Part I | Chapter 5 102 comparable to a single 7.25 Gy plan delivery time of around 10 min on the Unity MR-Linac.17 Also, on-table time with the sub-fractionation workflow was on average 42.7 min (range 35-58 min), which is approximately 4 min longer than with the previously applied 1xATS followed by 1xATP workflow.17 This makes the workflow feasible within a one-hour timeslot. Because the same DVH criteria are met in each sub-fractionation cycle, any discrepancies between the prescribed and actual delivered cumulative dose will be kept to a minimum by spreading out effects of intrafraction motion over multiple sub-fractions. This is identical to the approach in conventional fractionation and prevents the need for online dose accumulation. Theoretically, the sub-fractionation workflow can more accurately deliver the dose to the target while sparing OARs when compared to the clinical ATS workflow in which the daily dose is delivered without interruption in a single cycle. This is supported by our findings with respect to the residual 3D intrafraction CTV displacement, which was below 2.7 mm for all fractions with the sub-fractionation workflow. By increasing treatment accuracy, progression to extremely hypofractionated radiotherapy can be achieved. Furthermore, increased treatment accuracy could enable significant reduction in uncertainty margins. We calculated the required CTV-to-PTV margins needed using the sub-fractionation workflow and we therefore have now implemented anisotropic margins of 2 mm (LR and CC) and 3 mm (AP) for our prostate SBRT treatments on the MR-Linac. These margin reductions will potentially lower (acute) toxicity rates in these patients, as the dose to OAR can be significantly reduced.22 Still, the effects on clinical outcomes have to be assessed prospectively. Our future work will also focus new applications of the sub-fractionation workflow, such as two-fraction SBRT for recurrent prostate cancer. The clinical application of a similar approach on an MRIdian system was described in a case report by Lagerwaard et al.16 using conventional software and plan re-optimisation after half the dose was delivered. Contrary to Lagerwaard et al., our workflow is capable of simultaneous MRI acquisition and treatment planning during delivery of the previous sub-fractionation cycle within a single treatment session. This vastly reduces the overall treatment time compared to fully sequential imaging, treatment planning, and treatment delivery. Currently, the HERMES trial is investigating the safety and efficacy of two-fraction SBRT (2 x 12 / 13.5 Gy) for the treatment of primary prostate cancer.23 Because of the long beam-on times, treatment delivery in this trial is split in two parts. These are delivered in two separate, sequential treatment sessions and patients can leave the treatment table mid-treatment to empty their bladder. This leads to long treatment times of well over 90 min. Especially for this kind of treatment, our sub-fractionation workflow could significantly improve efficiency and overall fraction times, which will benefit departmental logistics. The sub-fractionation workflow has some limitations. The workflow mainly counteracts drift motion and cannot act upon sudden large anatomical changes. Ultimately real-time adaptation methods will become clinically available that counteract intrafraction motion on the fly. The proposed subfractionation workflow only guarantees fulfilment of DVH criteria for each sub-fractionation cycle and is aimed at bridging the gap between the interfraction adaptive ATS workflow and future fully online adaptive workflows. Furthermore, the workflow still needs an operator who remains in
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