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.

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.

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.

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.

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 .

An Intracortical Implantable Brain-Computer Interface for Telemetric Real-Time Recording and Manipulation of Neuronal Circuits for Closed-Loop Intervention.

Recording and manipulating neuronal ensemble activity is a key requirement in advanced neuromodulatory and behavior studies. Devices capable of both recording and manipulating neuronal activity brain-computer interfaces (BCIs) should ideally operate un-tethered and allow chronic longitudinal manipulations in the freely moving animal. In this study, we designed a new intracortical BCI feasible of telemetric recording and stimulating local gray and white matter of visual neural circuit after irradiation exposure. To increase the translational reliance, we put forward a Göttingen minipig model. The animal was stereotactically irradiated at the level of the visual cortex upon defining the target by a fused cerebral MRI and CT scan. A fully implantable neural telemetry system consisting of a 64 channel intracortical multielectrode array, a telemetry capsule, and an inductive rechargeable battery was then implanted into the visual cortex to record and manipulate local field potentials, and multi-unit activity. We achieved a 3-month stability of the functionality of the un-tethered BCI in terms of telemetric radio-communication, inductive battery charging, and device biocompatibility for 3 months. Finally, we could reliably record the local signature of sub- and suprathreshold neuronal activity in the visual cortex with high bandwidth without complications. The ability to wireless induction charging combined with the entirely implantable design, the rather high recording bandwidth, and the ability to record and stimulate simultaneously put forward a wireless BCI capable of long-term un-tethered real-time communication for causal preclinical circuit-based closed-loop interventions.

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.

Radionecrosis and cellular changes in small volume stereotactic brain radiosurgery in a porcine model.

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions. However, radiation-induced therapeutic effect in viable cells in functional SRS is also suggested. Evaluation of the proposed modulatory effect of irradiation on neuronal activity without causing cellular death requires the knowledge of radiation dose tolerance at very small tissue volume. Therefore, we aimed to establish a porcine model to study the effects of ultra-high radiosurgical doses in small volumes of the brain. Five minipigs received focal stereotactic radiosurgery with single large doses of 40-100 Gy to 5-7.5 mm fields in the left primary motor cortex and the right subcortical white matter, and one animal remained as unirradiated control. The animals were followed-up with serial MRI, PET scans, and histology 6 months post-radiation. We observed a dose-dependent relation of the histological and MRI changes at 6 months post-radiation. The necrotic lesions were seen in the grey matter at 100 Gy and in white matter at 60 Gy. Furthermore, small volume radiosurgery at different dose levels induced vascular, as well as neuronal cell changes and glial cell remodeling.

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.

Fully automated detection of heart irradiation in cine MV images acquired during breast cancer radiotherapy.

PURPOSE: To develop robust automated detection of heart irradiation in continuous portal images (cine MV images) of tangential breast cancer treatments. METHODS: Cine MV images of 302 tangential field deliveries were recorded for ten left-sided breast cancer patients receiving deep-inspiration breath-hold radiotherapy. An algorithm for fully automated heart edge detection in cine MV images was developed and tested for all images. The algorithm first enhances the heart edge contrast greatly by exploiting that pixels on the heart edge change their intensity cyclically, and highly correlated, at 1-3 Hz due to heartbeat. The algorithm then detects the heart edge in the enhanced image and calculates the exposed heart area within the field aperture. RESULTS: The algorithm correctly identified the heart edge in all cine MV series with heart exposure (169 of 302 field deliveries). With conservative selection criteria the algorithm on average identified 70 heart edge pixels in the heart-including field deliveries (range: 10-230) without false positives. With less strict criteria 106 heart edge pixels were identified on average (range: 13-262) with 0.6% being false positives. The heart edge bordering the lung was segmented highly reliably even a few millimeters outside the field edge. For six patients with frequent heart irradiation, the exposed heart area showed large interfraction variations and smaller intrafraction variations. CONCLUSIONS: Automated heart edge detection in cine MV images was proposed, developed and shown to be highly efficient for heart exposure detection in tangential breast fields. It may allow unsupervised surveillance of heart exposure at all tangential breast cancer treatments in a clinic.

Simulated multileaf collimator tracking for stereotactic liver radiotherapy guided by kilovoltage intrafraction monitoring: Dosimetric gain and target overdose trends.

