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The appearance of radiation-induced contrast enhancements (RICE) after radiotherapy for brain metastases can go along with severe neurological impairments and requires complex interdisciplinary management. Prior studies have reported the benefit of bevacizumab for first line treatment, but the radiological changes and risk of RICE recurrence have not been adequately explored. The aim of our analysis was to evaluate the course and recurrence of RICE and to identify any associated prognostic factors.

In this single institutional retrospective review, we identified patients diagnosed with brain metastases of varying histologies, who were treated with radiotherapy and subsequently developed RICE. Patient demographic and clinical data, radiation-, cancer-, and RICE-treatment, radiological results, toxicity, and oncological outcomes were reviewed in detail.

A total of 95 patients with a median follow-up of 28.8 months were identified. Most common primary tumor entity was lung cancer (n= 50, 52.6%), followed by breast cancer (n=16; 16.8%) and melanoma (n=12, 12.6%). All patients were treated with RT for brain metastases with either whole-brain RT (WBRT) or stereotactic radiosurgery. First RT treatment included stereotactic RT for 81 patients (85.3%), comprised with a median total dose of 20 Gy in one fraction in 55 patients and fractionated treatment in 26 patients. The remaining 14 patients (14.7%) received WBRT with a median dose of 30 Gy in 10 fractions. A total of 27 patients received re-irradiation treatment with WBRT (n=6,) single fraction radiosurgery (n=16) and fractionated radiosurgery (n=5) for the same lesion.

Ultimately, RICE appeared after a median time of 8.0 months after first RT treatment and after 6.4 months after re-irradiation. Correlations of treatment RT plans confirmed RICE localization to the previously treated lesion.

Bevacizumab achieved an improvement of clinical symptoms and imaging features in 65.9% and 75.6% of cases, respectively, both significantly superior compared to treatment with corticosteroids. Bevacizumab further significantly prolonged RICE-progression-free survival to a median of 5.6 months. Recurrence of RICE after initially improved or stable imaging occurred in 63.1% of cases, significantly more often in patients after re-irradiation and was associated with high mortality of 36.6% after the diagnosis of flare-up. Response of recurrence significantly depended on the applied treatment and multiple courses of bevacizumab achieved good response.

Our results suggest that bevacizumab is superior in achieving short-term imaging and symptom improvement of RICE and prolongs the progression-free time compared to corticosteroids alone. Long-term RICE flare-up rates after bevacizumab discontinuation are high, but repeated treatments achieved effective symptomatic control.