{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T11:58:48Z","timestamp":1780574328474,"version":"3.54.1"},"reference-count":43,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T00:00:00Z","timestamp":1686787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMS\u20101719828"],"award-info":[{"award-number":["DMS\u20101719828"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMS\u20101847865"],"award-info":[{"award-number":["DMS\u20101847865"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aapm.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medical Physics"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Stereotactic radiosurgery (SRS) is an established treatment for patients with brain metastases (BMs). However, damage to the healthy brain may limit the tumor dose for patients with multiple lesions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose<\/jats:title><jats:p>In this study, we investigate the potential of spatiotemporal fractionation schemes to reduce the biological dose received by the healthy brain in SRS of multiple BMs, and also demonstrate a novel concept of spatiotemporal fractionation for polymetastatic cancer patients that faces less hurdles for clinical implementation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Spatiotemporal fractionation (STF) schemes aim at partial hypofractionation in the metastases along with more uniform fractionation in the healthy brain. This is achieved by delivering distinct dose distributions in different fractions, which are designed based on their cumulative biologically effective dose () such that each fraction contributes with high doses to complementary parts of the target volume, while similar dose baths are delivered to the normal tissue. For patients with multiple brain metastases, a novel constrained approach to spatiotemporal fractionation (cSTF) is proposed, which is more robust against setup and biological uncertainties. The approach aims at irradiating entire metastases with possibly different doses, but spatially similar dose distributions in every fraction, where the optimal dose contribution of every fraction to each metastasis is determined using a new planning objective to be added to the BED\u2010based treatment plan optimization problem. The benefits of spatiotemporal fractionation schemes are evaluated for three patients, each with &gt;25 BMs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>For the same tumor BED<jats:sub>10<\/jats:sub> and the same brain volume exposed to high doses in all plans, the mean brain BED<jats:sub>2<\/jats:sub> can be reduced compared to uniformly fractionated plans by 9%\u201312% with the cSTF plans and by 13%\u201319% with the STF plans. In contrast to the STF plans, the cSTF plans avoid partial irradiation of the individual metastases and are less sensitive to misalignments of the fractional dose distributions when setup errors occur.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Spatiotemporal fractionation schemes represent an approach to lower the biological dose to the healthy brain in SRS\u2010based treatments of multiple BMs. Although cSTF cannot achieve the full BED reduction of STF, it improves on uniform fractionation and is more robust against both setup errors and biological uncertainties related to partial tumor irradiation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mp.16457","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T12:10:49Z","timestamp":1686831049000},"page":"5095-5114","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Spatiotemporal fractionation schemes for 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