# Ultra-hypofractionated prostate cancer radiotherapy: Dosimetric impact of real-time intrafraction prostate motion and daily anatomical changes

Francesca Di Franco, Thomas Baudier, Pierre Marie Pialat, Alexandre Munoz, Murielle Martinon, Pascal Pommier, David Sarrut, Marie-Claude Biston

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## To cite this version:

Francesca Di Franco, Thomas Baudier, Pierre Marie Pialat, Alexandre Munoz, Murielle Martinon, et al. Ultra-hypofractionated prostate cancer radiotherapy: Dosimetric impact of real-time intrafraction prostate motion and daily anatomical changes. Physica Medica European Journal of Medical Physics, 2024, 118, pp.103207. 10.1016/j.ejmp.2024.103207. hal-04489575

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# Ultra-hypofractionated prostate cancer radiotherapy: dosimetric impact of real-time intrafraction prostate motion and daily anatomical changes

Francesca di Franco<sup>1,2,3*</sup>, Thomas Baudier<sup>1,2</sup>, Pierre Marie Pialat<sup>1</sup>, Alexandre Munoz<sup>1</sup>, Murielle Martinon<sup>1</sup>, Pascal Pommier<sup>1</sup>, David Sarrut<sup>1,2</sup> and Marie-Claude Biston<sup>1,2</sup>

<sup>1</sup> Centre Léon Bérard, 28 rue Laennec 69373, LYON Cedex 08, France

<sup>2</sup> CREATIS, CNRS UMR5220, Inserm U1044, INSA-Lyon, Université Lyon 1, Villeurbanne, France

<sup>3</sup> Univ. Grenoble Alpes, CNRS, Grenoble INP*, LPSC-IN2P3, 38000 Grenoble, France

* Institute of Engineering Univ. Grenoble Alpes

*Corresponding author: difranco@lpsc.in2p3.fr
**Abstract**

**Purpose:** To retrospectively assess the differences between planned and delivered dose during ultra-hypofractionated (UHF) prostate cancer treatments, by evaluating the dosimetric impact of daily anatomical variations alone, and in combination with prostate intrafraction motion.

**Methods:** Prostate intrafraction motion was recorded with a transperineal ultrasound probe in 15 patients treated by UHF radiotherapy (36.25Gy/5 fractions). The dosimetric objective was to cover 99% of the clinical target volume with the 100% prescription isodose line. After treatment, planning CT (pCT) images were deformably registered onto daily Cone Beam CT to generate pseudo-CT for dose accumulation (accumulated CT, aCT). The interplay effect was accounted by synchronizing prostatic shifts and beam geometry. Finally, the shifted dose maps were accumulated (moved-accumulated CT, maCT).

**Results:** No significant change in daily CTV volumes was observed. Conversely, CTV V₁₀₀% was 98.2±0.8% and 94.7±2.6% on aCT and maCT, respectively, compared with 99.5±0.2% on pCT (p<0.0001). Bladder volume was smaller than planned in 76% of fractions and D₅cc was 33.8±3.2Gy and 34.4±3.4Gy on aCT (p=0.02) and maCT (p=0.01) compared with the pCT (36.0 ±1.1Gy). The rectum was smaller than planned in 50.3% of fractions, but the dosimetric differences were not statistically significant, except for D1cc, found smaller on the maCT (33.2±3.2Gy, p=0.02) compared with the pCT (35.3±0.7Gy).

**Conclusions:** Anatomical variations and prostate movements had more important dosimetric impact than anatomical variations alone, although, in some cases, the two phenomena compensated. Therefore, an efficient IGRT protocol is required for treatment implementation to reduce setup errors and control intrafraction motion.

**Keywords:** hypofractionation, prostate cancer, adaptive radiotherapy, image-guided radiotherapy, interplay effect.
Introduction

Ultra-hypofractionated (UHF) radiotherapy protocols (from 7 Gy per fraction) have shown
effectiveness in treating low and intermediate-risk prostate cancer patients (1,2). Indeed, the
low α/β ratio estimated for prostate cancer (1.4-1.9 Gy compared to 3-5 Gy for rectum and
bladder) suggests greater sensitivity to dose escalation. Intensity-modulated radiotherapy
(IMRT), and volumetric modulated arc therapy (VMAT) techniques allow higher dose
conformity to the tumor, showing the possibility of a safer dose increment (3). Furthermore,
the use of an online protocol of image-guided radiotherapy (IGRT) enables reducing the
geometric uncertainties of the treatment (4). In this regard, we recently showed the benefits
of continuous motion monitoring by using an ultrasound IGRT protocol (5).

