Online Radiotherapy

The Paradigm Shift to Real-Time Adaptive Radiotherapy

Background: Adaptive radiotherapy (ART) involves the continuous adaptation of the radiation plan according to patient- and tumor-specific feedback. In online ART, the plan is optimized in real time during the treatment; in offline ART, the plan is recalculated between treatment sessions. Hybrid linear accelerators with integrated CT, MRI, or PET are required to perform online ART.

Methods: This review is based on clinically relevant studies on online ART (January 2019 – May 2024) that were retrieved by a selective search in PubMed.

Results: Online ART is a new technique for which no phase 3 trials have been published; in contrast, multiple randomized trials are already available for offline ART. The initial findings of a randomized phase 2 trial of online ART for head and neck cancer showed lower rates of G2 or higher radiation-induced dermatitis (8% vs. 31%, p = 0.05) and a lower dose to the parotid gland (mean dose: 11.5 Gy vs. 16.0 Gy, p = 0.02) with online ART compared to standard radiochemotherapy. Moreover, observational studies show that online ART is feasible and spares organs at risk in patients with esophageal, pancreatic, rectal, and prostatic cancer. Additionally, online ART can enable simulation-free treatment planning and faster initiation of radiotherapy. It is, however, more demanding of time and resources and more costly than standard radiotherapy, and no studies with long-term clinical endpoints are available to date.

Conclusion: Initial studies confirm the feasibility of online ART and arouse the hope that it will enable more precise radiotherapy with less damage to surrounding structures. Phase 3 trials are needed so that the patient groups who stand to benefit most from online ART can be identified.

Cite this as:Kalinauskaite G, Nikolaou K, Wittig A, Zips D, Zöphel K, Senger C: Online radiotherapy—the paradigm shift to real-time adaptive radiotherapy. Dtsch Arztebl Int 2025; 122: 59–64. DOI: 10.3238/arztebl.m2024.0242

Adaptive radiotherapy (ART) enables continuous adaptation of the radiation plan according to systematic tumor-specific or patient-specific feedback (1). The patient’s anatomy of the day, the extent of the tumor, the findings of functional imaging such as positron emission tomography (PET), and those of diffusion-weighted magnetic resonance imaging (MRI) can all be taken into account, as can information provided by the patients themselves (2). In contrast to conventional radiotherapy, in which the radiation plan usually remains unchanged throughout the entire course of treatment, ART involves systematic modification. The primary goal of this adaptation is to ensure complete coverage of the tumor with the required radiation dose, including dose escalation if necessary, while as far as possible sparing the healthy organs (Figures a–d).

Figure

Cone-beam computed tomography (CBCT)-based online adaptive radiotherapy in prostate adenocarcinoma (P): comparison of a non-adaptive plan (a, c) with a plan adjusted in real time (b, d). a, b) Restoration of target volume coverage; c, d) sparing of the mobile small intestine (SI)

A distinction is made between online ART and offline ART. Online ART follows the scan–plan–treat principle, in which the radiation plan is modified in real time according to the findings of MRI or computed tomography (CT) scans generated directly on the treatment table. This can extend the duration of the session by 20–50 minutes. In offline ART, the radiation plan is recalculated between the treatment fractions after repetition of planning CT, either ad hoc (e.g., in the case of positional imprecision after weight loss), systematically (e.g., at weekly intervals), or when certain thresholds for tumor shrinkage or PET signal changes are reached (2). In conventional image-guided radiotherapy, cone-beam CT (CBCT) or kV imaging (kilovoltage radiographs) is used before every session to check the three-dimensional (3D) positioning of the patient without changing the radiation plan. Such a session takes about 10 minutes. Table 1 shows the differences between conventional radiotherapy, online ART, and offline ART.

Table 1

Comparison of the different methods for image-guided radiotherapy

The first evidence of the clinical benefits of ART came from studies of offline ART, which is currently considered good clinical practice. Technical advances such as artificial intelligence (AI), and new radiotherapy devices capable of adapting plans in real time have made online ART possible. (3). These new devices include hybrid instruments combining Linacs with MRI (MR-Linac), CT (CBCT-Linac), or PET (PET/CT-Linac) (2, 3). AI is used to accelerate particular steps in the process, e.g., for automatic normal-tissue segmentation, thus shortening considerably the time taken up by planning (3, 4, 5). MR-Linacs are currently in operation at four German university hospitals, and around 18 CBCT-Linacs are being used for online ART across the country (6, 7, 8, 9).

