Intra- and inter-fraction breath-hold variations and margins for radiotherapy of abdominal targets.

Radiotherapy in expiration breath-hold (EBH) has the potential to reduce treatment volumes of abdominal targets compared to an internal target volume concept in free-breathing. The reproducibility of EBH and required safety margins were investigated to quantify this volumetric benefit. Pre- and post-treatment diaphragm position difference and the positioning variability were determined on computed tomography. Systematic and random errors for EBH position reproducibility and positioning variability were calculated, resulting in margins of 7 to 12 mm depending on the prescription isodose and fractionation. A reduced volume was shown for EBH for lesions with superior-inferior breathing motion above 4 to 8 mm.

Dose escalation for stereotactic arrhythmia radioablation of recurrent ventricular tachyarrhythmia - a phase II clinical trial.

BACKGROUND: Stereotactic arrhythmia radioablation (STAR) is delivered with a planning target volume (PTV) prescription dose of 25 Gy, mostly to the surrounding 75-85% isodose line. This means that the average and maximum dose received by the target is less than 35 Gy, which is the minimum threshold required to create a homogenous transmural fibrosis. Similar to catheter ablation, the primary objective of STAR should be transmural fibrosis to prevent heterogenous intracardiac conduction velocities and the occurrence of sustained ventricular arrhythmias (sVA) caused by reentry. We hypothesize that the current dose prescription used in STAR is inadequate for the long-term prevention of sVA and that a significant increase in dose is necessary to induce transmural scar formation. OBJECTIVE: A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk. METHODS: Patients with ischemic or non-ischemic cardiomyopathy and recurrent sVA, with an ICD and history of ≥ 1 catheter ablation for sVA will be included. This is a prospective, multicenter, one-arm, dose-escalation trial utilizing the i3 + 3 design, a modified 3 + 3 specifically created to overcome limitations in traditional dose-finding studies. A total of 15 patients will be recruited. The trial aims to escalate the ITV dose from 27.0 Gy to an ITV prescription dose-equivalent level of maximum 35.1 Gy by keeping the PTV prescription dose constant at 25 Gy while increasing the dose to the target (i.e. the VT substrate without PTV margin) by step-wise reduction of the prescribing isodose line (85% down to 65%). The primary outcome of this trial is safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI at 90 days after STAR. The sample size was determined assuming an acceptable primary outcome event rate of 20%. Secondary outcomes include sVA burden at 6 months after STAR, time to first sVA recurrence, reduction in appropriate ICD therapies, the need for escalation of antiarrhythmic drugs, non-radiation associated safety and patient reported outcome measures such as SF-36 and EQ5D. DISCUSSION: DEFT-STAR is an innovative prospective phase II trial that aims to evaluate the optimal radiation dose for STAR in patients with therapy-refractory sVA. The trial has obtained IRB approval and focuses on determining the safe and effective radiation dose to be employed in the STAR procedure. TRIAL REGISTRATION: NCT05594368.

Reduction of patient specific quality assurance through plan complexity metrics for VMAT plans with an open-source TPS script.

PURPOSE: Volumetric modulated arc therapy (VMAT) is a widespread technique for the delivery of normo-fractionated radiation therapy (NFRT) and stereotactic body radiation therapy (SBRT). It is associated with a significant hardware burden requiring dose rate modulation, collimator movement and gantry rotation synchronisation. Patient specific quality assurance (PSQA) guarantees that the linacs can precisely and accurately deliver the planned dose. However, PSQA requires a significant time allocation and class solutions to reduce this while guaranteeing the deliverability of the plans should be investigated. METHODS: In this study, an in-house developed Eclipse Scripting API (ESAPI) script was used to extract five independent plan complexity metrics from N = 667 VMAT treatment fields. The correlation between metrics and portal dosimetry measurements was investigated with Pearson correlation, box plot analysis and receiver operating characteristic curves, which were used to defined the best performing metric and its threshold. RESULTS: The incidence of fields failing the clinical PSQA criteria of 3%/2mm (NFRT) and 3%/1.5mm (SBRT) was low (N = 1). The mean MLC opening was the metric with the highest correlation with the portal dosimetry data and among the best in discriminating the requirement of PSQA. The thresholds of 16.12 mm (NFRT) and 7.96 mm (SBRT) corresponded to true positive rates higher than 90%. CONCLUSIONS: This work presents a quantitative approach to reduce the time allocation for PSQA by identifying the most complex plans demanding a dedicated measurement. The proposed method requires PSQA for approximately 10% of the plans. The ESAPI script is distributed open-source to ease the investigation and implementation at other institutions.