The main sources of uncertainty during UHF treatment delivery are daily pelvic anatomical
changes (6), and inter and intrafraction prostate movements (5,7,8). Since the delivery time
for UHF treatment is generally longer (4 minutes or more) than the one for conventional
treatment (1.8Gy-2Gy per fraction), there is a higher chance for an extensive prostate motion
to occur (7). Thus, in a previous study, we demonstrated that increasing treatment time,
intrafraction prostate motion was increasingly impacting the target coverage (5).

Cone-beam CT (CBCT) is the standard technique for pretreatment positioning of prostate patients enabling the visualization of the pelvic area. Different studies have shown that bladder and rectum filling variation can impact the delivered dose (9,10). *Roch et al.* (10) observed an increase in the administered bladder dose compared with the theoretical treatment plan (ratio of 1.3), due to a lower bladder filling compared to the simulation CT in 66% of the fractions.

In practice, daily organs at risk (OARs) volume and shape variations are more complex to
manage than inter or intrafraction motion. However, using CBCT images, it is possible to
calculate the daily delivered dose considering the anatomy of the day, and to perform dose
accumulation to evaluate the agreement between the theoretical plan and its
implementation. Considering that a dose calculation requires knowledge of quantitative
information within the image, i.e., tissues' electronic density, it is not easily achievable using
low contrast CBCT images. Nevertheless, several methods, such as density assignment (11),
deformable image registration (DIR) (12), or machine learning have been proposed to
generate pseudo-CT or synthetic CT (syCT) images and then proceed to a new dose calculation
(13, 14).

The following study aimed to assess the differences between planned and delivered doses during UHF prostate cancer treatments. We evaluated the dosimetric impact of both daily anatomical variations alone and in combination with prostate intrafraction motion. To our knowledge, in the context of UHF prostate treatments, there is no other study using CBCT images and motion data from Clarity® (Elekta AB, Stockholm, Sweden). aiming at assessing the differences between planned and delivered dose distributions by accounting for both anatomical variations and real-time intrafraction motion. To do so, daily CBCT images were used to elaborate a pseudo-CT-based dose accumulation workflow accounting for the interplay effect by synchronizing prostatic shifts and beam geometry. The prostate shifts were recorded during treatment using an ultrasound (US) monitoring device (15). The voxel shifting method (VSM) (16) was used to move the dose maps according to the shifts retrieved during the treatment. This was particularly relevant for photons treatments since their range is little disturbed by anatomical changes. Finally, the static dose cloud approximation method (16) was used to calculate the dose distribution.

# Materials and Methods

## *TP-US monitoring probe*

The Clarity® 3D transperineal ultrasound (TP-US) system (15) (Elekta AB, Stockholm) was used to record 3D prostate's shifts (left-right (LR), superior-inferior (SI), and anterior-posterior (AP)) each 1s during the treatment. Details on the TP-US probe and on the used IGRT protocol can be found elsewhere (5). Briefly, a US reference image (US<sub>ref</sub>) is acquired just before the planning CT (pCT) acquisition, while keeping the patient in the same position (Figure 1). Then, during the dosimetry stage, the US<sub>ref</sub> image is superimposed onto the pCT, and a reference positioning volume (RPV) representing the prostate volume visible on the US image, is delineated onto the US<sub>ref</sub> image (5). At the beginning of each fraction, a daily US image (US<sub>daily</sub>) is acquired and the RPV manually registered on it. Finally, prostate monitoring is performed via continuous 3D automatic rigid registration of the RPV onto the live US image (5).

In routine, a gated treatment consisting in stopping the irradiation when prostatic movements exceed a 3 mm threshold (1 mm device uncertainty plus 2 mm dosimetric threshold) for more than 10 s in any of the three spatial directions was implemented.
However, this scenario was not evaluated in the present study, which considered no displacement correction during all the sessions.

