Understanding the Benefit of Magnetic Resonance-guided Adaptive Radiotherapy in Rectal Cancer Patients: a Single-centre Study.

AIMS: Neoadjuvant chemoradiotherapy followed by surgery is the mainstay of treatment for patients with rectal cancer. Standard clinical target volume (CTV) to planning target volume (PTV) margins of 10 mm are used to accommodate inter- and intrafraction motion of target. Treating on magnetic resonance-integrated linear accelerators (MR-linacs) allows for online manual recontouring and adaptation (MRgART) enabling the reduction of PTV margins. The aim of this study was to investigate motion of the primary CTV (CTVA; gross tumour volume and macroscopic nodes with 10 mm expansion to cover microscopic disease) in order to develop a simultaneous integrated boost protocol for use on MR-linacs. MATERIALS AND METHODS: Patients suitable for neoadjuvant chemoradiotherapy were recruited for treatment on MR-linac using a two-phase technique; only the five phase 1 fractions on MR-linac were used for analysis. Intrafraction motion of CTVA was measured between pre-treatment and post-treatment MRI scans. In MRgART, isotropically expanded pre-treatment PTV margins from 1 to 10 mm were rigidly propagated to post-treatment MRI to determine overlap with 95% of CTVA. The PTV margin was considered acceptable if overlap was >95% in 90% of fractions. To understand the benefit of MRgART, the same methodology was repeated using a reference computed tomography planning scan for pre-treatment imaging. RESULTS: In total, nine patients were recruited between January 2018 and December 2020 with T3a-T4, N0-N2, M0 disease. Forty-five fractions were analysed in total. The median motion across all planes was 0 mm, demonstrating minimal intrafraction motion. A PTV margin of 3 and 5mm was found to be acceptable in 96 and 98% of fractions, respectively. When comparing to the computed tomography reference scan, the analysis found that PTV margins to 5 and 10 mm only acceptably covered 51 and 76% of fractions, respectively. CONCLUSION: PTV margins can be reduced to 3-5 mm in MRgART for rectal cancer treatment on MR-linac within an simultaneous integrated boost protocol.

MRI-guided adaptive radiotherapy for prostate cancer: When do we need to account for intra-fraction motion?

A shift of the daily plan can mitigate target position changes that occur between daily MR acquisition and treatment for MR-linac radiotherapy, but increases the session time. We demonstrated that our workflow strategy and decision-making process, to determine whether a subsequent shift is necessary, is appropriate.

Feasibility of tumour-focused adaptive radiotherapy for bladder cancer on the MR-linac.

Bladder tumour-focused magnetic resonance image-guided adaptive radiotherapy using a 1.5 Tesla MR-linac is feasible. A full online workflow adapting to anatomy at each fraction is achievable in approximately 30 min. Intra-fraction bladder filling did not compromise target coverage with the class solution employed.

A Comparison of Isotoxic Dose-escalated Radiotherapy in Lung Cancer with Moderate Deep Inspiration Breath Hold, Mid-ventilation and Internal Target Volume Techniques.

AIMS: With interest in normal tissue sparing and dose-escalated radiotherapy in the treatment of inoperable locally advanced non-small cell lung cancer, this study investigated the impact of motion-managed moderate deep inspiration breath hold (mDIBH) on normal tissue sparing and dose-escalation potential and compared this to planning with a four-dimensional motion-encompassing internal target volume or motion-compensating mid-ventilation approach. MATERIALS AND METHODS: Twenty-one patients underwent four-dimensional and mDIBH planning computed tomography scans. Internal and mid-ventilation target volumes were generated on the four-dimensional scan, with mDIBH target volumes generated on the mDIBH scan. Isotoxic target dose-escalation guidelines were used to generate six plans per patient: three with a target dose cap and three without. Target dose-escalation potential, normal tissue complication probability and differences in pre-specified dose-volume metrics were evaluated for the three motion-management techniques. RESULTS: The mean total lung volume was significantly greater with mDIBH compared with four-dimensional scans. Lung dose (mean and V21 Gy) and mean heart dose were significantly reduced with mDIBH in comparison with four-dimensional-based approaches, and this translated to a significant reduction in heart and lung normal tissue complication probability with mDIBH. In 20/21 patients, the trial target prescription dose cap of 79.2 Gy was achievable with all motion-management techniques. CONCLUSION: mDIBH aids lung and heart dose sparing in isotoxic dose-escalated radiotherapy compared with four-dimensional planning techniques. Given concerns about lung and cardiac toxicity, particularly in an era of consolidation immunotherapy, reduced normal tissue doses may be advantageous for treatment tolerance and outcome.

