Study protocol of the LARK (TROG 17.03) clinical trial: a phase II trial investigating the dosimetric impact of Liver Ablative Radiotherapy using Kilovoltage intrafraction monitoring.

BACKGROUND: Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive treatment which allows delivery of an ablative radiation dose with high accuracy and precision. SABR is an established treatment for both primary and secondary liver malignancies, and technological advances have improved its efficacy and safety. Respiratory motion management to reduce tumour motion and image guidance to achieve targeting accuracy are crucial elements of liver SABR. This phase II multi-institutional TROG 17.03 study, Liver Ablative Radiotherapy using Kilovoltage intrafraction monitoring (LARK), aims to investigate and assess the dosimetric impact of the KIM real-time image guidance technology. KIM utilises standard linear accelerator equipment and therefore has the potential to be a widely available real-time image guidance technology for liver SABR. METHODS: Forty-six patients with either hepatocellular carcinoma or oligometastatic disease to the liver suitable for and treated with SABR using Kilovoltage Intrafraction Monitoring (KIM) guidance will be included in the study. The dosimetric impact will be assessed by quantifying accumulated patient dose distribution with or without the KIM intervention. The patient treatment outcomes of local control, toxicity and quality of life will be measured. DISCUSSION: Liver SABR is a highly effective treatment, but precise dose delivery is challenging due to organ motion. Currently, there is a lack of widely available options for performing real-time tumour localisation to assist with accurate delivery of liver SABR. This study will provide an assessment of the impact of KIM as a potential solution for real-time image guidance in liver SABR. TRIAL REGISTRATION: This trial was registered on December 7th 2016 on ClinicalTrials.gov under the trial-ID NCT02984566 .

Survival and morbidity following stereotactic radiotherapy of hepatocellular carcinoma: a ten-year, single institution experience.

BACKGROUND AND AIM: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment option in hepatocellular carcinoma (HCC) in patients ineligible for other local ablative therapies. This study reports on the safety and efficacy of SABR in a Danish cohort of HCC patients. MATERIALS AND METHODS: Between January 2009 and December 2018, 28 patients with HCCs were treated with SABR at our institution. The primary endpoint of this retrospective study was local control; secondary endpoints were progression-free survival, overall survival and toxicity. RESULTS: In 28 patients, 32 tumors (median size 3.7 cm, range 1.4-6.8 cm) were treated. The median follow-up time was 16 months. Most patients (68%) received previous liver-directed treatments. A dose of 48 Gy in three or six fractions were given to 43% of the patients. Grad 1 or 2 toxicity was reported in 13 patients (46%), whereas 4 patients (14%) needed hospitalization (grade 3). One-year local control and overall survivals were 90% and 71%, respectively. One-year progression-free survival was 32%, and 65% of patients with disease progression received further HCC therapy. In univariate analysis, none of the examined factors predicted recurrence or overall survival. CONCLUSION: SABR provides high local control to inoperable HCC. SABR can be delivered safely even after previous liver-directed therapies and subsequent therapies are feasible after treatment with SABR. Despite excellent local control, disease progression outside of the irradiated site remains prominent. Further studies are warranted to examine combined therapy approaches to maximize disease control.

Isotoxic dose prescription level strategies for stereotactic liver radiotherapy: the price of dose uniformity.

Introduction: To find the optimal dose prescription strategy for liver SBRT, this study investigated the tradeoffs between achievable target dose and healthy liver dose for a range of isotoxic uniform and non-uniform prescription level strategies.Material and methods: Nine patients received ten liver SBRT courses with intrafraction motion monitoring during treatment. After treatment, five VMAT treatment plans were made for each treatment course. The PTV margin was 5 mm (left-right, anterior-posterior) and 10 mm (cranio-caudal). All plans had a mean CTV dose of 56.25 Gy in three fractions, while the PTV was covered by 50%, 67%, 67 s% (steep dose gradient outside CTV), 80%, and 95% of this dose, respectively. The 50%, 67 s%, 80%, and 95% plans were then renormalized to be isotoxic with the standard 67% plan according to a Lyman-Kutcher-Burman normal tissue complication probability model for radiation induced liver disease. The CTV D98 and mean dose of the iso-toxic plans were calculated both without and with the observed intrafraction motion, using a validated method for motion-including dose reconstruction.Results: Under isotoxic conditions, the average [range] mean CTV dose per fraction decreased gradually from 21.2 [20.5-22.7] Gy to 15.5 [15.0-16.6] Gy and the D98 dose per fraction decreased from 20.4 [19.7-21.7] Gy to 15.0 [14.5-15.5] Gy, as the prescription level to the PTV rim was increased from 50% to 95%. With inclusion of target motion the mean CTV dose was 20.5 [16.5-22.5] Gy (50% PTV rim dose) and 15.4 [13.9-16.7] Gy (95% rim dose) while D98 was 17.8 [7.4-20.6] Gy (50% rim dose) and 14.6 [8.8-15.7] Gy (95% rim dose).Conclusion: Requirements of a uniform PTV dose come at the price of excess normal tissue dose. A non-uniform PTV dose allows increased CTV mean dose at the cost of robustness toward intrafraction motion. The increase in planned CTV dose by non-uniform prescription outbalanced the dose deterioration caused by motion.