Quality assurance process within the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial for the fusion of electroanatomical mapping and radiotherapy planning imaging data in cardiac radioablation.

A novel quality assurance process for electroanatomical mapping (EAM)-to-radiotherapy planning imaging (RTPI) target transport was assessed within the multi-center multi-platform framework of the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial. A stand-alone software (CARDIO-RT) was developed to enable platform independent registration of EAM and RTPI of the left ventricle (LV), based on pre-generated radiotherapy contours (RTC). LV-RTC were automatically segmented into the American-Heart-Association 17-segment-model and a manual 3D-3D method based on EAM 3D-geometry data and a semi-automated 2D-3D method based on EAM screenshot projections were developed. The quality of substrate transfer was evaluated in five clinical cases and the structural analyses showed substantial differences between manual target transfer and target transport using CARDIO-RT.

MR-guided beam gating: Residual motion, gating efficiency and dose reconstruction for stereotactic treatments of the liver and lung.

PURPOSE: This study aims to investigate the efficiency and the geometric as well as the dosimetric benefit of magnetic-resonance guided beam gating for stereotactic treatments in moving organs. METHOD: Patients treated with MR-guided (MRIdian system) SBRT for lung (n = 10) and liver (n = 10) targets were analyzed. Breath-hold gating was performed based on lesion tracking in sagittal cine MRI images. The target offset from the geometric center of the gating window with and without gating was evaluated. A dose reconstruction workflow based on convolution of these 2D position-probability maps and the daily 3D dose distribution was used to estimate the daily delivered dose including motion. The dose to the clinical target volume (CTV) and to a 2-cm ring structure around the planning target volume were evaluated. RESULTS: The applied gating protocol resulted in a mean (±standard deviation) gating efficiency of 55%±16%. Over all patients, the mean target offset (2D-root-mean-square error) was 8.3 ± 4.3 mm, which reduced to 2.4 ± 0.6 mm during gating. The dose reconstruction showed a mean deviation in CTV coverage (D95) from the static plans of -1.7%±1.8% with gating and -12.0%±8.4% if no gating would have been used. The mean dose (Dmean) in the ring structure, with respect to the static plans, showed mean deviations of -0.1%±0.3% with gating and -1.6%±1.8% without gating. CONCLUSION: The MRIdian system enables gating based on the inner anatomy and the implemented dose reconstruction workflow demonstrated geometric robust delivery of the planned radiation doses.

Treatment Planning for Cardiac Radioablation: Multicenter Multiplatform Benchmarking for the RAdiosurgery for VENtricular TAchycardia (RAVENTA) Trial.

