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

Official title

Randomized Trial of Radiotherapy With Protons vs. Radiotherapy With Photons for Patients With WHO Grade 2-3 Glioma (GliProPh)

Overview

Patients with grade 2 and 3 gliomas who received photon radiation therapy as part of their standard treatment are at risk of developing cognitive impairments, depending on the tumor's location and the size of the target volume. The extent to which these are caused in individual cases by the brain tissue within the target volume, which is necessarily exposed to a high dose, or whether they can be modified by differences in the exposure of surrounding brain regions exposed to low or moderate doses, is unknown. With the help of proton therapy, the risk of neurocognitive dysfunction could potentially be reduced by decreasing the brain volumes outside the target volume that are exposed to radiation therapy and receive a low dose. Based on current knowledge of relative biological effectiveness, the efficacy of proton therapy on the tumor compared to photon therapy can be considered equivalent with lower levels of uncertainty. In the present study, the impact of photon irradiation versus proton irradiation on neurocognition will now be directly compared. A bicentric, randomized study will investigate whether treating patients with WHO Grade 2 and 3 gliomas with proton radiation results in a different temporal course of neurocognitive function after treatment compared to photon radiation therapy.

Interventions

• Radiation Proton therapy
  Grade 2 gliomas: 5 × 1.8 GyRBE to a total of 54 GyRBE Grade 3 gliomas: 5 × 1.8 GyRBE to a total of 59.4 GyRBE (with concurrent chemotherapy) or 5 × 2.0 GyRBE to a total of 60 GyRBE
• Radiation Photon therapy
  Grade 2 gliomas: 5 × 1.8 GyRBE to a total of 54 GyRBE Grade 3 gliomas: 5 × 1.8 GyRBE to a total of 59.4 GyRBE (with concurrent chemotherapy) or 5 × 2.0 GyRBE to a total of 60 GyRBE

Primary outcome measures

• Neurocognition [Time frame: three years after finishing radiotherapy]

Secondary outcome measures (9)

• Neurocognition [Time frame: 4 weeks and 1, 2, 4, 5, and 6 years after completion of radiation therapy]
• Decline of cognitive domains [Time frame: At 4 weeks and 1, 2, 3, 4, 5, and 6 years after completion of radiation therapy]
• Quality of Life [Time frame: Pre radiation until 6 years after finishing radiotherapy]
• Quality of Life [Time frame: Pre radiation until 6 years after finishing radiotherapy]
• Overall survival [Time frame: From beginning until progression/death]
• Progression free survival [Time frame: From beginning until progression/death]
• Progression free survival [Time frame: From beginning until progression/death]
• Adverse events [Time frame: From pre radiation until progression or 3 years after completion of radiation therapy (whichever comes first)]
• Perilesional brain tissue changes [Time frame: At 4 weeks, 1, 2, 3, 4, 5, and 6 years after completion of radiation therapy]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 2 centers

• Universitätsklinikum Essen — Essen
• Universitätsklinikum Gießen und Marburg — Giessen

Identifiers

NCT: NCT07750457 · EXT-201613_GliProPh

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