Radiation treatment of benign tumours in NF2-related-schwannomatosis: a national study of 266 irradiated patients showing a significant increase in malignancy/malignant progression

Abstract Background Radiation treatment of benign tumours in tumour-predisposition syndromes is controversial, but short-term studies from treatment centres suggests safety despite apparent radiation associated malignancy being reported. We determined whether radiation treatment in NF2-related-schwannomatosis patients is associated with increased rates of subsequent malignancy-(M)/malignant progression-(MP). Methods All UK patients with NF2 were eligible if they had a clinical/molecular diagnosis. Cases were NF2 patients treated with radiation for benign tumours. Controls were matched for treatment location with surgical/medical treatments based on age and year of treatment. Prospective data collection began in 1990 with addition of retrospective cases to 1969. Kaplan-Meier analysis was performed for malignancy incidence and survival. Outcomes were CNS M/MP (2cm annualised diameter growth) and survival from index tumour treatment. Results 1345 NF2 patients, 266 (133-Male) underwent radiation treatments between 1969-2021 with median first radiotherapy aged 32.9-(IQR=22.4-46.0). Nine subsequent CNS malignancies/malignant progressions were identified in cases with only four in 1079 untreated-(p<0.001). Lifetime and 20-year CNS M/MP was ~6% in all irradiated patients-(4.9% for VS radiotherapy) versus <1% in the non-irradiated population-(p<0.001/0.01). Controls were well-matched for age at NF2 diagnosis and treatment-(Males=133-50%) and had no M/MP in the CNS post index-tumour treatment-(p=0.0016). Thirty-year survival from index tumour treatment was 45.62%-(95%CI=34.0–56.5) for cases and 66.4%-(57.3–74.0) for controls-(p=0.02), but was non-significantly worse for VS radiotherapy. Conclusion -NF2 patients should not be offered radiotherapy as first line treatment of benign tumours and should be given a frank discussion of the potential 5% excess absolute risk of M/MP.