# Adaptive radiotherapy, promises and pitfalls

Ariane Lapierre, Pierre Blanchard

► To cite this version:

Ariane Lapierre, Pierre Blanchard. Adaptive radiotherapy, promises and pitfalls. Cancer/Radiothérapie, 2025, 29 (5-6), pp.104677. 10.1016/j.canrad.2025.104677. inserm-05250560

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## Review article

# Adaptive radiotherapy, promises and pitfalls

### Avantages et limites de la radiothérapie adaptative

Ariane Lapierre<sup>a,b,*</sup>, Pierre Blanchard<sup>c</sup>

<figure><img src="image_3.png" /></figure>

## INFO ARTICLE

Keywords :

Radiotherapy

Methods

Computer-assisted

Image-guided

## ABSTRACT

Adaptive radiotherapy is a technique that adapts the radiotherapy to the changes of the patient's anatomy and tumour volume by using repeated images acquired during the treatment course. Adaptive radiotherapy aims to optimize the dose distribution, ensure that the tumour remains in the treatment volume and spare the organs at risk. Adaptive radiotherapy can be applied at three timescales: between fractions (offline), immediately before a fraction (online) or real-time (online, during a fraction). Over the last decade, manufacturers have developed linear accelerators dedicated to online adaptive radiotherapy, based on either computed tomography or magnetic resonance imaging. These systems allow for treatment plan adaptation according to deformable, registration-based segmentation and physicist-driven plan optimization. This has led to a rapid rise of this technique on a larger scale, although robust data on its benefits remains scarce. Adaptive radiotherapy has demonstrated dosimetric benefits, such as improved lesion coverage and sparing of organs at risk, in various tumour sites. However, the clinical benefit, in terms of toxicity reduction or improved tumour control, remains to be demonstrated in many disease sites. Furthermore, the implementation of adaptive radiotherapy requires careful planning, increased time, logistics and security, which represents an extra burden and impacts the cost-efficiency of the approach.

© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société française de radiothérapie oncologique (SFRO). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

La radiothérapie adaptative est une technique qui adapte la radiothérapie aux changements de l'anatomie du patient et du volume de la tumeur en utilisant des images répétées acquises au cours du traitement. La radiothérapie adaptative vise à optimiser la distribution de la dose, à s'assurer que la tumeur reste dans le volume de traitement et à épargner les organes à risque. La radiothérapie adaptative peut être appliquée à trois échelles de temps : entre les fractions (offline), immédiatement avant une fraction (online) ou en temps réel (online, pendant une fraction). Au cours de la dernière décennie, les fabricants ont mis au point des accélérateurs linéaires dédiés à la radiothérapie adaptative online, sur la base de l'imagerie par scanographie ou par résonance magnétique. Ces systèmes permettent d'adapter le plan de traitement sur la base d'un recalage déformable et d'une optimisation du plan par le physicien. Cela a conduit à un déploiement rapide de cette technique à plus grande échelle, bien que les données robustes sur ses avantages restent peu nombreuses. La radiothérapie adaptative a démontré des avantages dosimétriques, tels qu'une meilleure couverture de la tumeur et l'épargne des organes à risque, dans divers sites tumoraux. Cependant, les avantages cliniques, en termes de réduction de la toxicité ou d'amélioration du contrôle de la tumeur, restent à démontrer pour de nombreuses localisations. En outre, la mise en œuvre de la radiothérapie adaptative nécessite une planification minutieuse, plus de temps, de logistique et de sécurité, ce qui représente une charge supplémentaire et a un impact sur le rapport coût/efficacité de l'approche.

© 2025 Les Auteurs. Published par Elsevier Masson SAS au nom de Société française de radiothérapie oncologique (SFRO). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

Mots clés :

Radiothérapie

Méthodes

Radiothérapie assistée par ordinateur

Radiothérapie guidée par l'image

<footnote><sup>a</sup> Département de radiothérapie oncologie, centre hospitalier universitaire Lyon Sud, 165, chemin du Grand-Revoyet, 69495 Pierre-Bénite, France</footnote>

<footnote><sup>b</sup> Université de Lyon, 69000 Lyon, France</footnote>

<footnote><sup>c</sup> Inserm Oncostat U1018, Department of Radiotherapy, Gustave-Roussy, université Paris-Saclay, Villejuif, France</footnote>

<footnote>* Corresponding author. Département de radiothérapie Oncologie, centre hospitalier universitaire Lyon Sud, 165, chemin du Grand-Revoyet, 69495 Pierre-Bénite, France. Adresse e-mail : ariane.lapierre@chu-lyon.fr (A. Lapierre).</footnote>
# 1. Introduction

One of the major difficulties of radiotherapy has always been to make sure the daily anatomy of the patient and tumour matches that of the planning computed tomography (CT) imaging. This has been made evident with the widespread use of image-guided radiotherapy. While that is in part compensated by the planning target volume margins, this leads to a substantial amount of healthy tissues included in the treatment volume, resulting in significant toxicity. Adapting the treatment to measured variations of the tumour volume or patient anatomy is known as "adaptive radiotherapy" [1]. By using repeated images acquired during the treatment, adaptive radiotherapy can be used to generate treatment fractions personalized to the patient's anatomical changes [2]. This ensures that the tumour remains in the treatment volume, and that the anatomical changes are taken into account, in order to optimise the dose distribution, conformity index and spare the organs at risk, following the "as low as reasonably achievable" (ALARA) principle. Adaptive radiotherapy has been applied at three timescales: between fractions (offline), immediately before a fraction (online) or real-time (online, during a fraction) [3]. Over the last decades, adaptive radiotherapy has been considered as a transformative approach in the field of radiation oncology, offering a potential means to enhance treatment efficacy while minimizing radiation-related toxicity.