Cone beam CT-based set-up strategies with and without rotational correction for stereotactic body radiation therapy in the liver.

BACKGROUND: Accurate patient positioning is crucial in stereotactic body radiation therapy (SBRT) due to a high dose regimen. Cone-beam computed tomography (CBCT) is often used for patient positioning based on radio-opaque markers. We compared six CBCT-based set-up strategies with or without rotational correction. MATERIAL AND METHODS: Twenty-nine patients with three implanted markers received 3-6 fraction liver SBRT. The markers were delineated on the mid-ventilation phase of a 4D-planning-CT. One pretreatment CBCT was acquired per fraction. Set-up strategy 1 used only translational correction based on manual marker match between the CBCT and planning CT. Set-up strategy 2 used automatic 6 degrees-of-freedom registration of the vertebrae closest to the target. The 3D marker trajectories were also extracted from the projections and the mean position of each marker was calculated and used for set-up strategies 3-6. Translational correction only was used for strategy 3. Translational and rotational corrections were used for strategies 4-6 with the rotation being either vertebrae based (strategy 4), or marker based and constrained to ±3° (strategy 5) or unconstrained (strategy 6). The resulting set-up error was calculated as the 3D root-mean-square set-up error of the three markers. The set-up error of the spinal cord was calculated for all strategies. RESULTS: The bony anatomy set-up (2) had the largest set-up error (5.8 mm). The marker-based set-up with unconstrained rotations (6) had the smallest set-up error (0.8 mm) but the largest spinal cord set-up error (12.1 mm). The marker-based set-up with translational correction only (3) or with bony anatomy rotational correction (4) had equivalent set-up error (1.3 mm) but rotational correction reduced the spinal cord set-up error from 4.1 mm to 3.5 mm. CONCLUSIONS: Marker-based set-up was substantially better than bony-anatomy set-up. Rotational correction may improve the set-up, but further investigations are required to determine the optimal correction strategy.

A phase I study on stereotactic body radiotherapy of liver metastases based on functional treatment planning using positron emission tomography with 2-[18F]fluoro-2-deoxy-d-galactose.

BACKGROUND AND PURPOSE: The galactose analog 2-[18F]fluoro-2-deoxy-d-galactose (FDGal) is used for quantification of regional hepatic metabolic capacity by functional positron emission tomography computerized tomography (PET/CT). In the present study, FDGal PET/CT was used for functional treatment planning (FTP) of stereotactic body radiotherapy (SBRT) of liver metastases with the aim of minimizing radiation dose to the best functioning liver tissue. MATERIAL AND METHODS: Fourteen patients referred for SBRT had FDGal PET/CT performed before and one month after the treatment. The planning CT and the FDGal PET/CT images were deformable co-registered. RESULTS: A reduction in the mean dose of approximately 2 Gy to the best functioning sub-volumes was obtained. One patient developed grade 2 acute morbidity and no patients experienced grade 3 or higher acute morbidities. The regional hepatic metabolic function post-treatment was linearly correlated to the regional radiation dose and for each 10-Gy increase in dose (γ10Gy), the metabolic function was reduced by 12%. A 50% reduction was seen at 22.9 Gy in 3 fractions (CI 95%: 16.7-30.4 Gy). CONCLUSION: The clinical study demonstrates the feasibility for FTP in patients with liver metastases and it was possible to minimize the radiation dose to the best functioning liver tissue.

Respiratory gating based on internal electromagnetic motion monitoring during stereotactic liver radiation therapy: First results.