Online ART has the potential to increase the precision of dose delivery and thus enable narrowing of the safety margins around the target volumes to compensate for tumor or patient motion (10, 11, 12). The procedure is particularly suitable for patients whose tumor or surrounding organs display high mobility or variability, but demands good tolerance of long treatment times (13)

Investment in hybrid Linacs and the additional costs incurred by the time- and resource-intensive nature of online ART should be assessed according to the principles of Health Technology Assessment. This article analyzes the early evidence on online ART and formulates recommendations for clinical practice and future research.

Methods

A selective search of the publications indexed in PubMed between January 2019 and May 2024 was conducted to identify records featuring the terms “online”/“daily” and “adaptive radiotherapy”/“adaptive radiation therapy” in combination with the corresponding tumor entity. Studies that investigated clinical endpoints were included, while publications with a purely technical focus and case reports were excluded.

Results

Clinical trials, including prospective phase-2 studies and prospective cohort studies, explored the feasibility, safety, and clinical endpoints of online ART (Table 2). Because the method is still in development, so far only one randomized controlled phase-2 trial is available, in the form of an abstract (10). Several randomized controlled trials of offline ART have been published (14, 15, 16, 17). The following sections present the applications and potential benefits of online ART, based on the offline ART findings for different tumor types.

Table 2

Comparison of the prospective studies on online and offline adaptive radiotherapy

Head and neck

Anatomical changes (tumor response/weight loss/tissue edema) often occur during the course of radiotherapy in patients with tumors of the head and neck. For tumors located near organs at risk, such as the parotid gland or the constrictor muscle of the pharynx, use of conventional irradiation techniques may result in permanent impairment of organ function.

A randomized controlled phase-3 trial compared standard radiochemotherapy and offline ART with weekly plan adjustment in patients with oropharyngeal cancer (14). The primary endpoint, reduction of the xerostomia rate after 12 months, was not attained: the average saliva flow was 630 mg/min in the experimental arm and 584 mg/min in the standard arm (p = 0.64), with xerostomia rates of 47.5% and 47.9% respectively (p > 0.99). Parotid secretory function (secondary endpoint) tended to be better in the offline ART group (48% vs. 41%; p = 0.02).

The phase-2 DARTBOARD study on online ART in head and neck cancer investigated the xerostomia rate 12 months after online ART with a narrower safety margin (1–2 mm) versus standard treatment (5 mm) (10). After 7 months’ follow-up, the primary endpoint results were not yet available but preliminary analyses showed fewer cases of grade ≥ 2 acute dermatitis (8% versus 31%; p = 0.05) and better ipsilateral parotid sparing (mean parotid dose: 11.5 Gy versus 16.0 Gy; p = 0.02) in the online ART group. The patients spent an average of 33 minutes in the treatment room. ReSTART is an ongoing controlled phase-3 study to explore the reduction in xerostomia rate achieved by online ART in head and neck cancer (18).

Dysphagia, like xerostomia, is a common adverse effect of radiotherapy. A controlled phase-3 study on dysphagia-optimized radiotherapy showed that reducing the mean radiation dose to the pharyngeal constrictor muscles to < 50 Gy led to a reduction in patient-reported dysphagia (95% confidence interval [0.4; 13.9], p = 0.037) (19). Through greater precision of dose distribution and narrower safety margins, online ART has the potential to further improve on these results. This option is currently being pursued in a number of studies (NCT 05831917, NCT06216171, NCT06214611).