This article aims at summarizing the main techniques and workflows of adaptive radiotherapy and to discuss the potential dosimetric and clinical benefits of this approach.

# 2. Methods of adaptive radiotherapy

## 2.1. Offline adaptive radiotherapy

Historically, the first method developed for adaptive radiotherapy is offline adaptive radiotherapy. In offline adaptive radiotherapy, a new planning image is acquired at some point during the patient's treatment. The initial segmentation is either manually or automatically propagated on the new planning images and adapted to the anatomical changes. A new treatment plan is then calculated for the adapted anatomy, and the patient can be treated on this new plan. While this process is both time- and resource-consuming, it has led to significant benefit in doses to organs at risk for advanced lung cancer, where an offline adaptive radiotherapy workflow resulted in a lower mean lung dose and reduced the risk of radiation-induced pneumonitis [4].

However, planning CTs cannot be repeated numerous times throughout the treatment, and this is one of the main limitations of this process. Another way to achieve offline adaptive radiotherapy is to use the daily-acquired images (cone-beam CT, megavoltage CT or magnetic resonance imaging [MRI]) to create a new version of the treatment plan after the session has been treated.

Furthermore, some organs can have daily anatomical changes (such as the rectum or bladder), and offline adaptive radiotherapy might not be enough to account for the anatomy of the day.

## 2.2. Online adaptive radiotherapy

In cases with important daily anatomical variations such as in pelvic malignancies, daily online adaptive radiotherapy can in theory provide the best tumour coverage and sparing of organs at risk at each fraction.

The first online adaptive radiotherapy method developed is known as "plan of the day". In this technique, various planning target volumes are defined on the initial planning CT to fit the daily anatomy. This was mostly developed for bladder cancer radiotherapy

with planning target volumes of different margins to account for different levels of bladder repletion [5]. For cervical cancer, bladder repletion also affects the movements of the uterus in the pelvis. As such, using the plan of the day approach, different treatment plans could be produced at the start of the treatment to account for the different positions of the treatment volume [6]. The best-suited plan was then selected at each treatment session to ensure maximum planning target volume coverage. However, although this technique has shown promising results in pelvic tumours, it significantly increases workload, almost doubling it compared to a regular radiotherapy planning workflow [7].

More recently, the development of artificial intelligence (AI) and evolution of treatment planning systems have allowed for semi- or fully automated segmentation and rapid plan optimization. This has made online plan optimization possible without increasing treatment time over tolerable limits. However, this often requires specific adaptive radiotherapy dedicated systems.

## 2.3. Real-time adaptive radiotherapy

Real-time adaptive radiotherapy is the most precise method of adaptive radiotherapy. Its goal is to track the tumour deformations and movement occurring between each treatment sessions. As such, it is partly like tumour tracking, with the additional factor of tumour deformation and recontouring and optimization. Different tools and techniques are available for this purpose and are described below. Currently, real-time adaptive radiotherapy is based mostly on tumour tracking, offered by MRI-guided linear accelerators [8]. However no solution for real-time adaptive radiotherapy taking tumour deformation into account are commercialized, although several developments are ongoing [8].

## 2.4. Linear accelerator-based solutions

Over the last decade, linear accelerators dedicated to online adaptive radiotherapy have been developed by manufacturers. These can be based on either CT of MRI.

There are currently two CT-based linear accelerators designed for adaptive radiotherapy. The first solution developed is the Ethos™ system (Varian Medical Systems, a Siemens Healthineers Company). This is derived from a regular linear accelerator (Halcyon™) with an embarked AI-powered software. It offers semi-automated online adaptive radiotherapy based on the daily cone-beam CT images. AI allows for faster contour adaptation (not only based on deformable registration but also AI segmentation models) and plan optimization [9]. While this CT-based solution allows for shorter treatment times than their MRI counterparts, it still is limited by two major setbacks. The first one is the image definition: cone-beam CT images often lack contrast in soft tissue, making the delineation of abdominal and pelvic regions harder on non-contrast-enhanced images. However, the new HyperSight™ cone-beam CT, with improved image quality, can overcome part of this limitation. The remaining drawback of this system is the lack of possible interaction between the physicist and the system. Once the AI-generated plan is created, the physician can only choose between this plan and the original reference plan. The optimization process cannot be manually accessed and remains a black box. More recently, Elekta has developed a similar solution, called Evo™, using the Iris™ high definition cone-beam CT.

MR-guided radiotherapy is currently available under two platforms in France: the MRIdian® (ViewRay) and the Unity™ (Elekta) systems. A third system called Aurora-RT™ (MagnetTx) is approved by the US Food and Drug Administration (FDA) and compliant compliance with European Union legislation (CE-marked) but has not yet been launched in Europe. The MRIdian® system comes with a 0.35 T MRI. While the first version embarked three ⁶⁰Co heads
mounted on a ring gantry, the new version is equipped with a 6 MV linear accelerator [10]. The Unity® system comes with a 1.5 T MRI and a 7 MV linear accelerator [11]. The first advantage of MR-guided radiotherapy is the better contrast imaging for daily patient positioning. Compared to cone-beam CT, MRI offers better contrast definition, especially in the abdominal and pelvic regions. However, image acquisition time is longer and as such, overall treatment time is significantly longer than that of CT-based linear accelerators [12]. While these can perform non-adapted radiotherapy, they also offer adaptive radiotherapy workflows with deformable registration-based segmentation and physicist-driven plan optimization. They can also allow tumour tracking and gating during treatment time, making them especially appropriate for stereotactic body radiotherapy and moving targets.