BACKGROUND: Intrafraction motion may compromise the target dose in stereotactic body radiation therapy (SBRT) of tumors in the liver. Respiratory gating can improve the treatment delivery, but gating based on an external surrogate signal may be inaccurate. This is the first paper reporting on respiratory gating based on internal electromagnetic monitoring during liver SBRT. MATERIAL AND METHODS: Two patients with solitary liver metastases were treated with respiratory-gated SBRT guided by three implanted electromagnetic transponders. The treatment was delivered in end-exhale with beam-on when the centroid of the three transponders deviated less than 3 mm [left-right (LR) and anterior-posterior (AP) directions] and 4mm [cranio-caudal (CC)] from the planned position. For each treatment fraction, log files were used to determine the transponder motion during beam-on in the actual gated treatments and in simulated treatments without gating. The motion was used to reconstruct the dose to the clinical target volume (CTV) with and without gating. The reduction in D95 (minimum dose to 95% of the CTV) relative to the plan was calculated for both treatment courses. RESULTS: With gating the maximum course mean (standard deviation) geometrical error in any direction was 1.2 mm (1.8 mm). Without gating the course mean error would mainly increase for Patient 1 [to -2.8 mm (1.6 mm) (LR), 7.1 mm (5.8 mm) (CC), -2.6 mm (2.8mm) (AP)] due to a large systematic cranial baseline drift at each fraction. The errors without gating increased only slightly for Patient 2. The reduction in CTV D95 was 0.5% (gating) and 12.1% (non-gating) for Patient 1 and 0.3% (gating) and 1.7% (non-gating) for Patient 2. The mean duty cycle was 55%. CONCLUSION: Respiratory gating based on internal electromagnetic motion monitoring was performed for two liver SBRT patients. The gating added robustness to the dose delivery and ensured a high CTV dose even in the presence of large intrafraction motion.

Motion-induced dose perturbations in photon radiotherapy and proton therapy measured by deformable liver-shaped 3D dosimeters in an anthropomorphic phantom.

Background and purpose: The impact of intrafractional motion and deformations on clinical radiotherapy delivery has so far only been investigated by simulations as well as point and planar dose measurements. The aim of this study was to combine anthropomorphic 3D dosimetry with a deformable abdominal phantom to measure the influence of intra-fractional motion and gating in photon radiotherapy and evaluate the applicability in proton therapy. Material and methods: An abdominal phantom was modified to hold a deformable anthropomorphic 3D dosimeter shaped as a human liver. A liver-specific photon radiotherapy and a proton pencil beam scanning therapy plan were delivered to the phantom without motion as well as with 12 mm sinusoidal motion while using either no respiratory gating or respiratory gating. Results: Using the stationary irradiation as reference the local 3 %/2 mm 3D gamma index pass rate of the motion experiments in the planning target volume (PTV) was above 97 % (photon) and 78 % (proton) with gating whereas it was below 74 % (photon) and 45 % (proton) without gating. Conclusions: For the first time a high-resolution deformable anthropomorphic 3D dosimeter embedded in a deformable abdominal phantom was applied for experimental validation of both photon and proton treatments of targets exhibiting respiratory motion. It was experimentally shown that gating improves dose coverage and the geometrical accuracy for both photon radiotherapy and proton therapy.

Accuracy of four models and update strategies to estimate liver tumor motion from external respiratory motion.

Background: This study investigates different strategies for estimating internal liver tumor motion during radiotherapy based on continuous monitoring of external respiratory motion combined with sparse internal imaging. Methods: Fifteen patients underwent three-fraction stereotactic liver radiotherapy. The 3D internal tumor motion (INT) was monitored by electromagnetic transponders while a camera monitored the external marker block motion (EXT). The ability of four external-internal correlation models (ECM) to estimate INT as function of EXT was investigated: a simple linear model (ECM1), an augmented linear model (ECM2), an augmented quadratic model (ECM3), and an extended quadratic model (ECM4). Each ECM was constructed by fitting INT and EXT during the first 60s of each fraction. The fit accuracy was calculated as the root-mean-square error (RMSE) between ECM-estimated and actual tumor motion. Next, the RMSE of the ECM-estimated tumor motion throughout the fractions was calculated for four simulated ECM update strategies: (A) no update, 0.33Hz internal sampling with continuous update of either (B) all ECM parameters based on the last 2 minutes samples or (C) only the baseline term based on the last 5 samples, (D) full ECM update every minute using 20s continuous internal sampling. Results: The augmented quadratic ECM3 had best fit accuracy with mean (± SD)) RMSEs of 0.32 ± 0.11mm (left-right, LR), 0.79 ± 0.30mm (cranio-caudal, CC) and 0.56 ± 0.31mm (anterior-posterior, AP). However, the simpler augmented linear ECM2 combined with frequent baseline updates (update strategy C) gave best motion estimations with mean RMSEs of 0.41 ± 0.14mm (LR), 1.02 ± 0.33mm (CC) and 0.78 ± 0.48mm (AP). This was significantly better than all other ECM-update strategy combinations for CC motion (Wilcoxon signed rank p<0.05). Conclusion: The augmented linear ECM2 combined with frequent baseline updates provided the best compromise between fit accuracy and robustness towards irregular motion. It allows accurate internal motion monitoring by combining external motioning with sparse 0.33Hz kV imaging, which is available at conventional linacs.

