Accumulated bladder wall dose and urinary toxicity 145 entirely causal, since residual confounding due other to unmeasured and/or unknown variables could be present. Second, manual delineation of the bladder wall is labour-intensive. This makes it less practical for an online workflow, in which contours are generated while the patient is on the treatment couch. Improved automatic segmentation could make use of the bladder wall in clinical online planning feasible. Furthermore, the use of bladder surface histograms might be an easier alternative to delineating the entire bladder wall. However, this does not take into account bladder wall thickness differences within the bladder and variation in thickness with bladder filling status, which impacts its accuracy.31,32 Third, the interfraction dose accumulation pipeline we applied does not consider intrafraction motion that occurs between MRPV acquisition and end of beam-on. We have previously shown that significant intrafraction motion can occur, and this might affect the delivered dose.10,13 Intrafraction dose accumulation, in addition to interfraction dose accumulation, will probably yield an even better approximation of the actual dose compared to interfraction dose accumulation only. Nevertheless, we tried to minimise the effect of intrafraction motion in the current study by using the MRPV that is acquired shortly before beam-on time. Conclusion Concluding, we have shown that the accumulated dose to the bladder (wall) is highly correlated with patient-reported acute urinary toxicity in prostate cancer patients treated with daily adaptive MRI-guided SBRT. These correlations persisted after correction for several baseline characteristics. Our results suggests that bladder wall dosimetry is preferred over whole bladder dosimetry in case one wishes to predict acute urinary toxicity as accurately as possible, although further research should validate these findings. The preliminary dose constraints could be used as a starting point for defining stricter dose constraints for prostate SBRT, with the aim of reducing clinically relevant acute urinary toxicity in these patients. 7
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