PURPOSE: Cardiac radioablation is a novel treatment option for patients with refractory ventricular tachycardia unsuitable for catheter ablation. The quality of treatment planning depends on dose specifications, platform capabilities, and experience of the treating staff. To harmonize the treatment planning, benchmarking of this process is necessary for multicenter clinical studies such as the RAdiosurgery for VENtricular TAchycardia trial. METHODS AND MATERIALS: Planning computed tomography data and consensus structures from 3 patients were sent to 5 academic centers for independent plan development using a variety of platforms and techniques with the RAdiosurgery for VENtricular TAchycardia study protocol serving as guideline. Three-dimensional dose distributions and treatment plan details were collected and analyzed. In addition, an objective relative plan quality ranking system for ventricular tachycardia treatments was established. RESULTS: For each case, 3 coplanar volumetric modulated arc (VMAT) plans for C-arm linear accelerators (LINAC) and 3 noncoplanar treatment plans for robotic arm LINAC were generated. All plans were suitable for clinical applications with minor deviations from study guidelines in most centers. Eleven of 18 treatment plans showed maximal one minor deviation each for target and cardiac substructures. However, dose-volume histograms showed substantial differences: in one case, the planning target volume ≥30 Gy ranged from 0.0% to 79.9% and the ramus interventricularis anterior V14Gy ranged from 4.0% to 45.4%. Overall, the VMAT plans had steeper dose gradients in the high-dose region, while the plans for the robotic arm LINAC had smaller low-dose regions. Thereby, VMAT plans required only about half as many monitor units, resulting in shorter delivery times, possibly an important factor in treatment outcome. CONCLUSIONS: Cardiac radioablation is feasible with robotic arm and C-arm LINAC systems with comparable plan quality. Although cross-center training and best practice guidelines have been provided, further recommendations, especially for cardiac substructures, and ranking of dose guidelines will be helpful to optimize cardiac radioablation outcomes.

Synthetic 4DCT(MRI) lung phantom generation for 4D radiotherapy and image guidance investigations.

PURPOSE: Respiratory motion is one of the major challenges in radiotherapy. In this work, a comprehensive and clinically plausible set of 4D numerical phantoms, together with their corresponding "ground truths," have been developed and validated for 4D radiotherapy applications. METHODS: The phantoms are based on CTs providing density information and motion from multi-breathing-cycle 4D Magnetic Resonance imagings (MRIs). Deformable image registration (DIR) has been utilized to extract motion fields from 4DMRIs and to establish inter-subject correspondence by registering binary lung masks between Computer Tomography (CT) and MRI. The established correspondence is then used to warp the CT according to the 4DMRI motion. The resulting synthetic 4DCTs are called 4DCT(MRI)s. Validation of the 4DCT(MRI) workflow was conducted by directly comparing conventional 4DCTs to derived synthetic 4D images using the motion of the 4DCTs themselves (referred to as 4DCT(CT)s). Digitally reconstructed radiographs (DRRs) as well as 4D pencil beam scanned (PBS) proton dose calculations were used for validation. RESULTS: Based on the CT image appearance of 13 lung cancer patients and deformable motion of five volunteer 4DMRIs, synthetic 4DCT(MRI)s with a total of 871 different breathing cycles have been generated. The 4DCT(MRI)s exhibit an average superior-inferior tumor motion amplitude of 7 ± 5 mm (min: 0.5 mm, max: 22.7 mm). The relative change of the DRR image intensities of the conventional 4DCTs and the corresponding synthetic 4DCT(CT)s inside the body is smaller than 5% for at least 81% of the pixels for all studied cases. Comparison of 4D dose distributions calculated on 4DCTs and the synthetic 4DCT(CT)s using the same motion achieved similar dose distributions with an average 2%/2 mm gamma pass rate of 90.8% (min: 77.8%, max: 97.2%). CONCLUSION: We developed a series of numerical 4D lung phantoms based on real imaging and motion data, which give realistic representations of both anatomy and motion scenarios and the accessible "ground truth" deformation vector fields of each 4DCT(MRI). The open-source code and motion data allow foreseen users to generate further 4D data by themselves. These numeric 4D phantoms can be used for the development of new 4D treatment strategies, 4D dose calculations, DIR algorithm validations, as well as simulations of motion mitigation and different online image guidance techniques for both proton and photon radiation therapy.

Gating has a negligible impact on dose delivered in MRI-guided online adaptive radiotherapy of prostate cancer.

