In Reply to Marwaha, Shepard, and Wegner

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 al 2 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. 3,4There may be a window of opportunity for therapies (ie, immunotherapy) in an extended window between preoperative SRS and resection.