## 2.5. Software solutions

While online adaptive radiotherapy can be performed on specific particle accelerators designed with embarked adaptive software, independent software solutions can also provide the sufficient tools for real-time plan adaptation. RayStation® (RaySearch Laboratories) offers synthetic CT creation based on daily cone-beam CT and diagnostic CT images, creating a new plan that can be delivered on the same day. This software, also being a standard treatment planning system, enables real-time dose tracking to ensure that organs at risk dose constraints are met throughout the whole treatment. This is a major advantage over linear accelerator-based solutions where the adapted dose proposed at each session is derived from the reference treatment plan, without taking into account the modified plans delivered during the other sessions.

# 3. Clinical and dosimetric benefits of adaptive radiotherapy

The main benefit of adaptive radiotherapy, offline or online, is dosimetry related. It ensures correct dose coverage of the tumour volume and optimum sparing of organs at risk. Historically, this has been well described for offline adaptive radiotherapy, for head and neck and lung tumours, where the use of this technique provided a dosimetric benefit that might hint towards a reduction of toxicity, through a reduction in dose to parotid glands for instance [13,14].

For complex treatment plans, online adaptive radiotherapy allows for better sparing of organs at risk as well, ensuring that their constraints are kept on every treatment session. This can be of great help in tumour locations where organs at risk are close to the planning target volume and constraints are hard to meet on the reference plan, such as pancreatic cancer [15].

This reduction in dose to organs at risk can also be used to increase the dose delivered to the tumour, using adaptive dose painting or boost. This approach has been studied in prostate cancer stereotactic body radiotherapy, though the clinical benefits of this boost is still a matter of debate [16]. Furthermore, thanks to the spread of functional imaging, adaptive radiotherapy can also be used to tailor the treatment to the tumour biology, in order to enhance tumour control via adaptive dose painting [17,18].

## 3.1. Data on adaptive radiotherapy per tumour site

The foremost indications for online adaptive radiotherapy are pelvic malignancies, due to the presence of surrounding organs that change in shape and size on a daily basis (bladder and digestive track). This is the reason most of the early online adaptive radiotherapy studies were done on these types of malignancies. One of the earliest studies on the ETHOS® system was performed retrospectively on 39 patients with treated pelvic malignancies including pelvic lymph nodes (eight bladder, eight prostate, nine rectum, and 14 anus cancer). In this preclinical dosimetric study,

the online adaptive radiotherapy AI-generated plan was superior to the reference plan regarding tumour dose coverage and protection of organs at risk in 88 % of cases [19]. Furthermore, in this study, treatment time was kept under 20 min (median duration of 17.6 min), making it tolerable for real life implementation.

### 3.1.1. Prostate cancer

Prostate stereotactic body radiotherapy is one of the leading indications of MR-guided radiotherapy. Following the PACE trial, stereotactic body radiotherapy has become standard treatment for low- and intermediate-risk prostate cancer [20]. By allowing better visualization of the prostate before treatment and per fraction tracking, the use of MR-guided radiotherapy has allowed a reduction in planning target volume margins [21]. These reduced margins have shown a significant benefit on treatment related toxicity, even without the use of daily online planning [22]. The Momentum study, a prospective cohort study of patients treated for prostate cancer by stereotactic body radiation on a 1.5 T MR-guided linear accelerator, toxicity rates were very low, with 18.7 % of genitourinary toxicity grade 2 or above and 1.7 % of gastrointestinal toxicity at 3 months [23]. However, in this study, the use of daily online adaptive planning was not mandatory and some patients were treated with a conventional workflow. Still, MR-guided radiotherapy currently appears as the best technique for delivering prostate stereotactic body radiation.

Interestingly, MR-guidance can also be proposed for stereotactic body radiotherapy after radical prostatectomy, In the Scimitar phase 2 trial, patients with postoperative prostate-specific antigen serum concentration of 0.03 ng/mL or adverse pathologic features were treated with stereotactic body radiation (delivering 30 to 34 Gy in five fractions) to the prostate bed using either CT- or MR-guided system [24]. While both treatment modalities were acceptable in terms of toxicity, MR-guided radiotherapy was associated with a 30.5 % reduction in gastrointestinal toxicity and better bowel quality of life.

However, this might not apply to moderately hypofractionated treatment. Patients enrolled in the Momentum study treated with 20 fractions displayed toxicity rates similar to those published in the literature (with CT-guided radiotherapy), showing that the benefit in this setting might not be as clear as for stereotactic body radiotherapy [25].

Margin reduction in MR-guided radiotherapy has also allowed dose escalation to the prostate, either by delivering a boost to the tumour (delivering 40 to 45 Gy in five fractions), or by increasing fraction dose. The Hermes trial assessed a two fraction prostate stereotactic body radiotherapy scheme delivered using MR-guided adaptive technique [26]. Although still early, the first results of this trial showed promising results in terms of acute toxicity, with no grade 3 toxicity observed in the study.