Refining Treatment Planning in STereotactic Arrhythmia Radioablation: Benchmark Results and Consensus Statement From the STOPSTORM.eu Consortium.

PURPOSE: STereotactic Arrhythmia Radioablation (STAR) showed promising results in patients with refractory ventricular tachycardia. However, clinical data are scarce and heterogeneous. The STOPSTORM.eu consortium was established to investigate and harmonize STAR in Europe. The primary goal of this benchmark study was to investigate current treatment planning practice within the STOPSTORM project as a baseline for future harmonization. METHODS AND MATERIALS: Planning target volumes (PTVs) overlapping extracardiac organs-at-risk and/or cardiac substructures were generated for 3 STAR cases. Participating centers were asked to create single-fraction treatment plans with 25 Gy dose prescriptions based on in-house clinical practice. All treatment plans were reviewed by an expert panel and quantitative crowd knowledge-based analysis was performed with independent software using descriptive statistics for International Commission on Radiation Units and Measurements report 91 relevant parameters and crowd dose-volume histograms. Thereafter, treatment planning consensus statements were established using a dual-stage voting process. RESULTS: Twenty centers submitted 67 treatment plans for this study. In most plans (75%) intensity modulated arc therapy with 6 MV flattening filter free beams was used. Dose prescription was mainly based on PTV D95% (49%) or D96%-100% (19%). Many participants preferred to spare close extracardiac organs-at-risk (75%) and cardiac substructures (50%) by PTV coverage reduction. PTV D0.035cm3 ranged from 25.5 to 34.6 Gy, demonstrating a large variety of dose inhomogeneity. Estimated treatment times without motion compensation or setup ranged from 2 to 80 minutes. For the consensus statements, a strong agreement was reached for beam technique planning, dose calculation, prescription methods, and trade-offs between target and extracardiac critical structures. No agreement was reached on cardiac substructure dose limitations and on desired dose inhomogeneity in the target. CONCLUSIONS: This STOPSTORM multicenter treatment planning benchmark study not only showed strong agreement on several aspects of STAR treatment planning, but also revealed disagreement on others. To standardize and harmonize STAR in the future, consensus statements were established; however, clinical data are urgently needed for actionable guidelines for treatment planning.

Variations in magnitude and directionality of respiratory target motion throughout full treatment courses of stereotactic body radiotherapy for tumors in the liver.

PURPOSE: To investigate the stability of target motion amplitude and motion directionality throughout full stereotactic body radiotherapy (SBRT) treatments of tumors in the liver. MATERIAL AND METHODS: Ten patients with gold markers implanted in the liver received 11 courses of 3-fraction SBRT on a conventional linear accelerator. A four-dimensional computed tomography (4DCT) scan was obtained for treatment planning. The time-resolved marker motion was determined throughout full treatment field delivery using the kV and MV imagers of the accelerator. The motion amplitude and motion directionality of all individual respiratory cycles were determined using principal component analysis (PCA). The variations in motion amplitude and directionality within the treatment courses and the difference from the motion in the 4DCT scan were determined. RESULTS: The patient mean (± 1 standard deviation) peak-to-peak 3D motion amplitude of individual respiratory cycles during a treatment course was 7.9 ± 4.1 mm and its difference from the 4DCT scan was -0.8 ± 2.5 mm (max, 6.6 mm). The mean standard deviation of 3D respiratory cycle amplitude within a treatment course was 2.0 ± 1.6 mm. The motion directionality of individual respiratory cycles on average deviated 4.6 ± 1.6° from the treatment course mean directionality. The treatment course mean motion directionality on average deviated 7.6 ± 6.5° from the directionality in the 4DCT scan. A single patient-specific oblique direction in space explained 97.7 ± 1.7% and 88.3 ± 10.1% of all positional variance (motion) throughout the treatment courses, excluding and including baseline shifts between treatment fields, respectively. CONCLUSION: Due to variable breathing amplitudes a single 4DCT scan was not always representative of the mean motion amplitude during treatment. However, the motion was highly directional with a fairly stable direction throughout treatment, indicating a potential for more optimal individualized motion margins aligned to the preferred direction of motion.

