Part III | Chapter 11 220 biochemical disease-free survival (bDFS) in patients with intermediate- and high-risk prostate cancer.39 With the current interest in ultra-hypofractionated radiotherapy, a subsequent trial (hypoFLAME) was initiated to investigate the safety of prostate cancer SBRT with an additional integrated boost up to 50 Gy to the DIL.40 The analysis of the primary endpoint – safety – has shown promising results in terms of grade 3 or higher toxicity, with no acute grade ³ 3 GU and/or GI toxicity.40 Furthermore, grade 1-2 toxicity rates were similar to conventional SBRT studies without focal boosting, such as the PACE-B trial.50 The acceptable toxicity rates are mainly explained by the fact that OAR constraints were prioritised over the focal boost target dose (i.e. de-escalation of dose to the DIL in case OAR constraints were violated). Although longer follow-up is warranted and oncological outcomes are awaited, these results already stress the importance of small error margins and online adaptive radiotherapy for such treatments. In the hypo-FLAME study, patients were treated with 4 or 5 mmCTV-to-PTVmargins.40 Potentially, the target dose for the DIL can be achieved in more patients and more easily when online adaptation possibilities on an MR-Linac are employed that allow smaller error margins and that improve the actual delivered dose distribution. Although diagnostic 3 T MRI is still superior, 1.5 T MR-Linac systems allow for online visualisation of the DIL and therefore can improve targeting. In addition, seminal vesicle motion and deformation could be taken into account, as suggested in chapter 4. Besides targeting the DIL, MR-Linac systems can also be deployed to spare structures that are not visible with conventional computed tomography (CT) imaging, such as the neurovascular structures involved in erectile function.61 Currently, multiple studies are ongoing that investigate neurovascular sparing radiotherapy, including the POTEN-C (NCT0352526262) and ERECT trial (NCT0486119463,64). In the latter study, patients are treated on a 1.5 T MR-Linac with an ATS workflow. Similar to ‘regular’ MRI-guided SBRT, comparative studies (R-IDEAL stage III55) should be initiated when safety and early efficacy results are positive. These studies could compare different modalities (CT- versus MRI-guided neurovascular-sparing SBRT) as well as sparing and non-sparing MRI-guided SBRT. Extremely hypofractionated radiotherapy does not only offer (potential) advantages to patients. Also from a logistical and economical perspective, extremely hypofractionated treatment offers major advantages. As described by Hehakaya et al.65, for five-fraction MRI-guided SBRT to become costeffective (in comparison to conventional CT-guided treatment), a substantial reduction in toxicity is warranted. Provided the cost per fraction on an MR-Linac is similar for two-fraction treatment, this has a greater potential to be cost-effective.65 Two-fraction treatment would also positively affect the number of patients who can be treated on an MR-Linac. Currently, trials are ongoing that investigate single or two-fraction SBRT on conventional and MR-Linac systems.36,41,66 In the HERMES trial, patients are randomised between two-fraction and five-fraction SBRT on an MR-Linac, without real-time intrafraction adaptation.66 The two-fraction treatment will however be delivered in two subfractions. Results from these studies are eagerly awaited and prospective health technology assessments should determine the cost-effectiveness of these treatments.
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