PURPOSE: To investigate the potential benefit of multileaf collimator (MLC) tracking guided by kilovoltage intrafraction monitoring (KIM) during stereotactic body radiotherapy (SBRT) in the liver, and to understand trends of target overdose with MLC tracking. METHODS: Six liver SBRT patients with 2-3 implanted gold markers received SBRT delivered with volumetric modulated arc therapy (VMAT) in three fractions using daily cone-beam CT setup. The CTV-to-PTV margins were 5 mm in the axial plane and 10 mm in the cranio-caudal directions, and the plans were designed to give minimum target doses of 95% (CTV) and 67% (PTV). The three-dimensional marker trajectory estimated by post-treatment analysis of kV fluoroscopy images acquired throughout treatment delivery was assumed to represent the tumor motion. MLC tracking guided by real-time KIM was simulated. The reduction in CTV D95 (minimum dose to 95% of the clinical target volume) relative to the planned D95 (ΔD95) was compared between actual non-tracking and simulated MLC tracking treatments. RESULTS: MLC tracking maintained a high CTV dose coverage for all 18 fractions with ΔD95 (mean: 0.2 percentage points (pp), range: -1.7 to 1.9 pp) being significantly lower than for the actual non-tracking treatments (mean: 6.3 pp range: 0.6-16.0 pp) (p = 0.002). MLC tracking of large target motion perpendicular to the MLC leaves created dose artifacts with regions of overdose in the CTV. As a result, the mean dose in spherical volumes centered in the middle of the CTV was on average 2.4 pp (5 mm radius sphere) and 1.3 pp (15 mm radius sphere) higher than planned (p = 0.002). CONCLUSIONS: Intrafraction tumor motion can deteriorate the CTV dose of liver SBRT. The planned CTV dose coverage may be restored with KIM-guided MLC tracking. However, MLC tracking may have a tendency to create hotspots in the CTV.

Simulated real-time dose reconstruction for moving tumors in stereotactic liver radiotherapy.

PURPOSE: In radiotherapy, tumor motion may deteriorate the planned dose distribution. However, the dosimetric consequences of the motion are normally unknown for individual treatments. We here present a method for real-time motion-including tumor dose reconstruction and demonstrate its use for simulated stereotactic body radiotherapy (SBRT) of patients with liver cancer previously treated with Calypso-guided gating. METHODS: Real-time motion-including dose reconstruction was performed using in-house developed software, DoseTracker, on offline replays of previous clinical treatments. The patient cohort consisted of fifteen patients previously treated in our clinic with three-fraction SBRT to the liver using conformal or IMRT plans. The tumor motion at treatment was monitored with implanted electromagnetic transponders. The dose reconstruction was performed for both the actual gated treatments and simulated nongated treatments using a 21 Hz data stream containing accelerator parameters and the recorded motion. The dose was reconstructed in the same calculation points within the planning target volume (PTV) as used by the treatment planning system (TPS). The reconstructed doses were compared with calculations performed in the TPS, in which the motion was modeled as a series of isocenter shifts. The comparison included point doses as a function of treatment time and the dose volume histogram (DVH) for the clinical target volume (CTV). The motion-induced reduction in the dose to 95% of the CTV, Δ D 95 % , and in the mean CTV dose, ΔDMean , was compared between DoseTracker and the TPS for each simulated fraction. DoseTracker currently assumes water density within the patient contour, so for comparison, the TPS calculations were performed with both CT density and water density. The calculation times were additionally analyzed. RESULTS: Dose reconstruction was carried out for ninety SBRT sessions with calculation volumes ranging from 9.9 to 366.4 cm3 and median calculation times of 55-155 ms (equivalent to 18.2-6.5 Hz). Time-resolved trends of doses to a single calculation point in the patient were well replicated and dose differences between actual and planned calculations matched well. ΔDMean had a range of -0.1%-30.7%-points and was estimated by DoseTracker with a root-mean-square deviation (RMSD) to the TPS calculations of 0.43%-points (water density) and 0.79%-points (CT density). Similarly, Δ D 95 % had a range of 0.0%-35.2%-points and was estimated by DoseTracker with an RMSD of 0.80%-points (water density) and 1.33%-points (CT density). DoseTracker predicted losses in tumor dose coverage above 5%-points with high sensitivity (91.7%) and specificity (97.6%). CONCLUSIONS: Real-time dose reconstruction to moving tumors was demonstrated on offline replays of previous clinical treatments. DVHs of actually delivered dose are made available immediately after the end of treatment fractions. It shows promising results for liver SBRT with accurate estimation of CTV dose deteriorations caused by motion during treatment.

First clinical real-time motion-including tumor dose reconstruction during radiotherapy delivery.