A simple method to measure the gating latencies in photon and proton based radiotherapy using a scintillating crystal.

BACKGROUND: In respiratory gated radiotherapy, low latency between target motion into and out of the gating window and actual beam-on and beam-off is crucial for the treatment accuracy. However, there is presently a lack of guidelines and accurate methods for gating latency measurements. PURPOSE: To develop a simple and reliable method for gating latency measurements that work across different radiotherapy platforms. METHODS: Gating latencies were measured at a Varian ProBeam (protons, RPM gating system) and TrueBeam (photons, TrueBeam gating system) accelerator. A motion-stage performed 1 cm vertical sinusoidal motion of a marker block that was optically tracked by the gating system. An amplitude gating window was set to cover the posterior half of the motion (0-0.5 cm). Gated beams were delivered to a 5 mm cubic scintillating ZnSe:O crystal that emitted visible light when irradiated, thereby directly showing when the beam was on. During gated beam delivery, a video camera acquired images at 120 Hz of the moving marker block and light-emitting crystal. After treatment, the block position and crystal light intensity were determined in all video frames. Two methods were used to determine the gate-on (τon ) and gate-off (τoff ) latencies. By method 1, the video was synchronized with gating log files by temporal alignment of the same block motion recorded in both the video and the log files. τon was defined as the time from the block entered the gating window (from gating log files) to the actual beam-on as detected by the crystal light. Similarly, τoff was the time from the block exited the gating window to beam-off. By method 2, τon and τoff were found from the videos alone using motion of different sine periods (1-10 s). In each video, a sinusoidal fit of the block motion provided the times Tmin of the lowest block position. The mid-time, Tmid-light , of each beam-on period was determined as the time halfway between crystal light signal start and end. It can be shown that the directly measurable quantity Tmid-light - Tmin  = (τoff +τon )/2, which provided the sum (τoff +τon ) of the two latencies. It can also be shown that the beam-on (i.e., crystal light) duration ΔTlight increases linearly with the sine period and depends on τoff - τon : ΔTlight  = constant•period+(τoff - τon ). Hence, a linear fit of ΔTlight as a function of the period provided the difference of the two latencies. From the sum (τoff +τon ) and difference (τoff - τon ), the individual latencies were determined. RESULTS: Method 1 resulted in mean (±SD) latencies of τon  = 255 ± 33 ms, τoff  = 82 ± 15 ms for the ProBeam and τon  = 84 ± 13 ms, τoff  = 44 ± 11 ms for the TrueBeam. Method 2 resulted in latencies of τon  = 255 ± 23 ms, τoff  = 95 ± 23 ms for the ProBeam and τon  = 83 ± 8 ms, τoff  = 46 ± 8 ms for the TrueBeam. Hence, the mean latencies determined by the two methods agreed within 13 ms for the ProBeam and within 2 ms for the TrueBeam. CONCLUSIONS: A novel, simple and low-cost method for gating latency measurements that work across different radiotherapy platforms was demonstrated. Only the TrueBeam fully fulfilled the AAPM TG-142 recommendation of maximum 100 ms latencies.

Intrafraction tumor motion monitoring and dose reconstruction for liver pencil beam scanning proton therapy.

