Unexpected frequency of radiation induced contrast enhancement after proton radiotherapy in glioma patients treated within the Swedish PRO-CNS study

OBJECTIVES: Proton Radiotherapy (PRT) is increasingly used due to its capability to spare normal tissue from radiation. For diffuse gliomas the role of PRT is still not established because of insufficient data on safety and efficacy. While awaiting results from randomized trials we analysed a cohort of glioma patients treated with PRT in Sweden between 2015 and 2020. METHODS: 107 patients with diffuse glioma grade 2 and 3 with IDH-mutation (n = 98) or unknown IDH-status (n = 9) were included. We analysed the frequency of Radiation Induced Contrast Enhancing Lesions (RICE) as well as Overall Survival (OS). Possible risk factors for RICE were explored. RESULTS: RICE was found in 58.3% of patients receiving more than 54 Gy (RBE) compared to 19.8% of patients receiving ≤ 54 Gy (RBE) (p = 0.00048). Median time to RICE from end of PRT was 10.1 months (IQR 3.4-17.6) and median follow up was 6.2 years (IQR 4.9-7.2). RICE was symptomatic in 11 of 30 patients (37%). Five-year OS from diagnosis was 87.0% for astrocytoma grade 2, 71.4% for astrocytoma grade 3, 94.6% for oligodendroglioma grade 2 and 100.0% for oligodendroglioma grade 3. CONCLUSIONS: We report a high incidence of RICE in patients receiving > 54 Gy (RBE) with PRT for glioma grade 2-3 with IDH-mutation. This is of concern since more than one third of these patients experience symptoms from RICE. On a cautionary note, we suggest not to treat patients with IDH-mutated gliomas WHO grade 2-3 with PRT outside clinical trials.