Thorax and abdomen

Anatomical changes such as atelectasis, pulmonary infiltration, and tumor response indicate the potential benefit

of ART in non-small-cell lung cancer (NSCLC). Radiation pneumonitis and cardiac and esophageal toxicity are factors that limit radiotherapy (20, 21). Particularly interesting in this regard is the ongoing randomized controlled ARTIA-Lung trial, which is investigating the efficacy of daily online ART with narrower safety margins versus standard radiochemotherapy, including gating in both study arms, against locally advanced NSCLC (NCT05488626). The primary endpoint of this study is the rate of ≥ grade 3 (G3) toxicity for cough, dyspnea, and dysphagia. In a retrospective analysis of 439 patients with NSCLC, offline ART with daily CBCT scans matching on the tumor was compared with non-adaptive treatment with daily CBCT scans matching on the thoracic vertebrae. Offline ART was associated with a reduction in treatment volume by 186 cm³ (p < 0.001). There were fewer cases of symptomatic (hazard ratio [HR] 0.31 [0.22; 0.46], p < 0.001) and severe (HR 0.30 [0.17; 0.52], p < 0.001) radiation pneumonitis, and 2-year overall survival (HR 0.71 [0.57; 0.88], p = 0.002) was greater (22).

In a multicenter phase-2 study, 136 patients with pancreatic cancer received MR-guided adaptive stereotactic radiotherapy with 50 Gy in five fractions (23). Overall, 93% of the fractions were delivered in adaptive mode to prevent excessive radiation exposure of gastrointestinal organs. The primary endpoint, reduction of online ART-associated acute ≥ G3 gastrointestinal toxicity to below 8%, was achieved. The rate of local control (freedom from recurrence/progression of the primary tumor) after 2 years was 78%. In the non-controlled phase-1b/2a study R-IDEAL on the feasibility of treating esophageal cancer by means of online ART with MR-Linacs, nine patients received a total of 212 fractions, 86% of them delivered in adaptive mode (24). Feasibility was defined as ≤ 60 minutes on the treatment table for > 75% of the fractions and > 95% of the treatments with MR-Linacs. The average duration of treatment was 53 minutes. Two patients were switched to conventional Linacs because they experienced discomfort in > 5% of fractions. Online ART with a safety margin of 6 mm reduced the mean dose to the lungs and the heart by 26% and 12% (p < 0.001) respectively.

Pelvis

Anatomical fluctuations due to variable filling of the bladder and rectum can be adjusted for by daily dose modifications in patients being treated with online ART. Of the 1772 patients in the multicenter MOMENTUM study, 745 patients with prostate cancer were treated with the 1.5-T MR-Linac. Around 60% of the treatments were by means of online ART (25). The overall incidence of G3 toxicity was low: 1.4% [0.9; 2.0] in the entire cohort and 0.4% [0.1; 1.0] in the online ART group. In a phase-2 study on MRI-guided ultrahypofractionated stereotactic body radiotherapy (36.25 Gy/five fractions) with urethral protection in 101 patients with prostate cancer, acute gastrointestinal and urogenital toxicity ≥ G2 was lowered to 5.0% and 23.8% respectively, exceeding the study hypothesis (lowering to 15% and 40%) (12). The primary endpoint of another phase-2 study on ultrahypofractionated stereotactic body radiotherapy (37.5 Gy/five fractions, with optional dose escalation to 40 Gy) in 69 patients with prostate cancer was gastrointestinal and urogenital toxicity ≥ G2 within 12 months after treatment (13). There were no cases of G3 toxicity, and 23% of patients developed G2 toxicity within 3 months after treatment.

A feasibility study on organ preservation in distal rectal cancer investigated online ART with weekly MR-Linac-guided administration of 3 Gy in addition to standard radiochemotherapy (11). By three months after online ART, four of the five patients had achieved complete clinical remission and the other patient had a pathological remission after local excision. At 8–12 months after treatment, organ preservation was possible in all patients. G3 toxicities disappeared within 6 months, and the patients’ quality of life remained stable.

MRI- and CT-based adaptive radiotherapy

The high soft-tissue contrast, real-time visualization, and versatile MR sequences yielded by the combination of Linac and MRI enable precise definition of the target structures and organs at risk. Novel 3D real-time MR techniques minimize image latency, and the motion-guided (e.g., by respiration) radiotherapy (beam gating) automatically shuts the beam off if the target volume’s position changes. This may enable radiotherapy with a locally curative intent in complex, mobile areas such as the upper abdomen and the central lung (26, 27, 28).

