We thank the authors for their insightful comments on our recent publication.1 We wholeheartedly agree with them that additional investigations into optimizing preoperative stereotactic radiosurgery (SRS) outcomes via timing and/or dose-fractionation are warranted.
Despite no difference in outcomes between the standard-dose and reduced-dose single-fraction preoperative SRS cohorts and overall excellent results, we demonstrated significantly higher 2-year cavity local recurrence (LR) with increasing lesion size: ∼6% for lesions ≤2 cm, ∼20% for lesions >2 to 3 cm, and ∼25% for lesions >3 to 4 cm in the propensity score-matched analysis. A higher preoperative SRS dose in the form of standard dosing did not reduce this risk. Additionally, there is evidence that increasing the single-fraction preoperative SRS dose above standard dosing does not lead to improved outcomes. Murphy et al2 published a phase 1 trial of single-fraction preoperative SRS in which lesions >2 to 3 cm received up to 21 Gy, and lesions >3 to 4 cm and >4 to 6 cm both had a maximum tolerated dose of 18 Gy. Overall cavity local control at 1 year was 77%, but was 100%, 74%, and 68%, respectively, when stratified by the aforementioned lesion size cohorts, indicating the limited ability of dose-escalated single-fraction preoperative SRS to prevent cavity LR for larger tumors.
We agree that the primarily retrospective data on fractionated preoperative SRS for larger brain metastases as a means of optimizing local control are compelling and worthy of further investigation. In that light, we are in the process of designing a phase 3 randomized trial via NRG (NRG-BN2522) with the primary question of fractionated versus single-fraction preoperative SRS for larger brain metastases, with a planned primary composite endpoint of LR and/or radiation necrosis.
Other avenues also exist to potentially optimize outcomes after preoperative SRS based on recent findings of increased effector T-cell populations in brain metastases treated with preoperative SRS >6 days prior to resection and evidence of the safety of delayed resection (7-21 days) after preoperative SRS.3,4 There may be a window of opportunity for therapies (ie, immunotherapy) in an extended window between preoperative SRS and resection.
Disclosures
None.
Footnotes
Sources of support: This work had no specific funding.
References
- 1.Prabhu R.S., Russek R., Vaslow Z.K., et al. Standard dose versus reduced dose single fraction preoperative radiosurgery for resected brain metastases (PROPS-BM) International Multicenter Cohort Study. Adv Radiat Oncol. 2025;10 doi: 10.1016/j.adro.2025.101794. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Murphy E.S., Yang K., Suh J.H., et al. Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases. Neuro Oncol. 2024;26:1651–1659. doi: 10.1093/neuonc/noae076. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jansen C.S., Pagadala M.S., Cardenas M.A., et al. Pre-operative stereotactic radiosurgery and peri-operative dexamethasone for resectable brain metastases: a two-arm pilot study evaluating clinical outcomes and immunological correlates. Nat Commun. 2024;15:8854. doi: 10.1038/s41467-024-53034-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Schröder C., Haghighi N., Phillips C., et al. A feasibility trial of delayed resection for brain metastases following pre-operative stereotactic radiosurgery. J Neurooncol. 2025;174:599–607. doi: 10.1007/s11060-025-05081-2. [DOI] [PMC free article] [PubMed] [Google Scholar]