BACKGROUND AND PURPOSE: MR-guided radiotherapy (MRgRT) allows real-time beam-gating to compensate for intra-fractional target position variations. This study investigates the dosimetric impact of beam-gating and the impact of PTV margin on prostate coverage for prostate cancer patients treated with online-adaptive MRgRT. MATERIALS AND METHODS: 20 consecutive prostate cancer patients were treated with online-adaptive MRgRT SBRT with 36.25 Gy in 5 fractions (PTV D95% ≥ 95% (N = 5) and PTV D95% ≥ 100% (N = 15)). Sagittal 2D cine MRIs were used for gating on the prostate with a 3 mm expansion as the gating window. We computed motion-compensated dose distributions for (i) all prostate positions during treatment (simulating non-gated treatments) and (ii) for prostate positions within the gating window (gated treatments). To evaluate the impact of PTV margin on prostate coverage, we simulated coverage with smaller margins than clinically applied both for gated and non-gated treatments. Motion-compensated fraction doses were accumulated and dose metrics were compared. RESULTS: We found a negligible dosimetric impact of beam-gating on prostate coverage (median of 0.00 Gy for both D95% and Dmean). For 18/20 patients, prostate coverage (D95% ≥ 100%) would have been ensured with a prostate-to-PTV margin of 3 mm, even without gating. The same was true for all but one fraction. CONCLUSION: Beam-gating has negligible dosimetric impact in online-adaptive MRgRT of prostate cancer. Accounting for motion, the clinically used prostate-to-PTV margin could potentially be reduced from 5 mm to 3 mm for 18/20 patients.

Single-isocenter versus multiple-isocenters for multiple lung metastases: Evaluation of lung dose.

BACKGROUND AND PURPOSE: A potential challenge in single-isocenter multi-lesion lung stereotactic body radiotherapy (SBRT) is that patient positioning is not based on each lesion individually, but on the average position of all lesions. This may lead to larger margins compared to treating with one isocenter per lesion, but increases workflow efficiency. The aim of this study was to investigate whether a single-isocenter technique leads to increased normal lung dose compared to a conventional multiple-isocenters technique. MATERIALS AND METHODS: A cohort of 15 NSCLC patients with two or three lesions previously treated with SBRT was subjected to treatment planning with a multiple-isocenter technique and a single-isocenter technique. For the latter, two margin approaches were evaluated: (1) identical margins for each internal target volume (ITV), assuming an average registration for all lesions in cone-beam CT (CBCT) positioning verification and (2) a smaller margin for the largest lesion, assuming an optimal registration for that lesion. For all 45 treatment plans, mean lung dose (MLD) and lungs-V20Gy were evaluated. The study was performed following RATING guidelines. RESULTS: The MLD was 4.9 ± 1.9 Gy (mean ± SD) for multiple-isocenters and 5.4 ± 2.1 Gy and 5.3 ± 2.2 Gy for single-isocenter approach 1 and 2, respectively. V20Gy was 5.5 ± 3.7%, 5.5 ± 3.2% and 5.4 ± 3.3%. A median [range] increase in MLD of 11.6% [-14.9 - 26.8] was observed when comparing single-isocenter treatment plans to those with multiple isocenters. V20Gy increased by 0.2 [-3.4 - 1.3] percentage points. CONCLUSION: A single-isocenter SBRT technique for lung patients with multiple targets results in clinically acceptable increases in normal lung dose.

MR-Guided Adaptive Radiotherapy for Head and Neck Cancer: Prospective Evaluation of Migration and Anatomical Changes of the Major Salivary Glands.

The aim of this study was to quantify anatomical changes of parotids and submandibular glands and evaluate potential dosimetric advantages during weekly adaptive MR-guided radiotherapy (MRgRT) for the definitive treatment of head and neck cancer (HNC). The data and plans of 12 patients treated with bilateral intensity-modulated radiotherapy for HNC using MR-linac, with weekly offline adaptations, were prospectively evaluated. The positional and volumetric changes of the salivary glands were analyzed by manual segmentation in weekly MRI images and the dosimetric impact of these anatomical changes on the adapted treatment plans was assessed. The mean volume change in parotid and submandibular gland volume was -31.9% (p < 0.0001) and -29.7% (p < 0.0001) after five weeks, respectively. The volume change was significantly correlated with the cumulative dose for the respective gland at the time of volume measurement. Inter-parotid distance changed by -5.4% (6.5 mm) on average after five weeks (p = 0.0005). The distance became significantly smaller only in the left-right direction. The inter-submandibular gland distance changed by 0.7 mm (p = 0.38). This study demonstrated significant changes in salivary gland volumes and position following daily MR guidance and weekly plan adaptation. Ongoing clinical trials will provide data on the clinical impact of these changes and novel MR-based adaptation strategies.