Background: Pencil beam scanning (PBS) proton therapy can provide highly conformal target dose distributions and healthy tissue sparing. However, proton therapy of hepatocellular carcinoma (HCC) is prone to dosimetrical uncertainties induced by respiratory motion. This study aims to develop intra-treatment tumor motion monitoring during respiratory gated proton therapy and combine it with motion-including dose reconstruction to estimate the delivered tumor doses for individual HCC treatment fractions. Methods: Three HCC-patients were planned to receive 58 GyRBE (n=2) or 67.5 GyRBE (n=1) of exhale respiratory gated PBS proton therapy in 15 fractions. The treatment planning was based on the exhale phase of a 4-dimensional CT scan. Daily setup was based on cone-beam CT (CBCT) imaging of three implanted fiducial markers. An external marker block (RPM) on the patient's abdomen was used for exhale gating in free breathing. This study was based on 5 fractions (patient 1), 1 fraction (patient 2) and 6 fractions (patient 3) where a post-treatment control CBCT was available. After treatment, segmented 2D marker positions in the post-treatment CBCT projections provided the estimated 3D motion trajectory during the CBCT by a probability-based method. An external-internal correlation model (ECM) that estimated the tumor motion from the RPM motion was built from the synchronized RPM signal and marker motion in the CBCT. The ECM was then used to estimate intra-treatment tumor motion. Finally, the motion-including CTV dose was estimated using a dose reconstruction method that emulates tumor motion in beam's eye view as lateral spot shifts and in-depth motion as changes in the proton beam energy. The CTV homogeneity index (HI) The CTV homogeneity index (HI) was calculated as D 2 %  -  D 98 % D 50 %   × 100 % . Results: The tumor position during spot delivery had a root-mean-square error of 1.3 mm in left-right, 2.8 mm in cranio-caudal and 1.7 mm in anterior-posterior directions compared to the planned position. On average, the CTV HI was larger than planned by 3.7%-points (range: 1.0-6.6%-points) for individual fractions and by 0.7%-points (range: 0.3-1.1%-points) for the average dose of 5 or 6 fractions. Conclusions: A method to estimate internal tumor motion and reconstruct the motion-including fraction dose for PBS proton therapy of HCC was developed and demonstrated successfully clinically.

A method of dose reconstruction for moving targets compatible with dynamic treatments.

PURPOSE: To develop a method that allows a commercial treatment planning system (TPS) to perform accurate dose reconstruction for rigidly moving targets and to validate the method in phantom measurements for a range of treatments including intensity modulated radiation therapy (IMRT), volumetric arc therapy (VMAT), and dynamic multileaf collimator (DMLC) tracking. METHODS: An in-house computer program was developed to manipulate Dicom treatment plans exported from a TPS (Eclipse, Varian Medical Systems) such that target motion during treatment delivery was incorporated into the plans. For each treatment, a motion including plan was generated by dividing the intratreatment target motion into 1 mm position bins and construct sub-beams that represented the parts of the treatment that were delivered, while the target was located within each position bin. For each sub-beam, the target shift was modeled by a corresponding isocenter shift. The motion incorporating Dicom plans were reimported into the TPS, where dose calculation resulted in motion including target dose distributions. For experimental validation of the dose reconstruction a thorax phantom with a moveable lung equivalent rod with a tumor insert of solid water was first CT scanned. The tumor insert was delineated as a gross tumor volume (GTV), and a planning target volume (PTV) was formed by adding margins. A conformal plan, two IMRT plans (step-and-shoot and sliding windows), and a VMAT plan were generated giving minimum target doses of 95% (GTV) and 67% (PTV) of the prescription dose (3 Gy). Two conformal fields with MLC leaves perpendicular and parallel to the tumor motion, respectively, were generated for DMLC tracking. All treatment plans were delivered to the thorax phantom without tumor motion and with a sinusoidal tumor motion. The two conformal fields were delivered with and without portal image guided DMLC tracking based on an embedded gold marker. The target dose distribution was measured with a radiochromic film in the moving rod and compared with the reconstructed doses using gamma tests. RESULTS: Considerable interplay effects between machine motion and target motion were observed for the treatments without tracking. For nontracking experiments, the mean 2 mm∕2% gamma pass rate over all investigated scenarios was 99.6% between calculated and measured doses. For tracking experiments, the mean gamma pass rate was 99.4%. CONCLUSIONS: A method for accurate dose reconstruction for moving targets with dynamic treatments was developed and experimentally validated in a variety of delivery scenarios. The method is suitable for integration into TPSs, e.g., for reconstruction of the dose delivered to moving tumors or calculation of target doses delivered with DMLC tracking.

Accuracy and potential improvements of surface-guided breast cancer radiotherapy in deep inspiration breath-hold with daily image-guidance.