PURPOSE: To clinically implement and characterize real-time motion-including tumor dose reconstruction during radiotherapy delivery. METHODS: Seven patients with 2-3 fiducial markers implanted near liver tumors received stereotactic body radiotherapy on a conventional linear accelerator. The 3D marker motion during a setup CBCT scan was determined online from the CBCT projections and used to generate a correlation model between tumor and external marker block motion. During treatment, the correlation model was updated by kV imaging every three seconds and used for real-time tumor localization. Using streamed accelerator parameters and tumor positions, in-house developed software, DoseTracker, calculated the dose to the moving tumor in real-time assuming water density in the patient. Post-treatment, the real-time tumor localization was validated by comparison with independent marker segmentations and 3D motion estimations. Dose reconstruction was validated by comparison with treatment planning system (TPS) calculations that modeled motion as isocenter shifts and used both actual CT densities and water densities. RESULTS: The real-time estimated tumor position had a mean 3D root-mean-square error of 1.7 mm (range: 0.9-2.6 mm). The motion-induced reduction in the minimum dose to 95% of the clinical target volume (CTV D95) per fraction was up to 12.3%-points. It was estimated in real-time by DoseTracker during patient treatment with a root-mean-square difference relative to the TPS of 1.3%-points (TPS CT) and 1.0%-points (TPS water). CONCLUSIONS: The world's first clinical real-time motion-including tumor dose reconstruction during radiotherapy was demonstrated. This marks an important milestone for real-time in-treatment quality assurance and paves the way for real-time dose-guided treatment adaptation.

Validation of fast motion-including dose reconstruction for proton scanning therapy in the liver.

This study validates a method of fast motion-including dose reconstruction for proton pencil beam scanning in the liver. The method utilizes a commercial treatment planning system (TPS) and calculates the delivered dose for any translational 3D target motion. Data from ten liver patients previously treated with photon radiotherapy with intrafraction tumour motion monitoring were used. The dose reconstruction method utilises an in-house developed program to incorporate beam's-eye-view tumour motion by shifting each spot in the opposite direction of the tumour and in-depth motion as beam energy changes for each spot. The doses are then calculated on a single CT phase in the TPS. Two aspects of the dose reconstruction were assessed: (1) The accuracy of reconstruction, by comparing dose reconstructions created using 4DCT motion with ground truth doses obtained by calculating phase specific doses in all 4DCT phases and summing up these partial doses. (2) The error caused by assuming 4DCT motion, by comparing reconstructions with 4DCT motion and actual tumour motion. The CTV homogeneity index (HI) and the root-mean-square (rms) dose error for all dose points receiving >70%, >80% and >90% of the prescribed dose were calculated. The dose reconstruction resulted in mean (range) absolute CTV HI errors of 1.0% (0.0-3.0)% and rms dose errors of 2.5% (1.0%-5.3%), 2.1% (0.9%-4.5%), and 1.8% (0.7%-3.7%) for >70%, >80% and >90% doses, respectively, when compared with the ground truth. The assumption of 4DCT motion resulted in mean (range) absolute CTV HI errors of 5.9% (0.0-15.0)% and rms dose errors of 6.3% (3.9%-12.6%), 5.9% (3.4%-12.5%), and 5.4% (2.6%-12.1%) for >70%, >80% and >90% doses, respectively. The investigated method allows tumour dose reconstruction with the actual tumour motion and results in significantly smaller dose errors than those caused by assuming that motion at treatment is identical to the 4DCT motion.

Geometric and dosimetric comparison of four intrafraction motion adaptation strategies for stereotactic liver radiotherapy.

The accuracy of stereotactic body radiotherapy (SBRT) in the liver is limited by tumor motion. Selection of the most suitable motion mitigation strategy requires good understanding of the geometric and dosimetric consequences. This study compares the geometric and dosimetric accuracy of actually delivered respiratory gated SBRT treatments for 15 patients with liver tumors with three simulated alternative motion adaptation strategies. The simulated alternatives are MLC tracking, baseline shift adaptation by inter-field couch corrections and no intrafraction motion adaptation. The patients received electromagnetic transponder-guided respiratory gated IMRT or conformal treatments in three fractions with a 3-4 mm gating window around the full exhale position. The CTV-PTV margin was 5 mm axially and 7-10 mm cranio-caudally. The CTV and PTV were covered with 95% and 67% of the prescribed mean CTV dose, respectively. The time-resolved target position error during treatments with the four investigated motion adaptation strategies was used to calculate motion margins and the motion-induced reduction in CTV D 95 relative to the planned dose (ΔD 95). The mean (range) number of couch corrections per treatment session to compensate for tumor drift was 2.8 (0-7) with gating, 1.4 (0-5) with baseline shift adaptation, and zero for the other strategies. The motion margins were 3.5 mm (left-right), 9.4 mm (cranio-caudal) and 3.9 mm (anterior-posterior) without intrafraction motion adaptation, approximately half of that with baseline shift adaptation, and 1-2 mm with MLC tracking and gating. With 7 mm CC margins the mean (range) of ΔD 95 for the CTV was 8.1 (0.6-29.4)%-points (no intrafraction motion adaptation), 4.0 (0.4-13.3)%-points (baseline shift adaptation), 1.0 (0.3-2.2)%-points (MLC tracking) and 0.8 (0.1-1.8)%-points (gating). With 10 mm CC margins ΔD 95 was instead 4.8 (0.3-14.8)%-points (no intrafraction motion adaptation) and 2.9 (0.2-9.8)%-points (baseline shift adaptation). In conclusion, baseline shift adaptation can mitigate gross dose deficits without the requirement of real-time motion adaptation. MLC tracking and gating, however, more effectively ensure high similarity between planned and delivered doses.