Margin calculation for multiple lung metastases treated with single-isocenter SBRT.

BACKGROUND AND PURPOSE: A single-isocenter stereotactic body radiotherapy (SBRT) approach for multiple lung metastases has the potential to lower cumulative patient dose and reduce overall treatment time. However, the magnitude of inter-lesion position variation is currently unknown and not incorporated in margin calculations. The aim of this study was to quantify inter-lesion position variation and calculate safety margins for single-isocenter lung SBRT. MATERIALS AND METHODS: A total of 83 pairs of pulmonary metastases from 42 NSCLC patients were used to calculate relative inter-lesion position variation by lesion-based registration of planning CT and verification CBCT. Furthermore, ß-value assessment of van Herk's margin formula was performed by evaluating the distance between planned and blurred dose profiles of simulated spherical lesions, to evaluate its validity for heterogeneously planned dose distributions. Population-based ITV to PTV margins were calculated using the entire dataset and using subgroups with significant differences in relative inter-lesion position variation. RESULTS: The mean ± SD inter-lesion position variation was 1.2 ± 1.1 mm as 3D-vector. Inter-lesion position variation was significantly increased if ≥1 lesion was not attached to the pleura or lesions were distant. The simulation showed that the combined SD of the random errors contributed to the margin only in the SI direction with 0.25∙σtot for a 65% dose prescription. When incorporating inter-lesion position variation, the safety margins increased from 5.6, 5.8, 5.2 mm (AP, SI, LR) to 6.0, 6.6, 5.5 mm for the entire cohort. CONCLUSION: Relative inter-lesion position variation is influenced by inter-target distance and location and can be compensated with additional safety margins of <1 mm using single-isocenter SBRT.

Comparison of beam segment versus full plan re-optimization in daily magnetic resonance imaging-guided online-adaptive radiotherapy.

The optimal approach for magnetic resonance imaging-guided online adaptive radiotherapy is currently unknown and needs to consider patient on-couch time constraints. The aim of this study was to compare two different plan optimization approaches. The comparison was performed in 238 clinically applied online-adapted treatment plans from 55 patients, in which the approach of re-optimization was selected based on the physician's choice. For 33 patients where both optimization approaches were used at least once, the median treatment planning dose metrics of both target and organ at risk differed less than 1%. Therefore, we concluded that beam segment weight optimization was chosen adequately for most patients without compromising plan quality.

Interdisciplinary Clinical Target Volume Generation for Cardiac Radioablation: Multicenter Benchmarking for the RAdiosurgery for VENtricular TAchycardia (RAVENTA) Trial.

PURPOSE: Cardiac radioablation is a novel treatment option for therapy-refractory ventricular tachycardia (VT) ineligible for catheter ablation. Three-dimensional clinical target volume (CTV) definition is a key step, and this complex interdisciplinary procedure includes VT-substrate identification based on electroanatomical mapping (EAM) and its transfer to the planning computed tomography (PCT). Benchmarking of this process is necessary for multicenter clinical studies such as the RAVENTA trial. METHODS AND MATERIALS: For benchmarking of the RAVENTA trial, patient data (epicrisis, electrocardiogram, high-resolution EAM, contrast-enhanced cardiac computed tomography, PCT) of 3 cases were sent to 5 university centers for independent CTV generation, subsequent structure analysis, and consensus finding. VT substrates were first defined on multiple EAM screenshots/videos and manually transferred to the PCT. The generated structure characteristics were then independently analyzed (volume, localization, surface distance and conformity). After subsequent discussion, consensus structures were defined. RESULTS: VT substrate on the EAM showed visible variability in extent and localization for cases 1 and 2 and only minor variability for case 3. CTVs ranged from 6.7 to 22.9 cm3, 5.9 to 79.9 cm3, and 9.4 to 34.3 cm3; surface area varied from 1087 to 3285 mm2, 1077 to 9500 mm2, and 1620 to 4179 mm2, with a Hausdorff-distance of 15.7 to 39.5 mm, 23.1 to 43.5 mm, and 15.9 to 43.9 mm for cases 1 to 3, respectively. The absolute 3-dimensional center-of-mass difference was 5.8 to 28.0 mm, 8.4 to 26 mm, and 3.8 to 35.1 mm for cases 1 to 3, respectively. The entire process resulted in CTV structures with a conformity index of 0.2 to 0.83, 0.02 to 0.85, and 0.02 to 0.88 (ideal 1) with the consensus CTV as reference. CONCLUSIONS: Multicenter efficacy endpoint assessment of cardiac radioablation for therapy-refractory VT requires consistent CTV transfer methods from the EAM to the PCT. VT substrate definition and CTVs were comparable with current clinical practice. Remarkable differences regarding the degree of agreement of the CTV definition on the EAM and the PCT were noted, indicating a loss of agreement during the transfer process between EAM and PCT. Cardiac radioablation should be performed under well-defined protocols and in clinical trials with benchmarking and consensus forming.

