Clinical application of a sub-fractionation workflow 103 control and who needs to perform quality checks, which creates lag time due to manual intervention. Currently, the software is not fully optimised for speed and together with the manual operator intervention, this leads to idle time. This is reflected in the timings we have reported. This idle time in turn can lead to (significant) intrafraction motion occurring during the various steps of the workflow, such as the time between MRI acquisition and actual start of treatment delivery. These effects have yet to be determined in clinical practice and are depending on the tumour site, although for prostate cancer the effects will be relatively small. Nevertheless, the ultimate goal will always be to have cycle times that are as short as (technically) possible. With respect to MRI acquisition timings, compressed sensing could lead to significant a reduction while maintaining image quality.24 In addition, by applying an ATP step, we do not counteract intrafraction rotational motion. However, compared to interfraction rotations, which can be quite large, intrafraction rotations are relatively small.4,20 With the current clinical software, adopting an ATS workflow for the second sub-fraction is not effective due to long workflow times (including manual editing of the contours, see also Table 1), as this would diminish the benefit of sub-fractionation. While clinical feasibility of the workflow has been shown in prostate cancer patients and has led to significant PTV margin reduction in our clinic, this does not guarantee improved clinical outcomes. Future research should assess the clinical benefits, such as the effect on (accumulated) dose distribution and toxicity. Furthermore, future work should focus optimisation of individual workflow steps, such as deformable contour propagation and imaging, as this will increase efficiency and limit idle time. Different and/or improved DIR algorithms, such as anatomically-adaptive registration, deep learning-based auto-contouring, or hybrid solutions could improve contour accuracy and reduce the need for manual operator intervention even further.25,26 This would allow repetitive application of the ATS workflow within acceptable time frames. Conclusion Concluding, we have presented and clinically applied a sub-fractionation workflow for MRI-guided SBRT. Clinical feasibility was demonstrated with a focus on the timing of the workflow in 15 prostate cancer patients treated with SBRT. This workflow enables PTV margin reduction and can potentially bridge the gap between current clinical interfraction adaptive workflows and future fully, intrafraction adaptive workflows. Thereby, the sub-fractionation workflow allows the pursuit of extremely hypofractionated radiotherapy and/or margin reduction for various tumour sites on short term. 5
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