General discussion and future perspectives 219 systems already bring some advantages to prostate cancer patients: there is no need for fiducials and tattoos for positioning. However, the added benefits of MRI-guidance in terms of oncological and toxicity outcomes after prostate cancer SBRT have yet to be determined. As shown in chapter 6, a significant proportion of prostate cancer patients experience moderate (grade 2) acute genitourinary (GU) complaints and erectile dysfunction after MRI-guided SBRT, with clinically relevant effects on health-related quality of life. This is not entirely surprising given the reports on (early) toxicity after prostate cancer SBRT on conventional linacs, with acute grade ³ 2 urinary symptom rates of over 30%.46–51 Despite the modern treatment planning techniques and daily adaptive treatments, early results from other research groups show similar trends in acute toxicity after MRI-guided SBRT for prostate cancer. Bruynzeel et al.52 reported a cumulative grade ³ 2 early GU toxicity rate of 23.8% in 101 prostate cancer patients treated with MRI-guided SBRT on a 0.35 T MR-Linac. In a follow-up report on patient-reported outcomes, a transient but relevant increase in acute (at the end of treatment and 6 weeks post-treatment) urinary symptoms from the patients’ perspective was confirmed.53 Ugurluer et al.13 reported an early grade 2 urinary toxicity rate of 36% in a retrospective study on preliminary results after MRI-guided prostate cancer SBRT. Gastrointestinal (GI) toxicity rates, on the other hand, were much lower.13,52,53 In chapter 7, we observed significant dose-toxicity relationships between the accumulated dose to the bladder and bladder wall and patient-reported acute urinary toxicity in prostate cancer patients treated withMRIguided SBRT. The mean dose to the bladder wall as well as the medium- to high-dose volumes, such as V25Gy (absolute volume receiving 25 Gy, in cm3), were correlated with acute patient-reported urinary toxicity. With the 5 mm CTV-to-PTV margins used in these patients, the bladder wall near the prostate lies almost completely within the PTV. Combined with intrafraction drift in the posterior and caudal direction that often occurs (chapter 4), this can lead to large bladder wall volumes receiving a substantial dose. To be able to significantly reduce (GU) toxicity, improved treatment planning and more accurate dose delivery with smaller PTV margins are warranted. As described in chapter 5, currently all prostate cancer patients who undergo SBRT treatment on an MR-Linac at the UMC Utrecht, are treated with sub-fractionation and 2-3 mm PTV margins. In the near future, early toxicity results in patients treated with this new workflow in combination with smaller PTV margins will become available. While awaiting more mature data on MRI-guided prostate cancer SBRT from prospective, non-comparative studies such as the MOMENTUM study (NCT0407530524) and PRISM study (NCT0365852554), prospective, randomised studies should be initiated (R-IDEAL stage III as proposed by Verkooijen et al.55) to determine the real benefit of online adaptation possibilities on anMR-Linac with respect to oncological and toxicity outcomes. The first comparative study in prostate cancer (MIRAGE trial, NCT0438477056) is currently ongoing. To provide high-quality level-I evidence to support the use of MRI-guided SBRT over CT-guided SBRT for prostate cancer, international collaborations are necessary.57 Oncological outcomes are already excellent for patients with low- or intermediate-risk prostate cancer. However, recurrence rates of up to 50% within 10 years after treatment have been reported for high-risk prostate cancer patients.58–60 As these recurrences are often confined to the primary tumour, studies were initiated to increase the dose to the dominant intraprostatic lesion (DIL), such as the FLAME trial.39 The FLAME trial has shown a clear benefit of a focal boost to the DIL in terms of 11
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