Neuroinflammation following stereotactic radiosurgery-induced brain tumor disintegration is linked to persistent cognitive decline in a mouse model of metastatic disease.

Abstract Purpose Improved efficacy of anti-cancer therapy and a growing pool of survivors give rise to a question about their quality of life and return to premorbid status. Radiation is effective in brain metastasis eradication, though the optimal approach and long-term effects on brain function are largely unknown. Here, we studied the effects of radiosurgery on brain function. Methods Adult C57BL/6J mice with or without brain metastases (rat 9L gliosarcoma) were treated with cone-beam single-arc stereotactic radiosurgery (SRS; 40 Gy). Tumor growth was monitored using bioluminescence, while longitudinal MRI, behavioral studies and histology were performed to evaluate brain response to the treatment for up to 18 months. Results SRS resulted in 9L metastases eradication within 4 weeks with subsequent long-term survival of all treated animals, while all non-treated animals succumbed to the brain tumor. Behavioral impairment, as measured by a recognition memory test was observed earlier in mice subjected to radiosurgery of tumors (6 weeks) in comparison to SRS of healthy brain tissue (10 weeks). Notably, the deficit resolved by 18 weeks only in mice not bearing a tumor, while tumor eradication was complicated by the persistent cognitive deficits. While, MRI was unremarkable in both groups, histopathology revealed changes. SRS-induced tumor eradication triggered long-lasting and exacerbated neuroinflammatory response. No demyelination, neuronal loss or hemorrhage was detected in any of the groups. Conclusions Tumor disintegration by SRS leads to exacerbated neuroinflammation and persistent cognitive deficits, therefore methods aiming at reducing inflammation after tumor eradication or other therapeutic methods should be sought.