## Patients' cohort and clinical protocol

Fifteen patients (75 fractions) receiving a prostate UHF VMAT treatment were considered in this retrospective study, which was approved by the ethics committee (study number R201-004-289). The patients were assigned to receive 36.25 Gy delivered in 5 fractions to the clinical target volume (CTV), according to the phase 3 PACE-B trial (17,18). Planning constraints for target volumes and OARs are described in Table 1. The planning target volume (PTV) was obtained by a 5 mm homogeneous expansion of the CTV. The clinical protocol included covering 99% of the CTV with the 100% prescription isodose line (36.25Gy) and covering 95% of the PTV with the 95% prescription isodose line.

To evaluate the conformity of the dose to the CTV, the Paddick Conformity Index (PCI) was calculated using the following formula:

$$PCI = \frac{TV_{PI}^2}{PI * TV}$$

Where TV represented the target volume, PI the prescription isodose's volume, and TVPI represented the target volume contained into the prescription isodose.

Patients received specific dietary advices 7 days before the CT scanner and followed an individual bladder preparation 1 hour before the treatment (drink between 330 and 500 ml of water). In addition, they were encouraged to empty their bowels before each fraction.

VMAT treatments were planned using Monaco treatment planning system (TPS) using two 360° arcs. Sequencing parameters were: maximum number of control points = 100-140; minimum segment width = 1 cm; fluence smoothing = Low/medium. The treatment plans were delivered using 6 MV flattening filter photons beam from a VersaHD® (Elekta AB, Stockholm) linac. Daily kV-CBCT images of 1 mm slice thickness (XVI 5.0, Elekta AB, Stockholm) were acquired before the treatment start using 120 kV tube voltage and 132 mAs exposure time product. Pre-treatment positioning consisted in acquiring an USdaily image to initialize intrafraction monitoring, followed by a CBCT acquisition (figure 1). The reference modality for pretreatment positioning was the CBCT imaging. Treatment delivery durations ranged between 180-360 s.
## Pseudo CTs and dose accumulation workflow

A research version of a commercial DIR algorithm (Advanced Medical Imaging Registration Engine, ADMIRE V3.37 Elekta AB, Stockholm) (19) has been used to perform dose accumulation using an adaptive workflow (Figure 2).

The overall ADMIRE's intra-subject DIR workflow consists of three registration steps gradually increasing the degrees of freedom of the matching transformation. The first step is a conventional rigid registration between the 2 images to correct for global differences in position and orientation (with cross-correlation as a similarity measure). The second step is a block-matching DIR to get a first estimation of the deformation and the last step is a dense DIR to further refine the previous result and to align image details. During our workflow, the pCT (moving image) was deformably registered onto the daily CBCT (fixed image) to generate a pseudo-CT based on the Hounsfield Units (HU) of the pCT, for dose calculations. Daily pre-treatment shifts were applied prior the dose calculation procedure to move the treatment isocenter.

Target and OARs contours for each of the 75 CBCT images were obtained using the auto-segmentation tool provided by ADMIRE software, which uses the correspondence between pCT and CBCT images to propagate planned contours onto the CBCT. The contours were then reviewed and corrected by an expert radiation oncologist. In particular, the accuracy of the DIR procedure was evaluated by visually assessing the correspondence of the structure position and deformation between the pseudo-CTs and the CBCT images. In addition, for each analyzed structure the HU transfer between CBCT and pseudo-CTs was examined.

Finally, the daily dose was warped and accumulated back to the pCT, creating a so-called accumulated CT (aCT) for dosimetric comparison with the planned dose.

## Real-time intrafraction motion workflow

The dosimetric impact of prostate's intrafraction motion was evaluated by developing a homemade workflow (Figure 3). For each patient in the cohort, the RT-plan file was downloaded from Monaco TPS (V5.59, Elekta AB, Stockholm). It contained information about beam geometry, multileaf collimators, monitor units (MU), and number of control points (CP). The RT-plan was automatically split (Python script, V3.7.6) into N sub-plans corresponding to the number of CP (range: 172-285). Each sub-plan contained information about the delivered
MU at a precise beam angle.