Objective.Radiotherapy of left-sided breast cancer in deep inspiration breath-hold (DIBH) reduces the heart dose. Surface guided radiotherapy (SGRT) can guide the DIBH, but the accuracy is subject to variations in the chest wall position relative to the patient surface.Approach.In this study, ten left-sided breast cancer patients received DIBH radiotherapy with tangential fields in 15-18 fractions. After initial SGRT setup in free breathing an orthogonal MV/kV image pair was acquired during SGRT-guided breath-hold. The couch was corrected to align the chest wall during another breath-hold, and a new SGRT reference surface was acquired for the gating. The chest wall position error during treatment was determined from continuous cine MV images in the imager direction perpendicular to the cranio-caudal direction. A treatment error budget was made with individual contributions from the online registration of the setup MV image, the difference in breath-hold level between setup imaging and SGRT reference surface acquisition, the SGRT level during treatment, and intra-fraction shifts of the chest wall relative to the SGRT reference surface. In addition to the original setup protocol (Scenario A), SGRT was also simulated with better integration of image-guidance by capturing either the new reference surface (Scenario B) or the SGRT positional signal (Scenario C) simultaneously with the setup MV image, and accounting for the image-guided couch correction by shifting the SGRT reference surface digitally.Main results.In general, the external SGRT signal correlated well with the internal chest wall position error (correlation coefficient >0.7 for 75% of field deliveries), but external-to-internal target position offsets above 2 mm occasionally occurred (13% of fractions). The PTV margin required to account for the treatment error was 3.5 mm (Scenario A), 3.4 mm (B), and 3.1 mm (C).Significance. Further integration of SGRT with image-guidance may improve treatment accuracy and workflow although the current study did not show large accuracy improvements of scenario B and C compared to scenario A.

Non-ablative doses of focal ionizing radiation alters function of central neural circuits.

BACKGROUND: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. OBJECTIVE: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). METHODS: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. RESULTS: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. CONCLUSION: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Robust automatic segmentation of multiple implanted cylindrical gold fiducial markers in cone-beam CT projections.

PURPOSE: Implanted fiducial markers, which are used to correct for day-to-day variations, may potentially also be used to correct for intrafraction motion measurements. However, before any treatment can make use of, and react to, the position of the inserted markers they have to be segmented, either manually through expert user intervention or automatically from an imaging system. In the current study, we aimed to establish a robust and autonomous segmentation method for implanted cylindrical gold markers in a single set of projections from a cone-beam computed tomography (CBCT). METHODS: Multiple cylindrical gold markers were segmented in the projection images of CBCT scans by five sequential steps. Initially, marker candidates were identified in all projections with a blob detection routine, and then traced in subsequent projections. Traces inconsistent with a 3D marker position were rejected, and the best remaining traces were identified and used for the construction of a 3D marker constellation model, consisting of the size, position and orientation of the markers. Finally, projections of the model were used to generate templates for the final template-based marker segmentation. Hereby, challenging situations such as overlap of markers and low contrast regions were taken into account. The segmentation method was tested in 63 CBCT scans from 11 patients with 2-4 cylindrical gold markers implanted in the prostate and for 62 CBCT scans from six patients each with 2-3 cylindrical gold markers implanted in the liver and up to two cylindrical markers placed externally on the abdomen. After segmentation all projections of the 125 scans were manually inspected, and a successful segmentation was registered if the segmented position was within the projection of the marker. RESULTS: For prostate markers, the segmentation was successful in 99.8% of the projections. For the liver patients, liver markers and external markers were segmented successfully in 99.9 and 99.8% of the projections, respectively. All markers were identified in the 3D marker constellation model. The most common source of segmentation error was low contrast and motion of markers relative to each other, which resulted in a discrepancy between the template and actual projection appearance during marker overlap. Markers were overlapping in 20, 2.7, and 0.1% of the projections for prostate, liver, and external, respectively. CONCLUSIONS: We have successfully implemented a new method that, without prior knowledge on marker size, position, orientation, and number, autonomously segments cylindrical gold markers from CBCT projections with a high success rate, despite overlap, motion, and low contrast.

Geometric accuracy of dynamic MLC tracking with an implantable wired electromagnetic transponder.

BACKGROUND: Tumor motion during radiotherapy delivery can substantially deteriorate the target dose distribution. A promising method to overcome this problem is dynamic multi-leaf collimator (DMLC) tracking. The purpose of this phantom study was to integrate a wired electromagnetic (EM) transponder localization system with DMLC tracking and to investigate the geometric accuracy of the integrated system. MATERIAL AND METHODS: DMLC tracking experiments were performed on a Trilogy accelerator with a prototype DMLC tracking system. A wired implantable EM transponder was mounted on a motion stage with a 3 mm tungsten sphere used for target visualization in continuous portal images. The three dimensional (3D) transponder position signal was used for DMLC aperture adaption. The motion stage was programmed to reproduce eight representative patient-measured trajectories for prostate and for lung tumors. The tracking system latency was determined and prediction was used for the lung tumor trajectories to account for the latency. For each trajectory, three conformal fields with a 10 cm circular MLC aperture and 72 s treatment duration were delivered: (1) a 358° arc field; (2) an anterior static field; and (3) a lateral static field. The tracking error was measured as the difference between the marker position and the MLC aperture in the portal images. RESULTS: The tracking system latency was 140 ms. The mean root-mean-square (rms) of the 3D transponder localization error was 0.53/0.54 mm for prostate/lung tumor trajectories. The mean rms of the two dimensional (2D) tracking error was 0.69 mm (prostate) and 0.98 mm (lung tumors) with tracking and 3.4 mm (prostate) and 5.3 mm (lung tumors) without tracking. CONCLUSIONS: DMLC tracking was integrated with a wired EM transponder localization system and investigated for arc and static field delivery. The system provides sub-mm geometrical errors for most trajectories.