An Inter-observer Study to Determine Radiotherapy Planning Target Volumes for Recurrent Gynaecological Cancer Comparing Magnetic Resonance Imaging Only With Computed Tomography-Magnetic Resonance Imaging.

AIMS: Target delineation uncertainty is arguably the largest source of geometric uncertainty in radiotherapy. Several factors can affect it, including the imaging modality used for delineation. It is accounted for by applying safety margins to the target to produce a planning target volume (PTV), to which treatments are designed. To determine the margin, the delineation uncertainty is measured as the delineation error, and then a margin recipe used. However, there is no published evidence of such analysis for recurrent gynaecological cancers (RGC). The aims of this study were first to quantify the delineation uncertainty for RGC gross tumour volumes (GTVs) and to calculate the associated PTV margins and then to quantify the difference in GTV, delineation uncertainty and PTV margin, between a computed tomography-magnetic resonance imaging (CT-MRI) and MRI workflow. MATERIALS AND METHODS: Seven clinicians delineated the GTV for 20 RGC tumours on co-registered CT and MRI datasets (CT-MRI) and on MRI alone. The delineation error, the standard deviation of distances from each clinician's outline to a reference, was measured and the required PTV margin determined. Differences between using CT-MRI and MRI alone were assessed. RESULTS: The overall delineation error and the resulting margin were 3.1 mm and 8.5 mm, respectively, for CT-MRI, reducing to 2.5 mm and 7.1 mm, respectively, for MRI alone. Delineation errors and therefore the theoretical margins, varied widely between patients. MRI tumour volumes were on average 15% smaller than CT-MRI tumour volumes. DISCUSSION: This study is the first to quantify delineation error for RGC tumours and to calculate the corresponding PTV margin. The determined margins were larger than those reported in the literature for similar patients, bringing into question both current margins and margin calculation methods. The wide variation in delineation error between these patients suggests that applying a single population-based margin may result in PTVs that are suboptimal for many. Finally, the reduced tumour volumes and safety margins suggest that patients with RGC may benefit from an MRI-only treatment workflow.

Feasibility of magnetic resonance guided radiotherapy for the treatment of bladder cancer.

Whole bladder magnetic resonance image-guided radiotherapy using the 1.5 Telsa MR-linac is feasible. Full online adaptive planning workflow based on the anatomy seen at each fraction was performed. This was delivered within 45 min. Intra-fraction bladder filling did not compromise target coverage. Patients reported acceptable tolerance of treatment.

Feasibility of markerless fluoroscopic real-time tumor detection for adaptive radiotherapy: development and end-to-end testing.

Respiratory-gated radiotherapy treatments of lung tumors reduce the irradiated normal tissue volume and potentially lower the risk of side effects. However, in clinical routine, the gating signal is usually derived from external markers or other surrogate signals and may not always correlate well with the actual tumor position. This study uses the kV-imaging system of a LINAC in combination with a multiple template matching algorithm for markerless real-time detection of the tumor position in a dynamic anthropomorphic porcine lung phantom. The tumor was realized by a small container filled with polymer dosimetry gel, the so-called gel tumor. A full end-to-end test for a gated treatment was performed and the geometric and dosimetric accuracy was validated. The accuracy of the tumor detection algorithm in SI- direction was found to be [Formula: see text] mm and the gel tumor was automatically detected in 98 out of 100 images. The measured 3D dose distribution showed a uniform coverage of the gel tumor and comparison with the treatment plan revealed a high 3D [Formula: see text]-passing rate of [Formula: see text] ([Formula: see text]). The simulated treatment confirmed the employed margin sizes for residual motion within the gating window and serves as an end-to-end test for a gated treatment based on a markerless fluoroscopic real-time tumor detection.