Then, the scripting function available in Monaco TPS was used to calculate the dose in each of the N sub-plans. The scripting code was written in C# language using Visual Studio (V17.2) and divided in three main parts: 1) patient and template selection; 2) dose calculation; 3) RT-dose export. The dose calculation process was taking in input the pseudo-CTs and the daily structures. No dose re-optimization procedure was applied in our workflow.

To synchronize the prostate's shifts with the beam geometry, for each patient the treatment plan was delivered again on the LINAC. Thanks to the graphing function available on the LINAC remote treatment desktop console, we were able to graph the delivered MUs as a function of treatment time each 0.25 seconds, during the treatment delivery. Prostate movements as a function of treatment time were registered for each fraction by the Clarity® device. Finally, the VSM and the static dose cloud approximation (16) were applied to each sub-plan to correctly reproduce prostate displacements as during the patient's treatment. That way, intrafraction shifts were synchronized with the beam angle, accounting for the interplay effect. For this reason, the VSM was renamed as voxel shifting method per beam (VSMpB). Finally, the N sub-plans were accumulated creating the so-called moved-accumulated CT (maCT) accounting for both daily anatomical variations and intrafraction motion. In order to verify that our method of division into sub-plans was robust, we compared the sum of the subplans without introducing movements, with the reference dose obtained in the TPS and the difference resulted < 1%.

## Statistical analysis

To determine whether the dosimetric constraints among pCT, aCT, and maCT were significantly different, we first evaluated the normality of the different data by using the Kolmogorov-Smirnov test. Then, in function of the result, two-tailed t-test was chosen over a two-tailed Wilcoxon rank sum test when the population was assumed to be normally distributed. If p < 0.05, then the difference was considered significant.
# Results

## Motion analysis

Treatment delivery time ranged between 180 and 360 s. Mean displacements observed over the 75 fractions were -0.15±0.98 mm, -0.21±1.15 mm, and -0.11±1.57 mm in the LR, SI, and AP directions, respectively. Mean displacements between 3 and 8 mm were observed for 4% of the fractions in LR and SI directions. Rare large deviations > 8 mm were detected for 1.3% and 2.7% of fractions in LR and SI directions, respectively. Conversely, in the AP direction, displacements between 3-5 mm and 5-8 mm were detected for 23% and 12% of total fractions, respectively. Moreover, deviations > 8 mm were detected in 4% of fractions.

## Dosimetric impact of anatomical variations and real-time intrafraction motion

No significant change in CTV volumes delineated on pre-treatment CBCTs was observed (Figure 4). They were on average 4% bigger than those delineated on the pCT, with maximum variations reaching 10%. Regarding the rectum and bladder, the pCT volumes were generally poorly reproduced during treatment. Bladder and rectal volumes were found to be smaller during treatment than at the time of the pCT for 76% and 50.3% of the fractions, respectively. The bladder volume was found systematically smaller than on the pCT for 5 patients (P1, P2, P4, P9, P11), whereas, for P13 it was systematically bigger. The rectal volume was found systematically smaller than on the pCT for 4 patients (P2, P3, P9, P11) whereas it was systematically bigger for 5 patients (P5, P6, P10, P12, P14).

The dosimetric results of dose accumulations representing the effects of both daily anatomical variations alone (aCT) and in combination with real-time intrafraction prostate motion (maCT) on CTV, PTV and OARs are presented in Figure 5. All the statistical results were computed using the two-tailed t-test, except for rectum and bladder D<sub>1cc</sub>, and bladder D<sub>5cc</sub> which were not normally distributed and thus computed using the Wilcoxon test.

Regarding the CTV V<sub>100%</sub>, a significant mean loss of coverage was recorded, going from 99.5±0.2% on pCT, to 98.2±0.8% on aCT, and to 94.7±2.6% on maCT (p<0.0001). Note that a high degree of conformation was reached since, for the patient cohort the mean PCI was 0.86 [0.81-0.89] and for 12/15 patients the PCI was equal to 0.89.

