{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:09:08Z","timestamp":1768435748006,"version":"3.49.0"},"reference-count":52,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["aapm.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Applied Clin Med Phys"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Due to spatial uncertainty, patient setup errors are of major concern for radiosurgery of multiple brain metastases (m\u2010bm) when using single\u2010isocenter\/multitarget (SIMT) volumetric modulated arc therapy (VMAT) techniques. However, recent clinical outcome studies show high rates of tumor local control for SIMT\u2010VMAT. In addition to direct cell kill (DCK), another possible explanation includes the effects of indirect cell kill (ICK) via devascularization for a single dose of 15\u00a0Gy or more and by inducing a radiation immune intratumor response. This study quantifies the role of indirect cell death in dosimetric errors as a function of spatial patient setup uncertainty for stereotactic treatments of multiple lesions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>Nine complex patients with 61 total tumors (2\u201016 tumors\/patient) were planned using SIMT\u2010VMAT with geometry similar to HyperArc with a 10MV\u2010FFF beam (2400 MU\/min). Isocenter was placed at the geometric center of all tumors. Average gross tumor volume (GTV) and planning target volume (PTV) were 1.1 cc (0.02\u201311.5) and 1.9 cc (0.11\u201318.8) with an average distance to isocenter of 5.4\u00a0cm (2.2\u20138.9). The prescription was 20\u00a0Gy to each PTV. Plans were recalculated with induced clinically observable patient setup errors [\u00b12\u00a0mm, \u00b12<jats:sup>o<\/jats:sup>] in all six directions. Boolean structures were generated to calculate the effect of DCK via 20\u00a0Gy isodose volume (IDV) and ICK via 15\u00a0Gy IDV minus the 20\u00a0Gy IDV. Contributions of each IDV to the PTV coverage were analyzed along with normal brain toxicity due to the patient setup uncertainty. Induced uncertainty and minimum dose covering the entire PTV were analyzed to determine the maximum tolerable patient setup errors to utilize the ICK effect for radiosurgery of m\u2010bm via SIMT\u2010VMAT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patient setup errors of 1.3\u00a0mm \/1.3\u00b0 in all six directions must be maintained to achieve PTV coverage of the 15 Gy IDV for ICK. Setup errors of \u00b12\u00a0mm\/2\u00b0 showed clinically unacceptable loss of PTV coverage of 29.4 \u00b1 14.6% even accounting the ICK effect. However, no clinically significant effect on normal brain dosimetry was observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Radiosurgery of m\u2010bm using SIMT\u2010VMAT treatments have shown positive clinical outcomes even with small residual patient setup errors. These clinical outcomes, while largely due to DCK, may also potentially be due to the ICK. Potential mechanisms, such as devascularization and\/or radiation\u2010induced intratumor immune enhancement, should be explored to provide a better understanding of the radiobiological response of stereotactic radiosurgery of m\u2010bm using a SIMT\u2010VMAT plan.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acm2.13400","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:45:30Z","timestamp":1631148330000},"page":"94-103","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Predicting the effect of indirect cell kill in the treatment of multiple brain metastases via single\u2010isocenter\/multitarget volumetric modulated arc therapy stereotactic radiosurgery"],"prefix":"10.1002","volume":"22","author":[{"given":"Allison N","family":"Palmiero","sequence":"first","affiliation":[{"name":"Medical Physics Graduate Program Department of Radiation Medicine University of Kentucky  Lexington 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