State) and 1/3 of patients will also have an in-depth neuropsychological evaluation. The two methods will be compared.
3. In WP3, a battery of patient-reported outcome measures (PROMS) questionnaires will be used to establish which subjective challenges this patient group struggles the most with.

1. Patients must be 18 to 65 years old on the day of consent.
2. IDH-mutated astrocytoma grade 2 or 3, or oligodendroglioma grade 2 or 3 according to WHO 2021.
3. Indication for radiotherapy.
4. WHO/ECOG performance status 0-2.
5. Ability to undergo MRI.
6. No significant contrast enhancing tumour (more than 1 or 2 punctate contrast enhancing foci) at the time of randomization. In recurrence patients, no contrast enhancement is allowed unless a new biopsy confirms the diagnosis of IDH-mutated astrocytoma grade 2 or 3, or oligodendroglioma grade 2 or 3.
7. Ability and willingness to travel to a proton therapy centre if randomized to the proton therapy arm.
8. Women of child-bearing potential (WOCBP) must agree to use an effective method of contraception during radiotherapy, chemotherapy and 1 year after completion of chemotherapy. Pregnancy is not an ineligibility criterium if radiotherapy is indicated and cannot be postponed
9. Ability to understand the information about the study and included treatment.
10. Signed informed consent.
11. Ability to speak and understand Norwegian or Swedish language.

Exclusion Criteria:

1. Prior treatment (except surgery) for diffuse glioma
2. Concomitant or previous malignancies. Exceptions are adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, or in situ carcinoma of the cervix uteri with a follow-up time of at least 3 years, or other previous malignancy with a disease-free interval of at least 5 years
3. Known CDKN2A/B homozygous deletion
4. Presence of any medical, psychological, familial, sociological, or geographical characteristic that might impair patient compliance for study protocol procedures including follow-up
5. Body weight > 150 kg

In accordance with Norwegian Data Protection Law, the dataset is only available by physical appearance at Oslo University Hospital, Norway upon request. To access data, please contact principal investigator Petter Brandal (petter.brandal@ous-hf.no). Data will not be shared before planned analyses are performed and published. The study protocol is also available upon request.

Data will be available following publication of the primary and key secondary endpoints. The study protocol is available upon request from this date

Physical appearance at Oslo University Hospital, Norway.