Edge effects in 3D dosimetry: characterisation and correction of the non-uniform dose response of PRESAGE®.

Previous work has shown that PRESAGE® can be used successfully to perform 3D dosimetric measurements of complex radiotherapy treatments. However, measurements near the sample edges are known to be difficult to achieve. This is an issue when the doses at air-material interfaces are of interest, for example when investigating the electron return effect (ERE) present in treatments delivered by magnetic resonance (MR)-linac systems. To study this effect, a set of 3.5 cm-diameter cylindrical PRESAGE® samples was uniformly irradiated with multiple dose fractions, using either a conventional linac or an MR-linac. The samples were imaged between fractions using an optical-CT, to read out the corresponding accumulated doses. A calibration between TPS-predicted dose and optical-CT pixel value was determined for individual dosimeters as a function of radial distance from the axis of rotation. This data was used to develop a correction that was applied to four additional samples of PRESAGE® of the same formulation, irradiated with 3D-CRT and IMRT treatment plans, to recover significantly improved 3D measurements of dose. An alternative strategy was also tested, in which the outer surface of the sample was physically removed prior to irradiation. Results show that for the formulation studied here, PRESAGE® samples have a central region that responds uniformly and an edge region of 6-7 mm where there is gradual increase in dosimeter response, rising to an over-response of 24%-36% at the outer boundary. This non-uniform dose response increases in both extent and magnitude over time. Both mitigation strategies investigated were successful. In our four exemplar studies, we show how discrepancies at edges are reduced from 13%-37% of the maximum dose to between 2 and 8%. Quantitative analysis shows that the 3D gamma passing rates rise from 90.4, 69.3, 63.7 and 43.6% to 97.3, 99.9, 96.7 and 98.9% respectively.

Blurring the lines for better visualisation.

On-treatment imaging in radiotherapy has evolved over the last 60 years, bringing with it changes in the roles of radiographers, radiologists and oncologists. The ability to acquire and interpret high quality images (2D kilovoltage and megavoltage imaging and 3D CT and cone-beam CT) for radiotherapy planning and delivery requires therapy radiographers to have skills and knowledge that overlap with those of diagnostic radiographers. With the implementation of MRI-guided radiotherapy, treatment radiographers and clinical oncologists are exploring new territory, requiring truly collaborative working practices with their radiology partners. This short communication introduces the first images acquired using the hybrid MR Linac at our institution.

Novel adaptive beam-dependent margins for additional OAR sparing.

Margins are employed in radiotherapy treatment planning to mitigate the dosimetric effects of geometric uncertainties for the clinical target volume (CTV). Unfortunately, whilst the use of margins can increase the probability that sufficient dose is delivered to the CTV, it can also result in delivering high dose of radiation to surrounding organs at risk (OARs). We expand on our previous work on beam-dependent margins and propose a novel adaptive margin concept, where margins are moulded away from selected OARs for better OAR-high-dose sparing, whilst maintaining similar dose coverage probability to the CTV. This, however, comes at a cost of a larger irradiation volume, and thus can negatively impact other structures. We investigate the impact of the adaptive margin concept when applied to prostate radiotherapy treatments, and compare treatment plans generated using our beam-dependent margins without adaptation, with adaption from the rectum and with adaptation from both the rectum and bladder. Five prostate patients were used in this planning study. All plans achieved similar dose coverage probability, and were able to ensure at least 90% population coverage with the target receiving at least 95% of the prescribed dose to [Formula: see text]. We observed overall better high-dose sparing to OARs that were considered when using the adapted beam-dependent PTVs, with the degree of sparing dependent on both the number of OARs under consideration as well as the relative position between the CTV and the OARs.

Adaptive Radiotherapy Enabled by MRI Guidance.

