Clinical application of a sub-fractionation workflow 95 Introduction The clinical introduction of magnetic resonance imaging (MRI)-guided linear accelerators (MR-Linac) has majorly impacted radiotherapy workflows by enabling MR imaging prior to and during beamon.1–3 Currently, these systems can counteract anatomical changes, including rotation and deformations of the target(s) and organs-at-risk (OARs), between treatment fractions by performing interfraction plan adaptation.4–7 However, plan adaptation to counteract intrafraction changes has not yet been explored. Especially in case of ultra-hypofractionation or extreme hypofractionation (i.e. 1-5 fractions), the problem of intrafraction motion becomes more apparent due to long delivery times. Hypofractionated radiotherapy is of great interest for various tumour sites due to the potentially improved oncological outcomes in cancers with a higher intrinsic sensitivity to fractionation, such as prostate cancer.8–10 Besides oncological aspects, extremely hypofractionated radiotherapy also brings advantages in terms of patient comfort and departmental logistics (i.e. fewer visits and shorter overall treatment time). While oncological outcomes might be improved, a higher fractional dose also could increase the risk of toxicity due to a potentially higher dose received by the OARs when not properly considering intrafraction organ motion.11 The impact of this intrafraction motion problem has become even more evident as a result of MR imaging during beam-on time and dose reconstructions, as previously shown in prostate cancer treatment.4,11–13 To counteract the effect of organ motion prior to and during beam-on time, and to maximally protect the OARs, intrafraction adaptation methods – such as tracking, gating, and online dose accumulation – are warranted.12,14 However, these methods still face many technical hurdles, for example with respect to accuracy of online dose accumulation.15 The current lack of clinically implemented intrafraction adaptation methods on MR-Linac systems hinders the progression towards extremely hypofractionated MRI-guided radiotherapy in e.g. two fractions. By delivering the treatment fraction inmultiple parts (i.e. sub-fractions) during one treatment session using repetitive imaging and updated treatment plans, theoretically the effect of systematic intrafraction drift motion (drift) on a larger timescale (minutes) could be (partially) counteracted. As each sub-fraction complies with the dose-volume histogram (DVH) constraints, online dose accumulation is not required. Although the idea of sub-fractionation is not novel and prior studies have shown the possibility of treatment delivery in multiple parts16, the clinically available software currently requires two separate, subsequent treatment sessions to do so. This inherently makes the idea of sub-fractionation less attractive or even unfeasible, as treatment times can become extensive. Here, we propose a new and improved ‘sub-fractionation’ workflow that allows efficient treatment delivery in multiple sub-fractions within a single treatment session on a 1.5 Tesla (T) MRLinac by performing imaging, treatment planning, and treatment delivery processes in parallel. In addition, the first clinical application of the workflow in prostate cancer patients is described and the effect on intrafraction target motion is assessed. 5
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