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INTRODUCTION: Based on anecdotal evidence from our institution, we sought to investigate the hypothesis that systemic therapy, and in particular newer immune therapy agents (IT) would increase the risk of developing radiation necrosis (RN) following stereotactic radiosurgery (SRS) with Gamma Knife (GK) for brain metastases (BM). METHODS: All patients undergoing GK at our institution between 2006 and 2012 were reviewed. 189 patients were identified of whom 183 survived more than 6 months. Details including type of systemic therapy (cytotoxic chemotherapy (CT), targeted therapy (TT) and immune therapy (IT) were recorded. Timing of ST in relation to GK was also recorded (before, during, less than 6 months and more than 6 months post GK). Logisitic regression was used to calculate the odds of developing RN by type of ST. RESULTS: Median follow up was 11.7 months. 42 patients (23%) developed RN of which 13 received IT alone. On univariate analysis, IT alone was associated with an increased risk of developing RN compared to CT alone (OR-2.44 [95%CI 1.02-5.79], p= 0.044) ) Multivariate analysis showed a trend towards an increased risk of RN with any IT (OR 1.9 {95%CI 0.91-3.99], p = 0.09) while receving any CT was found to be protective against RN (OR 0.39 [95% CI 0.19-0.79}, p = 0.009). CONCLUSION: Use of immune based therapies in patients receiving SRS for BM was associated with an increased risk of RN. Further investigation is needed to characterize these changes including to determine whether the increased rate of RN is due to a pro inflammatory effect of immune therapy or an interaction with radiation.