General discussion and future perspectives 223 mostly retrospective studies have been published on salvage SBRT in five or six treatment fractions.86–94,95–97 Because of heterogeneous study populations, different studies and treatment modalities are difficult to compare.98 In general, the oncological outcomes after salvage SBRT seem comparable compared to other focal salvage treatments, and early toxicity rates seem very acceptable.98 There is a need for prospective, randomised trials to directly compare different strategies and their outcomes. The introduction of MR-Linac systems, however, also creates possibilities to provide a more HDR-like SBRT treatment in the salvage setting, without sacrificing OAR constraints.99 This could lead to similar (acceptable) toxicity profiles, while enabling e.g. twofraction treatment without major logistical challenges and improved patient comfort. There are, however, dosimetric benefits of HDR brachytherapy when it comes to conformality of the dose distribution and the target volume receiving a very high dose (150-200% of the prescribed dose), as was also shown in chapter 9. This results in slightly higher doses to the rectum and urethra with SBRT treatment. Because of the relatively steep dose fall-off with SBRT, minor intrafraction motion might drastically increase the dose to these OARs, especially the urethra. Therefore, intrafraction adaptation possibilities are warranted before progressing to single or two-fraction SBRT for recurrent prostate cancer. With respect to the high-dose areas, the clinical implication of this is still undetermined. Even with the large volumes receiving more than 150% of the prescribed dose with FS-HDR-BT, recurrence rates after salvage treatment are high and recurrences often occur in-field.74 This may partly be explained by the intrinsic radioresistance of the recurrent prostate cancer cells.100 As suggested, fractionation might be (more) important in achieving improved oncological outcomes and this has several radiobiological explanations. These include re-oxygenation of tissue between fractions, redistribution of tumour cells into radiosensitive phases of the cell cycle, and heterogeneity of α/β values of cells within the tumour, making some tumour cells more susceptible to fractionated treatment than others.85,101 In this light, functional MRI and/or PET for detection of radioresistance and (early) response assessment could be interesting to guide treatment and evaluate treatment response.15,56,102–105 Currently, data on single or two-fraction SBRT is lacking in the setting of recurrent prostate cancer. Future research should focus on the safety (R-IDEAL stage I-II55) and efficacy of single or two-fraction MRI-guided SBRT with small error margins once online adaptation possibilities have become available that allow safe margin reduction below 2 mm. Subsequently, comparative, prospective studies (R-IDEAL stage III55) are required to determine the safety and effectiveness compared to e.g. FS-HDR-BT. Prospective health technology assessments should be incorporated to determine the cost-effectiveness of these innovative treatments. 11
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