PRO-GLIO: PROton Versus Photon Therapy in IDH-mutated Diffuse Grade II and III GLIOmas

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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). 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. 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. 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.

Official Title
-----------------
PRO-GLIO: PROton Versus Photon Therapy in IDH-mutated Diffuse Grade II and III GLIOmas

Conditions
-----------------
Oligodendroglioma, Oligodendroglioma, Anaplastic, Diffuse Astrocytoma, IDH-Mutant

Intervention / Treatment
-----------------
* Radiation: Radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must be 18 to 65 years old at the day of consenting IDH-mutated astrocytoma grade II or III, or oligodendroglioma grade II or III according to WHO 2016 Indication for radiotherapy WHO/ECOG performance status 0-2 Ability to undergo MRI No significant contrast enhancing tumor 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. Ability and willingness to travel to The Skandion Clinic for proton therapy if randomized to the proton therapy arm 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 Ability to understand the information about the study and included treatment and give a written informed consent Signed informed consent Ability to speak and understand Norwegian or Swedish language Exclusion Criteria: Prior treatment (except surgery) for diffuse glioma 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 More than 2 months from randomization to start radiotherapy Known CDKN2A/B homozygous deletion Presence of any medical, psychological, familial, sociological, or geographical characteristic that might impair patient compliance for study protocol procedures including follow-up Body weight > 150 kg

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Experimental treatment arm with proton radiationtherapy Standard treatment arm with photon radiationtherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation therapy with protons<br>Radiation therapy with protons at The Skandion Clinic, Uppsala, Sweden | Radiation: Radiation therapy<br>* Radiation therapy either with protons or photons<br>|
| Active Comparator: Radiation therapy with photons<br>Radiation therapy with photons at an University Hospital nearby subject's home address | Radiation: Radiation therapy<br>* Radiation therapy either with protons or photons<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First intervention free survival (FIFS) at 2 years | Survival | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total fatigue score assessed by the fatigue questionnaire developed by T. Chalder et al. | Symptom | 2, 5, 10 and 15 years | 
| Change in cognitive functioning (composite score from CANTAB-tests) at 2 years | Objective examination | 5 months and 2, 5, 10 and 15 years | 
| Overall survival | Survival | Median and at 2, 5, 10 and 15 years | 
| FIFS | Survival | Median, 5, 10 and 15 years | 
| Progression-free survival | Survival | Median and at 2, 5, 10 and 15 years | 
| Change in neurological function as assessed by the NANO scale | Objective examination | 2, 5, 10 and 15 years | 
| Global cognitive impairment index | Neuropsychological endpoint | 2, 5, 10 and 15 years | 
| Rate of local, distant and combined recurrences | Disease development | 2, 5, 10 and 15 years | 
| Rate of patients without epileptic seizures | Symptom | 5 months and 2, 5, 10 and 15 years | 
| EORTC QLQ C30-based algorithm score | Quality of life | 2, 5, 10 and 15 years | 
| Incremental cost effectiveness ratio | Health economics | 2, 5, 10 and 15 years | 
| Rate of adverse events | Toxicity | At 6 weeks, 3 and 5 months and 1 year, 2 , 5, 10 and 15 years | 
| Costs in Norwegian kroner related to loss of production caused by disease and treatment | Health economics | 2, 5, 10 and 15 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
proton therapy, radiotherapy, IDH-mutated diffuse grade II astrocytoma, IDH-mutated diffuse grade III astrocytoma, oligodendroglioma