### 3.1.2. Bladder cancer

Due to the change of volume between fractions, bladder-targeted radiotherapy appears as a good indication of online adaptive method. In conventional radiotherapy, these changes were managed using a very large planning target volume margin, usually between 10 and 20 mm [27]. This results in large portions of organs at risk being included in the planning target volume and thus receiving high radiation doses. Using adaptive radiotherapy strategies, including plan of the day approaches, planning target volume margins can be significantly reduced, up to 5 mm [27]. Online adaptive radiotherapy can achieve even better conformation of the planning target volume to the bladder volume, reducing margins even further, down to 3 mm [28]. This led to a significant reduction in planning target volume (up to 33 % smaller volume using online adaptive radiotherapy) and reduction in bowel and rectum dose.
Furthermore, similarly to what was achieved in prostate cancer, planning target volume reduction in bladder cancer radiotherapy allows for a dose boost to the tumour. The Raider trial assessed a dose-escalated adaptive radiotherapy schedule (plan of the day), delivering up to 70 Gy in 32 fractions [29]. Toxicity events were low in the adaptive radiotherapy arm, and tumour control results were promising, although still preliminary. Although this was done using standard techniques in the Raider trial, the use of online adaptive radiotherapy could even decrease toxicity. Online adaptive radiotherapy indeed seems very promising for bladder cancer, and its clinical benefit compared to image-guided radiotherapy is currently being studied in the Bladapt trial (principal investigator: Dr Riou).

### 3.1.3. Cervical cancer

Gynaecological malignancies are good indications of MR-guided radiotherapy, MRI being the reference imaging modalities for this type of cancer. Furthermore, the benefit of online adaptive radiotherapy for cervical cancer has been historically demonstrated using the plan of the day approach, because of the uterine movement induced by filling of the bladder [6].

Another interesting aspect MR-guided radiotherapy might provide is tumour boost, especially in patients ineligible to brachytherapy. A pilot study has shown that MR-guided radiotherapy was safe in this setting, with acceptable toxicity (no toxicity grade 3 or above reported) [30].

### 3.1.4. Pancreatic cancer

The first trials of adaptive stereotactic body radiotherapy for pancreatic cancer showed a clear dosimetric benefit to this approach. Where organs at risk constraints were often not met on the reference plan, adapted plans improved tumour coverage and met most of the organs at risk criteria [15]. However, this first study was purely theoretical as it was performed in silico.

MR-guided radiotherapy has also shown to be a good treatment modality for pancreatic cancer. While allowing better visualization of the pancreas, MR-guided online adaptive radiotherapy also allows better sparing of the organs at risk and target coverage. A prospective register study on 30 patients undergoing stereotactic body radiotherapy on a 0.35 T MR-guided linear accelerator confirmed this dosimetric benefit, with an acceptable toxicity profile [31].

### 3.1.5. Head and neck cancer

While online adaptive radiotherapy might not be relevant for head and neck cancers, where organs hardly change on a daily basis, it remains one of the historical indications of offline adaptive radiotherapy due to anatomical changes over the treatment course. It has been shown that change in soft tissues (when the patient loses weight for example) can lead to higher doses in the organs at risk, namely parotid glands and spinal canal, without affecting tumour coverage. Besides, during treatment, the tumour and some organs at risk (parotid and submandibular glands for instance) demonstrate a decrease in volume, which may justify the use of adaptation. As such, offline adaptive planning once or twice during the treatment course significantly reduced to doses to organs at risk [32]. Therefore, it has been suggested that offline adaptive radiotherapy could help reduce the risk of xerostomia by sparing the parotid glands. However, the first randomized clinical trial assessing the role of adaptive radiotherapy on salivary function showed no clinical benefit of systematic weekly replanning compared with standard intensity-modulated radiotherapy in this purpose [33].

Another use of offline adaptive radiotherapy is to boost tumour regions with a high fluorodeoxyglucose uptake on positron-emission tomography (PET)-CT. This was assessed in the setting of head and neck cancer in the Artforce trial. Unfortunately, dose

redistribution and escalation did not lead to better local control or decrease of toxicity [18]. As such, although there is a clear dosimetric benefit of using offline adaptive radiotherapy for head and neck cancer, the lack of positive clinical data warrants against its systematic use, with a use that must be discussed on the individual basis.

### 3.1.6. Lung cancer

Offline adaptive radiotherapy has shown its benefits in fractionated lung cancer treatment, where replanning mid-course decreased mean lung dose and reduced the risk of radiation pneumonitis [4]. However, online adaptive method might also prove beneficial in lung cancer treatment, especially in stereotactic body radiotherapy for ultracentral lung tumours, where the planning target volume is in close relation to critical organs at risk such as the proximal bronchial tree. In this context, MR-guided, stereotactic body radiotherapy has been shown to improve sparing of organs at risk in ultracentral lung treatment, with the daily plan adaptation leading to a decrease in violation of the organs at risk objectives [34]. Furthermore, MR-guided radiotherapy may allow the delivery of higher fraction doses by improving tumour visualization and tracking. Although still preliminary, this paves the way for single dose lung stereotactic body radiotherapy, which has been performed safely on a 0.35 T MR-guided linear accelerator [35].

### 3.2. Other indications

Liver tumours (primitive of metastases) are good indications of MR-guided radiotherapy due to the better visualization of the tumour on MRI, but also to the adaptive possibilities offered. It is mostly interesting in lesions close to the organs at risk (digestive structures in most cases), where daily plan adaptation allows for their sparing [36]. Several studies are underway to confirm this interest.

Similar observations can be made about adrenal lesions. The first benefit of MR-guided radiotherapy in this context is to allow for better visualization of the adrenal gland. However, it has also been shown that adrenal gross tumour volume could change during stereotactic body radiotherapy and, as such, online adaptive method might be beneficial in this setting [37].

Abdominal or pelvic lymph nodes metastases may also benefit from online adaptive radiotherapy, especially MR-guided. In this setting, online adaptive radiotherapy significantly reduces dose constraints violations while ensuring good target coverage [38].

Available data on adaptive radiotherapy benefits are summarized in Tables 1–3. Ongoing randomized clinical trials are listed in Table 4.