Single-fraction prostate stereotactic body radiotherapy: Dose reconstruction with electromagnetic intrafraction motion tracking.

PURPOSE: To reconstruct the dose delivered during single-fraction urethra-sparing prostate stereotactic body radiotherapy (SBRT) accounting for intrafraction motion monitored by intraprostatic electromagnetic transponders (EMT). METHODS: We analyzed data of 15 patients included in the phase I/II "ONE SHOT" trial and treated with a single fraction of 19 Gy to the planning target volume (PTV) and 17 Gy to the urethra planning risk volume. During delivery, prostate motion was tracked with implanted EMT. SBRT was interrupted when a 3-mm threshold was trespassed and corrected unless the offset was transient. Motion-encoded reconstructed (MER) plans were obtained by splitting the original plans into multiple sub-beams with isocenter shifts based on recorded EMT positions, mimicking prostate motion during treatment. We analyzed intrafraction motion and compared MER to planned doses. RESULTS: The median EMT motion range (±SD) during delivery was 0.26 ± 0.09, 0.22 ± 0.14 and 0.18 ± 0.10 cm in the antero-posterior, supero-inferior, and left-right axes, respectively. Treatment interruptions were needed for 8 patients because of target motion beyond limits in the antero-posterior (n = 6) and/or supero-inferior directions (n = 4). Comparing MER vs. original plan there was a median relative dose difference of -1.9% (range, -7.9 to -1.0%) and of +0.5% (-0.3-1.7%) for PTV D98% and D2%, respectively. The clinical target volume remained sufficiently covered with a median D98% difference of -0.3% (-1.6-0.5%). Bladder and rectum dosimetric parameters showed significant differences between original and MER plans, but mostly remained within acceptable limits. CONCLUSIONS: The dosimetric impact of intrafraction prostate motion was minimal for target coverage for single-fraction prostate SBRT with real-time electromagnetic tracking combined with beam gating.

Treatment plan quality during online adaptive re-planning.

BACKGROUND: Online adaptive radiotherapy is intended to prevent plan degradation caused by inter-fractional tumor volume and shape changes, but time limitations make online re-planning challenging. The aim of this study was to compare the quality of online-adapted plans to their respective reference treatment plans. METHODS: Fifty-two patients treated on a ViewRay MRIdian Linac were included in this retrospective study. In total 238 online-adapted plans were analyzed, which were optimized with either changing of the segment weights (n = 85) or full re-optimization (n = 153). Five different treatment sites were evaluated: prostate, abdomen, liver, lung and pelvis. Dosimetric parameters of gross tumor volume (GTV), planning target volume (PTV), 2 cm ring around the PTV and organs at risk (OARs) were considered. The Wilcoxon signed-rank test was used to assess differences between online-adapted and reference treatment plans, p < 0.05 was considered significant. RESULTS: The average duration of the online adaptation, consisting of contour editing, plan optimization and quality assurance (QA), was 24 ± 6 min. The GTV was slightly larger (average ± SD: 1.9% ± 9.0%) in the adapted plans than in the reference plans (p < 0.001). GTV-D95% exhibited no significant changes when considering all plans, but GTV-D2% increased by 0.40% ± 1.5% on average (p < 0.001). There was a very small yet significant decrease in GTV-coverage for the abdomen plans. The ring Dmean increased on average by 1.0% ± 3.6% considering all plans (p < 0.001). There was a significant reduction of the dose to the rectum of 4.7% ± 16% on average (p < 0.001) for prostate plans. CONCLUSIONS: Dosimetric quality of online-adapted plans was comparable to reference treatment plans and OAR dose was either comparable or decreased, depending on treatment site. However, dose spillage was slightly increased.