PTV V<sub>95%</sub> was much more impacted, dropping from 98.8±0.7%, to 90.4±3.3%, and to 85.0±3.2% for the pCT, aCT, and maCT, respectively (p<0.0001).
Regarding the rectum, the dosimetric differences were not statistically significant, except for $D_{1cc}$, which was found significantly lower on the maCT (33.2±3.2Gy, p=0.02) compared with the pCT (35.3±0.7Gy). In addition, we observed that some dosimetric constraints were exceeded for 1 patient ($D_{1cc}$ (+0.4Gy)) and 2 patients ($D_{20\%}$ and $D_{1cc}$ (≥1.5Gy)), on the aCT, and maCT, respectively.

Regarding the bladder, averages $D_{5cc}$ obtained on the aCT (33.8±3.2Gy, p=0.02) and on the maCT (34.4±3.4Gy, p=0.01) were also found significantly lower compared with the pCT (36.0±1.1Gy). Similarly, mean $D_{1cc}$ significantly decreased from 37.4±0.6Gy for the pCT, to 36.4±2.4Gy (p=0.03), and 35.6±2.4 Gy (p=0.01) for the aCT, and maCT respectively. Finally, no significant difference was observed on the $D_{40\%}$.

Furthermore, on the aCT, the bladder's dosimetric constraints were exceeded by 2 and 0.6Gy, on $D_{5cc}$ and $D_{1cc}$, respectively, for only 1 patient (P9). On maCT, they were exceeded by less than 1Gy and less than 1.7Gy, on $D_{5cc}$ and $D_{40\%}$, respectively, for 5 patients (P2, P6, P7, P9, and P15). Compared to the bladder, the rectum appeared to be less impacted on maCTs. This could be due to prostatic movements which, on average, were found more important in the posterior direction.

To further investigate $D_{40\%}$ dosimetric results on bladder, a "per-patient" analysis on 3 patients with different behaviors/characteristics was conducted (Figure 6 and Table 2, respectively).

For the first patient (P13), the daily bladder volume was always significantly bigger than on the pCT, which also resulted in a significantly smaller daily $D_{40\%}$ on the aCT. Important motion in the posterior direction (mean = -1.3mm) during S3 logically resulted in an increase in the $D_{40\%}$ observed in the maCT compared with the aCT.

Conversely, when daily bladder volume was smaller than planned (P9), daily $D_{40\%}$ were systematically larger than on the pCT. Large shifts occurred in posterior direction during sessions 3 and 5 for P9, which was correlated with an increase in $D_{40\%}$ on the maCT compared with the aCT.

Regarding P7, where the bladder volume was on average similar to the pCT during all the sessions, the variation in $D_{40\%}$ on the maCT was only due to the prostate motion. Therefore, for mean displacement of 1.7 mm in posterior direction, an increment in $D_{40\%}$ of 2.5 Gy was observed.
Discussion

The aim of our study was to evaluate the differences between planned and delivered dose by
assessing the dosimetric impact on OARs and targets of the daily anatomical variations alone,
and in combination with prostate intrafraction motion.

To achieve this, prostate monitoring data obtained from a US-monitoring device were used
for the first time to simulate the interplay effect. Similar studies have also been reported using
other monitoring methods (Table 3). Unlike US-monitoring, methods based on
electromagnetic transponders (8, 20, 21) or implanted fiducial markers (22) lack insights into
the patient's internal anatomy and involve surgical procedures or require the insertion of a
temporary catheter (23). In addition, methods based on fiducial markers require additional
radiation dose. MR-linac technology has proven highly accurate in tracking prostate
intrafraction motion, but its high cost limits its accessibility to a limited number of treatment
centers (24,25). The robustness of the US-monitoring modality was previously demonstrated
by our research group compared with RayPilot system (Micropos, Gothenburg, Sweden) (20).
In this study, only accounting for pre-treatment anatomical variations, the mean accumulated
CTV V100% was decreased by 1.3% compared with the theoretical plan. Over the entire cohort,
the difference between planned and accumulated V100% was always < 2% except for one
patient (-3.8%). The PTV V95% was also decreased by 8.4% on aCT compared with the pCT. As
a comparison, in a similar study using the same dose protocol, an average decrease of 0.4%
and 7.9% in prostate CTV and PTV V100% was found, respectively, which was partly attributed
to residual intrafraction motion (26). Note that CTV-to-PTV margins were only 3 mm in the
posterior direction versus 5 mm in our study.