## 4. Clinical implementation of adaptive radiotherapy

The development of automated online adaptive radiotherapy systems, whether CT- or MR-based, has allowed its deployment in centres worldwide. However, the quality assurance requirements for these procedures involve substantial changes in the daily organization. Quality assurance programs must take into account the accuracy of the recontouring process, as well as the daily-adapted treatment plan. The European Society for Radiotherapy and Oncology (ESTRO) has issued guidelines for safe implementation of MR-guided adaptive radiotherapy systems, including training requirements, patient selection and specific quality assurance process [39].

One of the major clinical concerns of online adaptive radiotherapy is the time factor: more than the time required for recontouring and plan recalculation on a daily basis, the systems, whether CT- of MR-based, require the presence of a radiation oncologist and a physicist most of the time. As such, investment in one
<table><caption>**Table 1**
Dosimetric studies on online adaptive radiotherapy.</caption><thead><tr><td>Reference</td><td>Number of patients</td><td>Tumour type</td><td>Study type</td><td>Online adaptive radiotherapy method</td><td>Type of radiotherapy</td><td>Endpoint</td><td>Dosimetric benefit</td><td>Comments</td></tr></thead><tbody><tr><td>Sibolt et al., 2020 [19]</td><td>10</td><td>Bladder</td><td>N/A</td><td>Cone beam CT-based</td><td>Conventional</td><td>Dosimetric</td><td>Reduced margins, reduced bowel dose</td><td>Adaptive process 12 min</td></tr><tr><td>Vestergaard et al., 2014 [44]</td><td>20</td><td>Bladder</td><td>Phase 2</td><td>Plan of the day</td><td>Conventional</td><td>Dosimetric</td><td>Reduced planning target volume</td><td></td></tr><tr><td>Grønborg et al., 2015 [45]</td><td>9</td><td>Bladder</td><td>Phase 2</td><td>Plan of the day</td><td>Conventional</td><td>Dosimetric</td><td>Reduced margins</td><td></td></tr><tr><td>Vestergaard et al., 2015 [46]</td><td>9</td><td>Bladder</td><td>Planning study</td><td>MRI-guided</td><td>Conventional</td><td>Dosimetric</td><td>Reduced planning target volume, decreased bowel dose</td><td></td></tr><tr><td>Burridge et al., 2006 [5]</td><td>20</td><td>Bladder</td><td>Planning study</td><td>Plan of the day</td><td>Conventional</td><td>Dosimetric</td><td>Sparing of small bowel volume, planning target volume margin reduction</td><td></td></tr><tr><td>Åström et al., 2022 [28]</td><td>16</td><td>Bladder</td><td>Prospective observational study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Planning target volume reduction, reduction in dose to organs at risk</td><td>Median time 13.9 min</td></tr><tr><td>Khouya et al., 2023 [47]</td><td>9</td><td>Bladder</td><td>Prospective registry study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Reduced margins</td><td>Longer adaptation time requires larger margins</td></tr><tr><td>Varga et al., 2025 [48]</td><td>8</td><td>Bladder</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Reduced planning target volume, reduction in irradiation of healthy tissues</td><td>Average duration 15 min</td></tr><tr><td>Sun et al., 2025 [49]</td><td>10</td><td>Cervix</td><td>Dosimetric study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Better target coverage and sparing of organs at risk</td><td>Mean duration 22 min</td></tr><tr><td>Yen et al., 2024 [50]</td><td>10</td><td>Cervix</td><td>Prospective registry study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Reduced doses to organs at risk, improved planning target volume coverage</td><td></td></tr><tr><td>Yock et al., 2021 [51]</td><td>28</td><td>Cervix or rectum</td><td>Dosimetric study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Better planning target volume coverage and sparing of organs at risk</td><td>Average duration 24 and 9 min</td></tr><tr><td>Wang et al., 2024 [52]</td><td>15</td><td>Endometrial</td><td>Phase 2</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Reduced margins</td><td>Average time 22 min</td></tr><tr><td>Dohopolski et al., 2022 [53]</td><td>10</td><td>Head and neck</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Good target coverage, reduced margins and doses to organs at risk</td><td></td></tr><tr><td>Enocson et al., 2025 [54]</td><td>31</td><td>Head and neck</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Good target coverage</td><td>Reduced margins are needed to see dosimetric benefits</td></tr><tr><td>Weykamp et al., 2022 [55]</td><td>23</td><td>Liver metastases</td><td>Prospective registry study</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Better planning target volume coverage, fewer organs at risk dose violations</td><td>Mean duration 72 min</td></tr></tbody></table>
<table><caption>Table 1 (Suite)</caption><thead><tr><th>Reference</th><th>Number of patients</th><th>Tumour type</th><th>Study type</th><th>Online adaptive radiotherapy method</th><th>Type of radiotherapy</th><th>Endpoint</th><th>Dosimetric benefit</th><th>Comments</th></tr></thead><tbody><tr><td>Regnery et al., 2022 [34]</td><td>21</td><td>Lung</td><td>Prospective cohort</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Less organs at risk constraint violations</td><td>Accuracy of Ethos automatic contouring considered acceptable</td></tr><tr><td>Mao et al., 2022 [56]</td><td>10</td><td>Lung</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Improved planning target volume coverage</td><td></td></tr><tr><td>Winkel et al., 2020 [38]</td><td>14</td><td>Lymph nodes</td><td>Retrospective</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Better planning target volume coverage, fewer organs at risk dose violations</td><td></td></tr><tr><td>Schiff et al., 2022 [15]</td><td>8</td><td>Pancreas</td><td>Dosimetric study</td><td>Ethos™<sup>a</sup></td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Improved target coverage and sparing of organs at risk</td><td>Workflow time 36 min</td></tr><tr><td>Li et al., 2015 [57]</td><td>10</td><td>Pancreas</td><td>Retrospective</td><td>Cone-beam CT-based</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Improved planning target volume coverage, reduced dose to duodenum</td><td>Variation of amount of air significantly changed dose to the planning target volume</td></tr><tr><td>El-Bared et al., 2019 [58]</td><td>10</td><td>Pancreas</td><td>Retrospective</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Better tumour coverage, lower doses to organs at risk</td><td>Higher doses in some organs at risk for online adaptive radiotherapy plans (spinal cord)</td></tr><tr><td>Dunlop et al., 2020 [59]</td><td>5</td><td>Prostate</td><td>Prospective</td><td>MRI-guided linear accelerator</td><td>Hypofractionated</td><td>Dosimetric</td><td>Coverage increase, organs at risk constraints achieved</td><td></td></tr><tr><td>Brennan et al., 2023 [16]</td><td>15</td><td>Prostate</td><td>Retrospective</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Good tumour coverage, reduced dose to the organs at risk</td><td></td></tr><tr><td>Fischer et al., 2024 [60]</td><td>6</td><td>Prostate bed</td><td>Prospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Better planning target volume coverage</td><td>Medium time 25 min vs. 8 min for image-guided radiotherapy</td></tr><tr><td>Morgan et al., 2022 [61]</td><td>20</td><td>Prostate bed</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Small margins</td><td></td></tr><tr><td>Eijkelenkamp et al., 2021 [62]</td><td>15</td><td>Rectum</td><td>Dosimetric study</td><td>MRI-guided linear accelerator</td><td>Hypofractionated</td><td>Dosimetric</td><td>Reduced margins</td><td>The shorter the treatment time, the smaller the margins needed to cover for the gross tumour volume movement</td></tr></tbody></table>