A tumor-immune interaction model for hepatocellular carcinoma based on measured lymphocyte counts in patients undergoing radiotherapy.

PURPOSE: The impact of radiation therapy on the immune system has recently gained attention particularly when delivered in combination with immunotherapy. However, it is unclear how different treatment fractionation regimens influence the interaction between the immune system and radiation. The goal of this work was to develop a mathematical model that quantifies both the immune stimulating as well as the immunosuppressive effects of radiotherapy and simulates the effects of different fractionation regimens based on patient data. METHODS AND MATERIALS: The framework describes the temporal evolution of tumor cells, lymphocytes, and inactivated dying tumor cells releasing antigens during radiation therapy, specifically modeling how recruited lymphocytes inhibit tumor progression. The parameters of the model were partly taken from the literature and in part extracted from blood samples (circulating lymphocytes: CLs) collected from hepatocellular carcinoma patients undergoing radiotherapy and their outcomes. The dose volume histograms to circulating lymphocytes were calculated with a probability-based model. RESULTS: Based on the fitted parameters, the model enabled a study into the depletion and recovery of CLs in patients as a function of fractionation regimen. Our results quantify the ability of short fractionation regimens to lead to shorter periods of lymphocyte depletion and predict faster recovery after the end of treatment. The model shows that treatment breaks between fractions can prolong the period of lymphocyte depletion and should be avoided. CONCLUSIONS: This study introduces a mathematical model for tumor-immune interactions using clinically extracted radiotherapy patient data, which can be applied to design trials aimed at minimizing lymphocyte depleting effects in radiation therapy.

Carbon Fiber/Polyether Ether Ketone (CF/PEEK) Implants Allow for More Effective Radiation in Long Bones.

BACKGROUND: Metallic implants show dose-modulating effects in radiotherapy and complicate its computed tomography (CT)-based planning. Dose deviations might not only affect the surrounding tissues due to backscattering and inadvertent dose increase but might also compromise the therapeutic effect to the target lesion due to beam attenuation. Later on, follow-up imaging is often obscured by metallic artefacts. Purposes: This study investigates the dosimetric impact of titanium and radiolucent carbon fiber/polyether ether ketone (CF/PEEK) implants during adjuvant radiation therapy in long bones. (1) Does the use of CF/PEEK implants allow for a more homogenous application of radiation? (2) Is the dose delivery to the target volume more efficient when using CF/PEEK implants? (3) Do CF/PEEK implants facilitate CT-based radiation therapy planning? Materials and methods: After CT-based planning, bone models of six ovine femora were irradiated within a water phantom in two immersion depths to simulate different soft-tissue envelopes. Plates and intramedullary nails of both titanium and CF/PEEK were investigated. Radiation dosage and distribution patterns were mapped using dosimetry films. Results: First, the planned implant-related beam attenuation was lower for the CF/PEEK plate (1% vs. 5%) and the CF/PEEK nail (2% vs. 9%) than for corresponding titanium implants. Secondly, the effective decrease of radiation dosage behind the implants was noticeably smaller when using CF/PEEK implants. The radiation dose was not significantly affected by the amount of surrounding soft tissues. A significant imaging artefact reduction was seen in all CF/PEEK models. Conclusion: CF/PEEK implants lead to a more reliable and more effective delivery of radiation dose to an osseous target volume. With regard to radiation therapy, the use of CF/PEEK implants appears to be particularly beneficial for intramedullary nails.