Prostate's rotations or anatomical deformations during treatment could also explain these
changes. Indeed, the use of MRI has revealed daily fluctuations in prostate volume, with a
swelling of 10-15% observed during hypofractionated radiation therapy (27).

In our study, a maximum increase of the contoured prostate volume of 10% over all fractions
has been observed on daily pseudo-CTs. For the majority of the patients, a high degree of
conformity of the dose was observed on the CTV volumes (PCI ≥ 0.8) meaning that even a
small variation in volume or contouring could have an impact on CTV and PTV coverages.

OARs accumulated doses differed from planned ones because of daily filling variability, as also
reported elsewhere (10). In 76% of the fractions, we observed a significant decrease in
bladder volume compared to the pCT, with the rectum being smaller in half of the fractions.
This highlighted the patients' struggle to consistently replicate the desired bladder and
rectum filling, despite their willingness to follow recommended procedures.

Note that, to reduce rectal doses, other teams achieved much more reproducible results,
notably using endorectal balloons (28), rectal retractors (29), or hydrogel spacers, which,
however, could induce rectal irritation (30). In contrast, bladder filling is more difficult to
control, and the proposed methods use expensive and invasive urinary catheters (31, 32).

In the present study, the monitored intrafraction prostate shifts were generally small in LR
and SI directions (>3mm in 4% of fractions) but larger in AP direction (>8mm in 4% of
fractions), as also reported elsewhere (5,7,8). Existing literature has highlighted that increased
delivery time led to an increased variance of prostate displacements (5,8) related to an
increased risk of late radiation effects.

In a previous work we demonstrated the need of time dependent minimum non-isotropic and
asymmetric treatment margins to take motion into account for hypofractionated prostate
treatment (5). Therefore, an accurate management of intrafraction prostate motion becomes
crucial since the dosimetric effect of prostatic shifts is not averaged out as for conventionally
fractionated treatments (33). Moreover, this is a key point regarding dynamic treatment
techniques (IMRT and VMAT) where the interplay effect could cause hotspots and coldspots
in the dose distribution because of the simultaneous motion of target volume and beam
geometry.

As expected, considering that no displacement correction was performed, a loss of targets
coverage was observed due to prostate intrafraction motion: differences between planned
and delivered CTV V₁₀₀% and PTV V₉₅% were 5% and 14% on average, respectively. Similar to
our study, using monitoring data from kilovoltage intrafraction monitoring, Colvill et al. (34)
observed a significant loss of CTV and PTV coverages (up to 34%) due to intrafraction motion
(Table 3). In contrast, loss of targets coverages was less important in other studies using other
monitoring modalities (Table 3). These observations must be correlated to the treatment
margin used and to the delivery time.

In all the studies, no rotation or deformation of the target was considered. However, it was
shown that not correcting prostate deformation or rotation could add an uncertainty of less
than 1mm (6).

Regarding the OARs, dosimetric constraints were exceeded for 2 and 5 patients, when
considering rectal and bladder doses, respectively. Over all the cohort, a significant decrease
in the bladder D<sub>5cc</sub> and D<sub>1cc</sub> was observed on the maCT, compared with the pCT. In addition,
the per-patient and per-fraction analysis showed that large displacements in posterior and
inferior directions led to an increase in the daily D<sub>40%</sub>. Conversely, mean rectal D<sub>1cc</sub> decreased
significantly when considering intrafraction motion, as expected due to the preferential
posterior and inferior directions of prostate movements.

As in our study, results from Table 3 show that prostatic motion typically led to an increase in
bladder dose, while the rectum dose was generally reduced, with the exception of Vanahaen
et al, who observed an increase in the dose of both rectal and bladder (21). In a study similar
to our own, where real-time prostate motion data were integrated into the patient's initial
plan through an isocenter shift method, plan recalculation demonstrated that, in addition to
the maximum dose to the bladder, the D40% was also affected by prostate motion (32, see
Table 3).