CT: computed tomography; MRI: magnetic resonance imaging; N/A: data not available.

<footnote>a Device manufactured by Varian Medical Systems, Inc.</footnote>
<table><caption>**Table 2**
Non-comparative trials on online adaptive radiotherapy.</caption><thead><tr><th>Reference</th><th>Number of patients</th><th>Tumour type</th><th>Study type</th><th>Online adaptive radiotherapy method</th><th>Type of radiotherapy</th><th>Endpoint</th><th>Dosimetric benefit</th><th>Clinical benefit</th><th>Comments</th></tr></thead><tbody><tr><td>Alongi et al., 2020 [63]</td><td>25</td><td>Prostate</td><td>Prospective observational study</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low reported toxicity</td><td></td></tr><tr><td>Bordeau et al., 2023 [36]</td><td>56</td><td>Liver</td><td>Prospective registry study</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low toxicity and good local control</td><td></td></tr><tr><td>Bruynzeel et al., 2019 [64]</td><td>101</td><td>Prostate</td><td>Phase 2</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low genitourinary and gastrointestinal toxicity</td><td></td></tr><tr><td>Chuong et al., 2024 [65]</td><td>136</td><td>Pancreas</td><td>Phase 2</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low toxicity rate</td><td></td></tr><tr><td>de Jong et al., 2021 [66]</td><td>12</td><td>Rectum</td><td>Prospective observational study</td><td>Ethos<sup>TMa</sup></td><td>Hypofractionated</td><td>Both</td><td>Good target coverage</td><td></td><td>Thirty-four min for treatment</td></tr><tr><td>Finazzi et al., 2020 [35]</td><td>10</td><td>Lung</td><td>Prospective</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td>Allows single fraction with good planning target volume coverage</td><td></td><td>Acceptable treatment time, need of real-time guidance</td></tr><tr><td>Finazzi et al., 2020 [67]</td><td>54</td><td>Lung</td><td>Retrospective</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td>Low toxicity rate</td><td></td><td></td></tr><tr><td>Henke et al., 2017 [68]</td><td>20</td><td>Abdominal malignancies</td><td>Phase 1</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Both</td><td>Sparing of organs at risk, better planning target volume coverage, dose escalation</td><td>No toxicity</td><td></td></tr><tr><td>Henke et al., 2022 [69]</td><td>10</td><td>Ovarian oligometastases</td><td>Phase 1</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Both</td><td>Sparing of organs at risk, better planning target volume coverage</td><td></td><td></td></tr><tr><td>Leeman et al., 2022 [22]</td><td>22</td><td>Prostate</td><td>Phase 1</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Both</td><td>Sparing of organs at risk</td><td>Low reported toxicity</td><td></td></tr><tr><td>Michalet et al., 2022 [31]</td><td>30</td><td>Pancreas</td><td>Prospective registry study</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Both</td><td>Benefit in tumour coverage and sparing of organs at risk</td><td>Low toxicity</td><td></td></tr><tr><td>Poon et al., 2021 [70]</td><td>51</td><td>Prostate</td><td>Prospective observational study</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low reported toxicity</td><td></td></tr><tr><td>Potkrajcic et al., 2024 [71]</td><td>23</td><td>Prostate</td><td>Prospective basket study</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>No late toxicity</td><td>Mean duration 38 min</td></tr><tr><td>Stanley et al., 2023 [72]</td><td>97</td><td>All</td><td>Retrospective</td><td>Ethos<sup>TMa</sup></td><td>All</td><td>Quality assurance</td><td></td><td></td><td>Average session time 35 min</td></tr><tr><td>Tetar et al., 2021 [73]</td><td>101</td><td>Prostate</td><td>Phase 2</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low toxicity</td><td></td></tr><tr><td>Tetar et al., 2019 [74]</td><td>140</td><td>Prostate</td><td>Phase 2</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Feasibility</td><td></td><td></td><td>Average duration 45 min but well tolerated</td></tr><tr><td>Teunissen et al., 2023 [23]</td><td></td><td>Prostate</td><td>Prospective cohort</td><td>MRI-guided linear accelerator</td><td>S stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low toxicity</td><td>Increase in erectile dysfunction</td></tr><tr><td>Ugurluer et al., 2024 [30]</td><td>12</td><td>Cervix</td><td>Prospective cohort</td><td>MRI-guided linear accelerator</td><td>Conventional or boost</td><td>Clinical</td><td></td><td>Good clinical outcomes</td><td></td></tr><tr><td>Ugurluer et al., 2020 [75]</td><td>50</td><td>Prostate</td><td>Retrospective</td><td>MRI-guided linear accelerators linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low toxicity</td><td>Median time 45 min</td></tr><tr><td>Westley et al., 2024 [26]</td><td>20</td><td>Prostate</td><td>Phase 2</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Acceptable toxicity</td><td></td></tr><tr><td>Yim et al., 2024 [76]</td><td>20</td><td>Kidney</td><td>Phase 1</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Low toxicity rate</td><td></td></tr></tbody></table>