First online real-time evaluation of motion-induced 4D dose errors during radiotherapy delivery.

PURPOSE: In radiotherapy, dose deficits caused by tumor motion often far outweigh the discrepancies typically allowed in plan-specific quality assurance (QA). Yet, tumor motion is not usually included in present QA. We here present a novel method for online treatment verification by real-time motion-including four-dimensional (4D) dose reconstruction and dose evaluation and demonstrate its use during stereotactic body radiotherapy (SBRT) delivery with and without MLC tracking. METHODS: Five volumetric-modulated arc therapy (VMAT) plans were delivered with and without MLC tracking to a motion stage carrying a Delta4 dosimeter. The VMAT plans have previously been used for (nontracking) liver SBRT with intratreatment tumor motion recorded by kilovoltage intrafraction monitoring (KIM). The motion stage reproduced the KIM-measured tumor motions in three dimensions (3D) while optical monitoring guided the MLC tracking. Linac parameters and the target position were streamed to an in-house developed software program (DoseTracker) that performed real-time 4D dose reconstructions and 3%/3 mm γ-evaluations of the reconstructed cumulative dose using a concurrently reconstructed planned dose without target motion as reference. Offline, the real-time reconstructed doses and γ-evaluations were validated against 4D dosimeter measurements performed during the experiments. RESULTS: In total, 181,120 dose reconstructions and 5,237 γ-evaluations were performed online and in real time with median computation times of 30 ms and 1.2 s, respectively. The mean (standard deviation) difference between reconstructed and measured doses was -1.2% (4.9%) for transient doses and -1.5% (3.9%) for cumulative doses. The root-mean-square deviation between reconstructed and measured motion-induced γ-fail rates was 2.0%-point. The mean (standard deviation) sensitivity and specificity of DoseTracker to predict γ-fail rates above a given threshold was 96.8% (3.5%) and 99.2% (0.4%), respectively, for clinically relevant thresholds between 1% and 30% γ-fail rate. CONCLUSIONS: Real-time delivery-specific QA during radiotherapy of moving targets was demonstrated for the first time. It allows supervision of treatment accuracy and action on treatment discrepancy within 2 s with high sensitivity and specificity.

Automatic online and real-time tumour motion monitoring during stereotactic liver treatments on a conventional linac by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK).

The purpose of this study was to develop, validate and clinically demonstrate fully automatic tumour motion monitoring on a conventional linear accelerator by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK). COSMIK combines auto-segmentation of implanted fiducial markers in cone-beam computed tomography (CBCT) projections and intra-treatment kV images with simultaneous streaming of an external motion signal. A pre-treatment CBCT is acquired with simultaneous recording of the motion of an external marker block on the abdomen. The 3-dimensional (3D) marker motion during the CBCT is estimated from the auto-segmented positions in the projections and used to optimize an external correlation model (ECM) of internal motion as a function of external motion. During treatment, the ECM estimates the internal motion from the external motion at 20 Hz. KV images are acquired every 3 s, auto-segmented, and used to update the ECM for baseline shifts between internal and external motion. The COSMIK method was validated using Calypso-recorded internal tumour motion with simultaneous camera-recorded external motion for 15 liver stereotactic body radiotherapy (SBRT) patients. The validation included phantom experiments and simulations hereof for 12 fractions and further simulations for 42 fractions. The simulations compared the accuracy of COSMIK with ECM-based monitoring without model updates and with model updates based on stereoscopic imaging as well as continuous kilovoltage intrafraction monitoring (KIM) at 10 Hz without an external signal. Clinical real-time tumour motion monitoring with COSMIK was performed offline for 14 liver SBRT patients (41 fractions) and online for one patient (two fractions). The mean 3D root-mean-square error for the four monitoring methods was 1.61 mm (COSMIK), 2.31 mm (ECM without updates), 1.49 mm (ECM with stereoscopic updates) and 0.75 mm (KIM). COSMIK is the first combined kV/optical real-time motion monitoring method used clinically online on a conventional accelerator. COSMIK gives less imaging dose than KIM and is in addition applicable when the kV imager cannot be deployed such as during non-coplanar fields.