Quantitative MR biomarkers such as the apparent diffusion coefficient (ADC) are becoming increasingly important in personalized tumor treatment because of their potential to detect early treatment effects or predict the disease course (29). A study of nine patients with prostate cancer showed a significant increase in tumor ADC compared with baseline during the second week of online ART with an MR-Linac. This was the case with both the 1.5-T MR-Linac and with 3-T MRI (30). Despite different absolute values, the dynamics were comparable, supporting the potential use of the ADC as a biomarker for tumor response in online ART. The translation of reproducible MR biomarkers to MR-guided radiotherapy systems and their verification are crucial for future clinical studies.

As a result of significant advances in CBCT technology (larger detector, faster scans, more sophisticated reconstruction algorithms), online ART can now also be performed with CBCT-Linacs (31). To date, the dose distribution has been calculated with the aid of AI on the basis of a synthetic CT that is generated from planning CT and CBCT data and ensures high HU accuracy (HU, Hounsfield unit) (3). Systems such as HyperSight CBCT enhance image quality, particularly in tumors with high soft-tissue contrast, and permit direct dose calculation on the CBCT scans (32). However, the acquisition costs of this technology amount to several hundred thousand Euros.

Radiation planning usually involves a dedicated planning CT with the patient in a defined position, which involves additional time, extra visits to the hospital, and higher personnel costs. Simulation-free radiotherapy generates treatment plans directly based on diagnostic imaging data and eliminates the need for a planning CT. The goal of the prospective FAST-METS study was to perform simulation-free palliative radiotherapy of patients with bone metastases in a single hospital visit of < 2 hours (33). The entire process, comprising consultation, planning, and irradiation (1 × 8 Gy), lasted 85 minutes, compared with 335 minutes for the conventional process. The average time of 30 minutes on the treatment table was tolerated well by 60% of the patients.

PET-based adaptive radiotherapy

PET/CT has a well-established role in radiation planning. The radiopharmaceutical 2-(18F)-fluorodeoxyglucose (18F-FDG) visualizes tumor metabolism and is used for precise tumor volume definition and assessment of treatment response (34). In this regard, studies on dose painting investigate localized dose adjustment within the tumor based on specific tumor properties.

A randomized controlled phase-3 trial on advanced head and neck cancer compared offline adaptive 18F-FDG-PET-guided dose escalation (up to 84 Gy/35 fractions) with conventional radiochemotherapy (70 Gy/35 fractions). The primary endpoints were 2-year locoregional control (freedom from recurrence and progression of the primary tumor and the regional lymph nodes). The locoregional control rate was 6.7% higher in the experimental arm, but the difference was not significant (HR 0.75 [0.43; 1.31], p = 0.31) (15). Post-hoc analyses showed that patients with N0–1 lymph nodes (HR 0.21 [0.05; 0.93]) and those with oropharyngeal cancer (HR 0.31 [0.10; 0.95]) benefited from dose escalation in terms of locoregional control. The rates of toxicity were similar, except for an increase in G3 pharyngolaryngeal stenoses in the dose escalation arm (0% versus 4%, p = 0.05).

In a controlled phase-2 study, offline ART with 18F-FDG-PET-based dose escalation in head and neck cancer (< 1.75 cm³ tumor volume > 84 Gy) led to an improved local control rate after 1 and 2 years compared to standard radiochemotherapy (HR 3.13 [1.13; 8.71], p = 0.021) (16). There was no difference in the regional control rate (HR 1.04 [0.39; 2.78], p = 0.935). The rates of late toxicity were similar, but more cases of G3 to G4 mucosal ulceration (33% versus 7%, p = 0.03), together with one case of G5 toxicity, occurred in the experimental arm. The experimental arm contained significantly more patients with oropharyngeal cancer (72% versus 40%, p = 0.01), so the improvement in local control should be viewed with caution. In addition to 18F-FDG, radiotracers such as [18F]-fluoromisonidazole detect tumor-specific properties such as hypoxia and can be used in adaptive radiotherapy (35, 36).