MRI: magnetic resonance imaging.

<footnote>a Device manufactured by Varian Medical Systems, Inc.</footnote>
<table><caption>**Table 3**
Comparative trials on online adaptive radiotherapy.</caption><thead><tr><th>Reference</th><th>Number of patients</th><th>Tumour type</th><th>Study type</th><th>Online adaptive radiotherapy method</th><th>Type of radiotherapy</th><th>Endpoint</th><th>Dosimetric benefit</th><th>Clinical benefit</th><th>Comments</th></tr></thead><tbody><tr><td>Varga et al., 2025 [48]</td><td>8</td><td>Bladder</td><td>Retrospective</td><td>Ethos™</td><td>Conventional</td><td>Dosimetric</td><td>Reduced planning target volume, reduction in irradiated healthy tissues</td><td></td><td>Average duration 15 min</td></tr><tr><td>Åström et al., 2022 [28]</td><td>16</td><td>Bladder</td><td>Prospective observational study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Reduction in planning target volume and dose to organs at risk</td><td></td><td>Median time 13.9 min</td></tr><tr><td>Huddart et al., 2025 [29]</td><td>345</td><td>Bladder</td><td>Phase 2</td><td>Plan of the day</td><td>Conventional</td><td>Both</td><td>Enables dose escalation without compromising organs at risk</td><td>Acceptable toxicity</td><td>N/A</td></tr><tr><td>Vestergaard et al., 2014 [44]</td><td>20</td><td>Bladder</td><td>Phase 2</td><td>Plan of the day</td><td>Conventional</td><td>Dosimetric</td><td>Reduced planning target volume</td><td></td><td>N/A</td></tr><tr><td>Yen et al., 2024 [50]</td><td>10</td><td>Cervix</td><td>Prospective registry study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Reduced doses to organs at risk, improved planning target volume coverage</td><td></td><td></td></tr><tr><td>Dohopolski et al., 2022 [53]</td><td>10</td><td>Head and neck</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Good target coverage, reduced margins and doses to organs at risk</td><td></td><td>Reduced margins are needed to see dosimetric benefits</td></tr><tr><td>Enocson et al., 2025 [54]</td><td>31</td><td>Head and neck</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Good target coverage</td><td></td><td>Accuracy of Ethos automatic contouring considered acceptable</td></tr><tr><td>Mao et al., 2022 [56]</td><td>10</td><td>Lung</td><td>Retrospective</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Improved planning target volume coverage</td><td></td><td></td></tr><tr><td>Winkel et al., 2020 [38]</td><td>14</td><td>Lymph nodes</td><td>Retrospective</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Better planning target volume coverage, fewer organs at risk dose violations</td><td></td><td></td></tr><tr><td>El-Bared et al., 2019 [58]</td><td>10</td><td>Pancreas</td><td>Retrospective</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Better tumour coverage, lower doses to organs at risk</td><td></td><td>Higher doses in some organs at risk for online adaptive radiotherapy plans (spinal cord)</td></tr><tr><td>Li et al., 2015 [57]</td><td>10</td><td>Pancreas</td><td>Retrospective</td><td>Cone-beam CT-based</td><td>Stereotactic body radiotherapy</td><td>Dosimetric</td><td>Improved planning target volume coverage, reduced dose to duodenum</td><td></td><td>Variation of amount of air significantly changed dose to the planning target volume</td></tr><tr><td>Weisz Ejlsmark et al., 2024 [77]</td><td>28</td><td>Pancreas</td><td>Phase 2</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Acceptable toxicity</td><td>N/A</td></tr><tr><td>Fischer et al., 2024 [60]</td><td>6</td><td>Prostate bed</td><td>Dosimetric study</td><td>Ethos™<sup>a</sup></td><td>Conventional</td><td>Dosimetric</td><td>Better planning target volume coverage</td><td></td><td>Medium time 25 min vs. 8 min for image-guided radiotherapy</td></tr><tr><td>Ma et al., 2023 [24]</td><td></td><td>Prostate bed</td><td>Phase 2</td><td>MRI-guided linear accelerator</td><td>Stereotactic body radiotherapy</td><td>Clinical</td><td></td><td>Significantly lower rate of toxicity</td><td>N/A</td></tr></tbody></table>

CT: computed tomography; N/A: data not available; MRI: magnetic resonance imaging.