Uniform versus non-uniform dose prescription for proton stereotactic body radiotherapy of liver tumors investigated by extensive motion-including treatment simulations.

Compared to x-ray-based stereotactic body radiotherapy (SBRT) of liver cancer, proton SBRT may reduce the normal liver tissue dose. For an optimal trade-off between target and liver dose, a non-uniform dose prescription is often applied in x-ray SBRT, but lacks investigation for proton SBRT. Also, proton SBRT is prone to breathing-induced motion-uncertainties causing target mishit or dose alterations by interplay with the proton delivery. This study investigated non-uniform and uniform dose prescription in proton-based liver SBRT, including effects of rigid target motion observed during planning-4DCT and treatment. The study was based on 42 x-ray SBRT fractions delivered to 14 patients under electromagnetic motion-monitoring. For each patient, a non-uniform and uniform proton plan were made. The uniform plan was renormalized to be iso-toxic with the non-uniform plan using a NTCP model for radiation-induced liver disease. The motion data were used in treatment simulations to estimate the delivered target dose with rigid motion. Treatment simulations were performed with and without a repainting scheme designed to mitigate interplay effects. Including rigid motion, the achieved CTV mean dose after three fractions delivered without repainting was on average (±SD) 24.8 ± 8.4% higher and the D98%was 16.2 ± 11.3% higher for non-uniform plans than for uniform plans. The interplay-induced increase in D2%relative to the static plans was reduced from 3.2 ± 4.1% without repainting to -0.5 ± 1.7% with repainting for non-uniform plans and from 1.5 ± 2.0% to 0.1 ± 1.3% for uniform plans. Considerable differences were observed between estimated CTV doses based on 4DCT motion and intra-treatment motion. In conclusion, non-uniform dose prescription in proton SBRT may provide considerably higher tumor doses than uniform prescription for the same complication risk. Due to motion variability, target doses estimated from 4DCT motion may not accurately reflect the delivered dose. Future studies including modelling of deformations and associated range uncertainties are warranted to confirm the findings.

Real-time dose-guidance in radiotherapy: Proof of principle.

PURPOSE: The outcome of radiotherapy is a direct consequence of the dose delivered to the patient. Yet image-guidance and motion management to date focus on geometrical considerations as a practical surrogate for dose. Here, we propose real-time dose-guidance realized through continuous motion-including dose reconstructions and demonstrate this new concept in simulated liver stereotactic body radiotherapy (SBRT) delivery. MATERIALS AND METHODS: During simulated liver SBRT delivery, in-house developed software performed real-time motion-including reconstruction of the tumor dose delivered so far and continuously predicted the remaining fraction tumor dose. The total fraction dose was estimated as the sum of the delivered and predicted doses, both with and without the emulated couch correction that maximized the predicted final CTV D95% (minimum dose to 95% of the clinical target volume). Dose-guided treatments were simulated for 15 liver SBRT patients previously treated with tumor motion monitoring, using both sinusoidal tumor motion and the actual patient-measured motion. A dose-guided couch correction was triggered if it improved the predicted final CTV D95% with 3, 4 or 5 %-points. The final CTV D95% of the dose-guidance strategy was compared with simulated treatments using geometry guided couch corrections (Wilcoxon signed-rank test). RESULTS: Compared to geometry guidance, dose-guided couch corrections improved the median CTV D95% with 0.5-1.5 %-points (p < 0.01) for sinusoidal motions and with 0.9 %-points (p < 0.01, 3 %-points trigger threshold), 0.5 %-points (p = 0.03, 4 %-points threshold) and 1.2 %-points (p = 0.09, 5 %-points threshold) for patient-measured tumor motion. CONCLUSION: Real-time dose-guidance was proposed and demonstrated to be superior to geometrical adaptation in liver SBRT simulations.