PET-guided online ART demands close cooperation between specialists in nuclear medicine and radiation oncology as well as medical physicists, rendering the procedure more personnel-intensive and therefore costlier. The first PET hybrid device recently received FDA approval for radiotherapy of lung and bone tumors (2). The development of more sensitive PET detectors and AI-based reconstruction and correction algorithms has greatly improved PET both qualitatively and quantitatively, making it a highly interesting tool for use in online ART (2).

Discussion

Online ART is a new procedure and, as yet, no randomized controlled phase-3 trials have yet been published and there is only one phase-2 study. In contrast, offline ART has been in use for some time and there are a number of randomized controlled phase-2/3 trials. While one phase-2 study on offline ART for oropharyngeal cancer showed no improvement in the rate of xerostomia, the DARTBOARD study (phase 2) on daily online ART of head and neck cancer demonstrated better protection of the parotid gland and a lower incidence of dermatitis (10, 14). Moreover, toxicity levels comparable to those of standard treatment were achieved in randomized controlled trials of adaptive 18F-FDG-PET-based dose escalation in head and neck cancer (15, 16). The results regarding locoregional control were, however, inconsistent.

Prospective observational studies have confirmed the feasibility of online ART in different anatomical regions, and early research results indicate that ablative doses are possible at sites where local curative treatment is difficult, e.g., pancreatic cancer (23, 24, 37). The two published studies on ultrahypofractionated stereotactic body radiotherapy of the prostate both show a promising toxicity profile (12, 13). However, the limitations of online ART include much longer treatment times (24, 33). The online ART workflow currently still requires human intervention at many stages of the procedure, especially in verification of the segmentation of tumors and organs at risk. In some countries, for instance Germany, every adaptive plan has to be approved by physicians and medical physicists, a personnel-intensive and time-consuming process. Online ART is associated with high costs, not only due to equipment acquisition and clinical effort, but also because it is currently not specifically covered by health insurance. Online ART can enable simulation-free treatment planning, which may lead to swifter commencement of treatment, lower demand on personnel resources, and fewer hospital visits for the patients (33).

Furthermore, to date there are no studies with robust clinical endpoints, e.g., local control, which could potentially benefit from more precise dose coverage but might also be negatively impacted by narrower safety margins. Moreover, most studies lack direct comparisons with standard radiotherapy, no long-term data on clinical efficacy, and no patient-reported outcomes, including quality of life. Future research should focus on these aspects. Strategies must be developed to identify adaptation trigger points and for patient selection, e.g., by prediction of the anticipated adverse effects or tumor response by means of functional imaging.

Key areas for further development of online ART include:

• Development of new workflows
• Compilation of guidelines
• Preparation of financing models
• Establishment of safety measures
• Enhancement of the competence of radiotherapy technologists

Systematic evaluation of such techniques, e.g., in R-IDEAL studies, could enable evidence-based introduction of online ART—from the initial feasibility assessment through to long-term monitoring of efficacy and adverse effects (38). This structured approach will ensure that implementation of ART is not only medically beneficial, but also cost-effective and practicable.

Implications for clinical practice

The goal of online ART is to enable more precise and more individualized treatment of patients with different tumor entities by means of systematic adaptation of the radiation plan in real time. Initial studies have shown the feasibility and dosimetric benefits of this approach; the data on patient-relevant endpoints, including patient-reported outcomes, are sparse. Multicenter randomized studies at specialized centers are necessary to establish and validate online ART.

Conflict of interest statement

AW is secretary of the executive committee of the German Society of Radiooncology (Deutsche Gesellschaft für Radioonkologie, DEGRO).

DZ has received study support (third-party funds) from DFG, the medical faculties of Tübingen University and Charité Berlin, the federal state of Baden–Württemberg, Elekta, Philips, Varian/Siemens, Therapanacea, and PTW.

The remaining authors declare that no conflict of interest exists.

Submitted on 29 May 2024, revised version accepted on 13 November 2024

Translated from the original German by David Roseveare

Corresponding author
Dr. med. Goda Kalinauskaite
Klinik für Radioonkologie und Strahlentherapie
Charité – Universitätsmedizin Berlin
Augustenberger Platz 1
13353 Berlin, Germany

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