First magnetic resonance imaging-guided cardiac radioablation of sustained ventricular tachycardia.

PURPOSE: To report the feasibility of magnetic resonance imaging-guided cardiac single fraction radioablation (MRgRA) in a patient with dilated cardiomyopathy and recurrent sustained ventricular tachycardia (VT) leading to electrical storms (ES). MATERIALS/METHODS: A workflow to perform Stereotactic Arrhythmia Radioablation (STAR) on a hybrid MR-Linac with real-time tracking and beam-gating was established. Challenges of the MRgRA approach included: (a) the safety of a non-MR compatible cardiac implantable electronic device (CIED) in the MR-Linac field, (b) artefacts caused by the CIED and (c) respiratory motion management with cine-tracking of the moving heart. The specific absorption rate and slew rate of the MR-Linac were within the specifications of a MR-conditional CIED. Phantom measurements showed CIED distortion artefacts of less than 1.5 mm. During MR simulation, tracking could be established on the upper liver to avoid interference with the moving heart and CIED extinction artefacts. Areas of anatomical scarring and critical substrate were identified using invasive three-dimensional electroanatomical mapping of the clinical VT during electrophysiological studies and cardiac MR imaging/computed tomography to build a volumetric target. RESULTS: A 71-year-old male patient with non-ischemic dilated cardiomyopathy and recurrent therapy-refractory sustained VT with repetitive implantable cardioverter-defibrillator (ICD) shocks was treated with a single fraction of 25 Gy @85% isodose, cine-tracking time was 46 min, beam-on time 24 min. 24 h post intervention the patient developed an aggravation of the clinical VT and prolonged ES. VT ceased following high-dose dexamethasone administration after 48 h. After this point, the patient remained without any episodes of sustained ventricular tachyarrhythmia requiring ICD interventions until the last follow-up at three months. CONCLUSION: Real-time tracking and beam-gating were successfully applied in this first MRgRA to treat sustained VT.

Dosimetric and geometric end-to-end accuracy of a magnetic resonance guided linear accelerator.

The introduction of real-time imaging by magnetic resonance guided linear accelerators (MR-Linacs) enabled adaptive treatments and gating on the tumor position. Different end-to-end tests monitored the accuracy of our MR-Linac during the first year of clinical operation. We report on the stability of these tests covering a static, adaptive and gating workflow. Film measurements showed gamma passing rates of 96.4% ± 3.4% for the static tests (five measurements) and for the two adaptive tests 98.9% and 99.99%, respectively (criterion 2%/2mm). The gated point dose measurements in the breathing phantom were 2.7% lower than in the static phantom.

Performance comparison of prediction filters for respiratory motion tracking in radiotherapy.

PURPOSE: In precision radiotherapy, the intrafractional motion causes substantial uncertainty. Traditionally, the target volume is expanded to cover the tumor in all positions. Alternative approaches are gating and adaptive tracking, which require a time delay as small as possible between the actual tumor motion and the reaction to effectively compensate the motion. Current treatment machines often exhibit large time delays. Prediction filters offer a promising means to mitigate these time delays by predicting the future respiratory motion. METHODS: A total of 18 prediction filters were implemented and their hyperparameters optimized for various time delays and noise levels. A set of 93 traces were standardized to a sampling frequency of 25 Hz and smoothed using the Fourier transform with a 3 Hz cutoff frequency. The hyperparameter optimization was carried out with ten traces, and the optimal hyperparameters were evaluated on the remaining 83 traces. RESULTS: For smooth traces, the wavelet least mean squares prediction filter and the linear filter reached normalized root mean square errors of below 0.05 for time delays of 160 and 480 ms, respectively. For noisy signals, the performance of the prediction filters deteriorated and led to similar results. CONCLUSIONS: Linear methods for prediction filters are sufficient for respiratory motion signals. Reducing the measurement noise generally improves the performance of the prediction filters investigated in this study, even during breathing irregularities.