<footnote>a Device manufactured by Varian Medical Systems, Inc.</footnote>
<table><caption>**Table 4**
Ongoing randomized clinical trials on adaptive radiotherapy.</caption><thead><tr><th>NCT reference</th><th>Conditions</th><th>Intervention</th><th>Control arm</th><th>Radiotherapy modality</th><th>Phases</th></tr></thead><tbody><tr><td>NCT06230549</td><td>Cervical cancer</td><td>Online adaptive radiotherapy</td><td>Image-guided radiotherapy</td><td>Conventional fractionation</td><td>N/A</td></tr><tr><td>NCT06562166</td><td>Cervical cancer</td><td>Online adaptive radiotherapy</td><td>Image-guided radiotherapy</td><td>Conventional fractionation</td><td>2</td></tr><tr><td>NCT06641635</td><td>Cervical cancer</td><td>Moderated hypofractionated online adaptive radiotherapy</td><td>Conventional fractionation image-guided radiotherapy</td><td>Hypofractionation</td><td>3</td></tr><tr><td>NCT04984343</td><td>Prostate cancer</td><td>Two fractions MRI-guided stereotactic body radiotherapy</td><td>Five fractions MRI-guided stereotactic body radiotherapy</td><td>Stereotactic body radiotherapy</td><td>3</td></tr><tr><td>NCT06518226</td><td>Prostate cancer</td><td>Two fractions MRI-guided stereotactic body radiotherapy</td><td>Five fractions MRI-guided stereotactic body radiotherapy</td><td>Stereotactic body radiotherapy</td><td>N/A</td></tr><tr><td>NCT06216171</td><td>Head and neck cancer</td><td>Online adaptive radiotherapy</td><td>Image-guided radiotherapy</td><td>Conventional fractionation</td><td>N/A</td></tr><tr><td>NCT06516133</td><td>Head and neck cancer (nasopharynx)</td><td>Online adaptive radiotherapy with reduced margins</td><td>Image-guided radiotherapy with conventional margins</td><td>Conventional fractionation</td><td>3</td></tr><tr><td>NCT06568705</td><td>Breast cancer</td><td>Hypofractionated online adaptive radiotherapy</td><td>Moderately hypofractionated online adaptive radiotherapy</td><td>Hypofractionation</td><td>2</td></tr><tr><td>NCT06840665</td><td>Locally advanced rectal cancer</td><td>MRI-guided radiotherapy with lymph node sparing</td><td>MRI-guided conventional volumes</td><td>Hypofractionation</td><td>2</td></tr><tr><td>NCT06542159</td><td>Non-small cell lung cancer or pulmonary oligometastases</td><td>Online adaptive radiotherapy</td><td>Image-guided radiotherapy</td><td>Stereotactic body radiotherapy</td><td>2</td></tr></tbody></table>

MRI: magnetic resonance imaging; N/A: data not available.

of these systems may require hiring additional personnel as well. However, although these techniques require additional personnel and thorough organization, treatment time can be reduced after an initial learning curve. Furthermore, delegating recontouring and plan validation through radiation therapist-led workflows have eased their implementation in daily clinical practice [12]. However, one of the main concerns with prolonged treatment time is the patient positioning. MR-guided linear accelerators now embark a tracking system, ensuring the real-time adequacy of patient positioning during the treatment session. Thus, despite the prolonged treatment time, radiation dose can be delivered safely to the target region [40].

However, this prolonged treatment time can hinder the daily number of patients treated. Therefore, many centres equipped with CT-based online adaptive radiotherapy linear accelerators (ETHOS®) only use its workflow for a small number of patients, using the system as a conventional linear accelerator for most. Thus, online adaptive radiotherapy systems might be more relevant as additional systems in an already well-functioning department.

Another setback of online adaptive radiotherapy systems, especially MR-guided linear accelerators, is their cost. Apart from the equipment itself, which represents a substantial investment, direct clinical costs include additional personnel, space and material costs, leading to an overall cost much higher than that of CT-guided radiotherapy [41]. Nonetheless, by allowing higher dose per fraction (and thus shorter treatments) and by reducing treatment-related toxicity, MR-guided radiotherapy can still be cost-effective [42]. However, this might not be true for all adaptive radiotherapy workflows. In conventionally fractionated treatments, the additional cost due to adaptive radiotherapy might not be balanced by the toxicity benefits: in the Artix study, in head and neck cancer, the cost-effectiveness ratio of weekly adaptive radiotherapy for parotid sparing was in favour of conventional intensity-modulated radiotherapy [43].

## 5. Conclusion

Adaptive radiotherapy, whether offline or online has shown numerous dosimetric clinical benefits for most tumour localizations. Adaptive radiotherapy and more recently the online method

potentially represent a major turning point in modern radiotherapy. Although there is a dosimetric benefit, the clinical benefit remains to be demonstrated in many disease sites, in terms of toxicity reduction or improved tumour control. However, its implementation must be subject to careful foreplaning, as it requires increased time, logistics and security. This represents an extra burden, and the cost/efficiency of the approach must be discussed. Taking all these elements into account, the online method might be more suited for adaptive stereotactic body radiotherapy to limit the setbacks due to these workflows. In many cases, facilitating offline adaptive radiotherapy through improved workflows, which is becoming available through commercial-based softwares, will likely be sufficient. Last, clinical trials should be encouraged to demonstrate the clinical benefit of adaptive radiotherapy approaches.

## Authors' contributions

AL, PB: conceptualization, investigation, writing – original draft preparation, reviewing and editing.

## Funding

This work has not received any specific grant from public, commercial or not-for-profit funding bodies.

## Disclosure of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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