Proton vs. Photon Radiotherapy for Patients With WHO Grade 2-3 Glioma

Inclusion Criteria:

* 1\. Histologically confirmed IDH-mutated WHO Grade 2 or 3 glioma with an indication for radiation therapy as determined by the local tumorboard at the study center
* 2\. Tumor classification according to the 2021 WHO Classification, including the presence of the following markers:

  * IDH1/2 mutation
  * ATRX and/or 1p19q codeletion status
  * CDKN2A/B codeletion status
* 3\. A Karnofsky Performance Status of ≥ 70%
* 4\. Patients must be ≥ 18 years of age
* 5\. Radiation therapy must begin within 7 weeks of surgery in patients with CNS WHO Grade 2 IDH-mutated gliomas. In individual cases, the start may be delayed, but not later than 10 weeks after surgery
* 6\. For patients with WHO Grade 2 IDH-mutated CNS gliomas, the following applies:

  * There is an indication for radiation therapy (partial tumor resection, age \> 40 years, relevant neurological deficit)
  * Enrollment in the study at the time of tumor progression is possible, even without a time constraint relative to the initial surgery, if the following criteria are met:
* There was initially no indication for radiation therapy
* At the time of tumor progression, there is an indication for radiation therapy as determined by the local tumor board
* At the time of recurrence, no repeat surgery is required to confirm the diagnosis if there is no imaging evidence of malignancy (see exclusion criterion No. 4)
* Radiation therapy must begin within 7 weeks after the recurrence MRI (or surgery, if a repeat surgery has been performed). In individual cases, treatment may begin later, but no later than 10 weeks after the recurrence MRI/surgery
* 7\. For patients with WHO Grade 3 IDH-mutated CNS gliomas, radiation therapy must begin within 7 weeks after surgery . In individual cases, treatment may begin later, but no later than 10 weeks after surgery
* 8\. At the time of study enrollment, the interval since the last surgery should be ≥ 2 weeks. Patients must have recovered from the effects of the surgery
* 9\. The patient must consent and be able to undergo a neurocognitive baseline assessment prior to administration of the first radiation dose
* 10\. The patient must provide written informed consent to participate in the study prior to enrollment
* 11\. The study participant must be able to understand the purpose and implications of the study and must be willing to follow the clinical study instructions and, as far as can be anticipated, attend all scheduled study visits.
* 12\. Women of childbearing potential must have a negative pregnancy test (serum or urine) that is no older than 7 days at the time of the first study intervention.
* 13\. Laboratory values not older than 3 weeks prior to study enrollment: Absolute neutrophil count ≥ 1,500/mm³, Platelet count ≥ 100,000/mm³, Hemoglobin (Hb) level \> 10 g/dL, Total bilirubin level ≤ 1.5 times the upper limit of normal, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 3 times the upper limit of normal, Creatinine level ≤ 1.5 times the upper limit of normal
* Exclusion Criteria Patients who meet any of the following criteria will not be enrolled in the study.

General exclusion criteria:

* 1\. Concurrent participation in another clinical interventional study or participation in a clinical study that requires administration of an investigational drug within 30 days prior to study enrollment.
* 2\. A physical or mental condition of the patient that, in the judgment of the study physician, could endanger the patient, could bias the study results, or could negatively affect the patient's participation in the clinical trial.
* 3\. Known or ongoing abuse of drugs, alcohol, or medications.

Indication-specific exclusion criteria:

* 4\. At the time of tumor recurrence in patients with WHO Grade 2 IDH-mutated CNS gliomas, there is evidence on MRI of malignancy (e.g., marked contrast enhancement indicating Grade 3-4).
* 5\. Previous radiation therapy to the head or head and neck region
* 6\. Previous chemotherapy due to a CNS neoplasm
* 7\. Severe comorbidities that limit compliance with study requirements
* 8\. Malignant invasive tumor disease with a tumor-free period of \< 3 years
* 9\. Evidence of leptomeningeal dissemination
* 10\. Spinal or infratentorial tumor location
* 11\. Patients with a known infection with the human immunodeficiency virus (HIV)
* 12\. Patients with a newly diagnosed hepatitis infection or-at the discretion of the responsible study physician-a significant risk of reactivation