Thus, by performing dose accumulation using CBCT images, and accounting for the interplay
effect, we showed that prostate intrafraction motion combined with anatomical variations
had a more important dosimetric impact on target volumes and OARs than daily anatomical
variations alone during UHF prostate cancer treatments, which was in agreement with the
literature.

The presented offline CBCT-based workflow has much potential for clinical implementation,
but enhancing CBCT image quality is crucial for streamlined contour segmentation and
correction. Recently, CBCT-based dose assessment in radiotherapy using DIR gained
importance, especially in pelvic cancer, demonstrating high accuracy (<1% dose calculation
errors) (35). However, DIR algorithms are strongly influenced by organs deformation (36, 37)
and image quality. The use of iterative CBCT reconstruction algorithms (36) or the US-based
generation of daily pseudo-CT (38) would improve DIR results.

Among existing DIR procedures, intensity-based algorithms evaluate image similarity
between CT volumes using image intensities in an optimization problem. However, they are
not robust in presence of large deformations, or when structures' boundaries are not clear
because of limited image quality, and this is particularly relevant in the pelvic region (37).
Feature-based algorithms can handle noisy CBCTs using specific image features (i.e.,
landmarks or contours) to guide the registration process. However, this procedure is time-
consuming and, sometimes, similarity in image structures may hide non-realistic
transformations (39). Hybrid DIR algorithms combine these approaches, enhancing DIR accuracy even when dealing with significant interfractional variations (40). In parallel, strategies integrating DIR with deep learning algorithms have gained importance (12, 14, 41). In our study, a CBCT-based DIR was used, and occasional inconsistencies between CBCT and pseudo-CT (e.g., bladder volume), were detected, necessitating cautious DIR assessment before implementation.

Concerning dose warping and DDA, literature lacks comprehensive methods to assess deformed dose distributions (42). Voxel-based mapping of deformed dose doesn't account for cellular spatial changes (i.e., volume reduction). A reasonable approach is to assess individual patient circumstances. Indeed, significant patient changes during the radiotherapy course are one of the main uncertainties in DDA procedures. In our study, the primary uncertainty was due to the bladder volume. For other structures, this uncertainty was limited due to the short treatment length (5 fractions delivered in one week) with no significant changes observed in patient BMI.

## Conclusions

In conclusion, this study showed that, over the entire patients' cohort, the dosimetric impact of anatomical variations and prostate's intrafraction motion was strongly patient and fractions dependent. The largest deviations observed in dose distributions between pCT and aCT were because of large differences in bladder volume between simulation and treatment. The observed prostate displacements were also patient and fraction dependent. On average, they were more important in inferior and posterior directions, which means that CTV-to-PTV margin reduction towards the rectum generally adopted in most international protocols should be reconsidered. In addition, the dosimetric impact was more important considering both anatomical changes and prostate movements, than anatomical changes alone, although, in some cases, the 2 phenomena compensated each other. Finally, these results highlight that to secure such treatment, the best solution remains, first, to perform 3D imaging before the treatment start to control patient's anatomy, and secondly, to use a robust IGRT device to monitor prostate motion during the treatment. According to our results, we have introduced systematic monitoring of prostate displacement for all our patients included in a UHF treatment protocol, by setting an interruption threshold of 3 mm and 10 s. This ensures that
dose distribution is not significantly affected by prostate displacement, while minimizing the
number of interruptions during the session.

**Declaration of Competing Interest**

This work was performed in a research cooperation agreement with Elekta AB. F.dF was
supported by a grant from Elekta AB.

**Acknowledgments**

This work was carried out as part of the projects: SIRIC LYriCAN Grant INCa-INSERM-DGOS-12563, LABEX PRIMES (ANR- 11-LABX-0063, Université de Lyon), and Investissements d'Avenir (ANR-11-IDEX-0007). We would like to thank Thierry Martel for his contribution to this work.

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<figure><img src="image_4.png" /><figcaption>Figure 2</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Figure 3</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>Figure 4</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>Figure 5</figcaption></figure>
<figure><img src="image_8.png" /><figcaption>Figure 6</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>Supp mat fig 1</figcaption></figure>