Adaptive radiotherapy (ART) strategies systematically monitor variations in target and neighbouring structures to inform treatment-plan modification during radiotherapy. This is necessary because a single plan designed before treatment is insufficient to capture the actual dose delivered to the target and adjacent critical structures during the course of radiotherapy. Magnetic resonance imaging (MRI) provides superior soft-tissue image contrast over current standard X-ray-based technologies without additional radiation exposure. With integrated MRI and radiotherapy platforms permitting motion monitoring during treatment delivery, it is possible that adaption can be informed by real-time anatomical imaging. This allows greater treatment accuracy in terms of dose delivered to target with smaller, individualised treatment margins. The use of functional MRI sequences would permit ART to be informed by imaging biomarkers, so allowing both personalised geometric and biological adaption. In this review, we discuss ART solutions enabled by MRI guidance and its potential gains for our patients across tumour types.

Geometric and dosimetric evaluations of atlas-based segmentation methods of MR images in the head and neck region.

Owing to its excellent soft-tissue contrast, magnetic resonance (MR) imaging has found an increased application in radiation therapy (RT). By harnessing these properties for treatment planning, automated segmentation methods can alleviate the manual workload burden to the clinical workflow. We investigated atlas-based segmentation methods of organs at risk (OARs) in the head and neck (H&N) region using one approach that selected the most similar atlas from a library of segmented images and two multi-atlas approaches. The latter were based on weighted majority voting and an iterative atlas-fusion approach called STEPS. We built the atlas library from pre-treatment T1-weighted MR images of 12 patients with manual contours of the parotids, spinal cord and mandible, delineated by a clinician. Following a leave-one-out cross-validation strategy, we measured the geometric accuracy by calculating Dice similarity coefficients (DSC), standard and 95% Hausdorff distances (HD and HD95), and the mean surface distance (MSD), whereby the manual contours served as the gold standard. To benchmark the algorithm, we determined the inter-observer variability (IOV) between three observers. To investigate the dosimetric effect of segmentation inaccuracies, we implemented an auto-planning strategy within the treatment planning system Monaco (Elekta AB, Stockholm, Sweden). For each set of auto-segmented OARs, we generated a plan for a 9-beam step and shoot intensity modulated RT treatment, designed according to our institution's clinical H&N protocol. Superimposing the dose distributions on the gold standard OARs, we calculated dose differences to OARs caused by delineation differences between auto-segmented and gold standard OARs. We investigated the correlations between geometric and dosimetric differences. The mean DSC was larger than 0.8 and the mean MSD smaller than 2 mm for the multi-atlas approaches, resulting in a geometric accuracy comparable to previously published results and within the range of the IOV. While dosimetric differences could be as large as 23% of the clinical goal, treatment plans fulfilled all imposed clinical goals for the gold standard OARs. Correlations between geometric and dosimetric measures were low with R2 < 0.5. The geometric accuracy and the ability to achieve clinically acceptable treatment plans indicate the suitability of using atlas-based contours for RT treatment planning purposes. The low correlations between geometric and dosimetric measures suggest that geometric measures alone are not sufficient to predict the dosimetric impact of segmentation inaccuracies on treatment planning for the data utilised in this study.

Combining radiation with hyperthermia: a multiscale model informed by in vitro experiments.

Combined radiotherapy and hyperthermia offer great potential for the successful treatment of radio-resistant tumours through thermo-radiosensitization. Tumour response heterogeneity, due to intrinsic, or micro-environmentally induced factors, may greatly influence treatment outcome, but is difficult to account for using traditional treatment planning approaches. Systems oncology simulation, using mathematical models designed to predict tumour growth and treatment response, provides a powerful tool for analysis and optimization of combined treatments. We present a framework that simulates such combination treatments on a cellular level. This multiscale hybrid cellular automaton simulates large cell populations (up to 107 cells) in vitro, while allowing individual cell-cycle progression, and treatment response by modelling radiation-induced mitotic cell death, and immediate cell kill in response to heating. Based on a calibration using a number of experimental growth, cell cycle and survival datasets for HCT116 cells, model predictions agreed well (R2 > 0.95) with experimental data within the range of (thermal and radiation) doses tested (0-40 CEM43, 0-5 Gy). The proposed framework offers flexibility for modelling multimodality treatment combinations in different scenarios. It may therefore provide an important step towards the modelling of personalized therapies using a virtual patient tumour.

A novel probabilistic approach to generating PTV with partial voxel contributions.

Radiotherapy treatment planning for use with high-energy photon beams currently employs a binary approach in defining the planning target volume (PTV). We propose a margin concept that takes the beam directions into account, generating beam-dependent PTVs (bdPTVs) on a beam-by-beam basis. The resulting degree of overlaps between the bdPTVs are used within the optimisation process; the optimiser effectively considers the same voxel to be both target and organ at risk (OAR) with fractional contributions. We investigate the impact of this novel approach when applied to prostate radiotherapy treatments, and compare treatment plans generated using beam dependent margins to conventional margins. Five prostate patients were used in this planning study, and plans using beam dependent margins improved the sparing of high doses to target-surrounding OARs, though a trade-off in delivering additional low dose to the OARs can be observed. Plans using beam dependent margins are observed to have a slightly reduced target coverage. Nevertheless, all plans are able to satisfy 90% population coverage with the target receiving at least 95% of the prescribed dose to [Formula: see text].

Evaluation of a multi-atlas CT synthesis approach for MRI-only radiotherapy treatment planning.

BACKGROUND AND PURPOSE: Computed tomography (CT) imaging is the current gold standard for radiotherapy treatment planning (RTP). The establishment of a magnetic resonance imaging (MRI) only RTP workflow requires the generation of a synthetic CT (sCT) for dose calculation. This study evaluates the feasibility of using a multi-atlas sCT synthesis approach (sCTa) for head and neck and prostate patients. MATERIAL AND METHODS: The multi-atlas method was based on pairs of non-rigidly aligned MR and CT images. The sCTa was obtained by registering the MRI atlases to the patient's MRI and by fusing the mapped atlases according to morphological similarity to the patient. For comparison, a bulk density assignment approach (sCTbda) was also evaluated. The sCTbda was obtained by assigning density values to MRI tissue classes (air, bone and soft-tissue). After evaluating the synthesis accuracy of the sCTs (mean absolute error), sCT-based delineations were geometrically compared to the CT-based delineations. Clinical plans were re-calculated on both sCTs and a dose-volume histogram and a gamma analysis was performed using the CT dose as ground truth. RESULTS: Results showed that both sCTs were suitable to perform clinical dose calculations with mean dose differences less than 1% for both the planning target volume and the organs at risk. However, only the sCTa provided an accurate and automatic delineation of bone. CONCLUSIONS: Combining MR delineations with our multi-atlas CT synthesis method could enable MRI-only treatment planning and thus improve the dosimetric and geometric accuracy of the treatment, and reduce the number of imaging procedures.

Real-time auto-adaptive margin generation for MLC-tracked radiotherapy.

In radiotherapy, abdominal and thoracic sites are candidates for performing motion tracking. With real-time control it is possible to adjust the multileaf collimator (MLC) position to the target position. However, positions are not perfectly matched and position errors arise from system delays and complicated response of the electromechanic MLC system. Although, it is possible to compensate parts of these errors by using predictors, residual errors remain and need to be compensated to retain target coverage. This work presents a method to statistically describe tracking errors and to automatically derive a patient-specific, per-segment margin to compensate the arising underdosage on-line, i.e. during plan delivery. The statistics of the geometric error between intended and actual machine position are derived using kernel density estimators. Subsequently a margin is calculated on-line according to a selected coverage parameter, which determines the amount of accepted underdosage. The margin is then applied onto the actual segment to accommodate the positioning errors in the enlarged segment. The proof-of-concept was tested in an on-line tracking experiment and showed the ability to recover underdosages for two test cases, increasing [Formula: see text] in the underdosed area about [Formula: see text] and [Formula: see text], respectively. The used dose model was able to predict the loss of dose due to tracking errors and could be used to infer the necessary margins. The implementation had a running time of 23 ms which is compatible with real-time requirements of MLC tracking systems. The auto-adaptivity to machine and patient characteristics makes the technique a generic yet intuitive candidate to avoid underdosages due to MLC tracking errors.

Evaluation of radiotherapy techniques for radical treatment of lateralised oropharyngeal cancers : Dosimetry and NTCP.

AIM: The aim of this study was to investigate potential advantages and disadvantages of three-dimensional conformal radiotherapy (3DCRT), multiple fixed-field intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in terms of dose to the planning target volume (PTV), organs at risk (OARs) and normal tissue complication probability (NTCP) for delivering ipsilateral radiotherapy. MATERIALS AND METHODS: 3DCRT, IMRT and VMAT were compared in patients with well-lateralised primary tonsillar cancers who underwent primary radical ipsilateral radiotherapy. The following parameters were compared: conformity index (CI); homogeneity index (HI); dose-volume histograms (DVHs) of PTVs and OARs; NTCP, risk of radiation-induced cancer and dose accumulation during treatment. RESULTS: IMRT and VMAT were superior to 3DCRT in terms of CI, HI and dose to the target volumes, as well as mandible and dose accumulation robustness. The techniques were equivalent in terms of dose and NTCP for the contralateral oral cavity, contralateral submandibular gland and mandible, when specific dose constraint objectives were used on the oral cavity volume. Although the volume of normal tissue exposed to low-dose radiation was significantly higher with IMRT and VMAT, the risk of radiation-induced secondary malignancy was dependant on the mathematical model used. CONCLUSION: This study demonstrates the superiority of IMRT/VMAT techniques over 3DCRT in terms of dose homogeneity, conformity and consistent dose delivery to the PTV throughout the course of treatment in patients with lateralised oropharyngeal cancers. Dosimetry and NTCP calculations show that these techniques are equivalent to 3DCRT with regard to the risk of acute mucositis when specific dose constraint objectives were used on the contralateral oral cavity OAR.

Assessment of MLC tracking performance during hypofractionated prostate radiotherapy using real-time dose reconstruction.

By adapting to the actual patient anatomy during treatment, tracked multi-leaf collimator (MLC) treatment deliveries offer an opportunity for margin reduction and healthy tissue sparing. This is assumed to be especially relevant for hypofractionated protocols in which intrafractional motion does not easily average out. In order to confidently deliver tracked treatments with potentially reduced margins, it is necessary to monitor not only the patient anatomy but also the actually delivered dose during irradiation. In this study, we present a novel real-time online dose reconstruction tool which calculates actually delivered dose based on pre-calculated dose influence data in less than 10 ms at a rate of 25 Hz. Using this tool we investigate the impact of clinical target volume (CTV) to planning target volume (PTV) margins on CTV coverage and organ-at-risk dose. On our research linear accelerator, a set of four different CTV-to-PTV margins were tested for three patient cases subject to four different motion conditions. Based on this data, we can conclude that tracking eliminates dose cold spots which can occur in the CTV during conventional deliveries even for the smallest CTV-to-PTV margin of 1 mm. Changes of organ-at-risk dose do occur frequently during MLC tracking and are not negligible in some cases. Intrafractional dose reconstruction is expected to become an important element in any attempt of re-planning the treatment plan during the delivery based on the observed anatomy of the day.

Automated marker tracking using noisy X-ray images degraded by the treatment beam.

This study demonstrates the feasibility of automated marker tracking for the real-time detection of intrafractional target motion using noisy kilovoltage (kV) X-ray images degraded by the megavoltage (MV) treatment beam. The authors previously introduced the in-line imaging geometry, in which the flat-panel detector (FPD) is mounted directly underneath the treatment head of the linear accelerator. They found that the 121 kVp image quality was severely compromised by the 6 MV beam passing through the FPD at the same time. Specific MV-induced artefacts present a considerable challenge for automated marker detection algorithms. For this study, the authors developed a new imaging geometry by re-positioning the FPD and the X-ray tube. This improved the contrast-to-noise-ratio between 40% and 72% at the 1.2 mAs/image exposure setting. The increase in image quality clearly facilitates the quick and stable detection of motion with the aid of a template matching algorithm. The setup was tested with an anthropomorphic lung phantom (including an artificial lung tumour). In the tumour one or three Calypso beacons were embedded to achieve better contrast during MV radiation. For a single beacon, image acquisition and automated marker detection typically took around 76 ± 6 ms. The success rate was found to be highly dependent on imaging dose and gantry angle. To eliminate possible false detections, the authors implemented a training phase prior to treatment beam irradiation and also introduced speed limits for motion between subsequent images.