Evaluation of in vitro irradiation setup: Designed for the horizontal beamline at the Danish Centre for Particle Therapy.

BACKGROUND: Radiobiological experimental setups are challenged by precise sample positioning along depth dose profile, scattering conditions, and practical difficulties that must be addressed in individual designs. The aim of this study was to produce cell survival curves with several irradiation modalities, by using a setup designed at the Danish Centre for Particle Therapy (DCPT) for in vitro proton irradiations using a horizontal beam line and thereby evaluating the setups use for in vitro irradiations experiments. MATERIALS AND METHODS: The setup is a water phantom suitable for in vitro research with multiple irradiation modalities, in particular the pencil scanning proton beam available from a horizontal experimental beamline. The phantom included a water tank of 39.0 × 17.0 × 20.5 cm. Cell survival-curves were produced using the cell line V79 Chinese hamster lung fibroblast cells (V79s) in biological triplicates of clonogenic assays. Cell survival curves were produced with both a 18 MeV electron beam, 6 MV photon beam, and a Spread-Out Bragg Peak (SOBP) proton beam formed by pristine energies of 85-111 MeV where three positions were examined. RESULTS: Survival curves with uncertainty areas were made for all modalities. Dosimetric uncertainty amounted to, respectively, 4%, 3% and 3% for proton, electron, and high energy photon irradiations. Cell survival fraction uncertainty was depicted as the standard deviation between replications of the experiment. CONCLUSION: Cell survival curves could be produced with acceptable uncertainties using this novel water phantom and cellular laboratory workflow. The setup is useful for future in vitro irradiation experiments.

Setup error and motion during deep inspiration breath-hold breast radiotherapy measured with continuous portal imaging.

BACKGROUND: The position and residual motion of the chest wall of breast cancer patients during treatment in deep inspiration breath-hold (DIBH) were investigated. MATERIAL AND METHODS: The study included 58 left-sided breast cancer patients treated with DIBH three-dimensional (3D) conformal radiotherapy in 15 or 25 fractions. The DIBH levels were monitored using an external marker block placed on the chest, either shifted 5 cm to the right at the level of the xiphoid process (Group 1, 27 consecutive patients) or placed medially on the inferior part of the sternum (Group 2, 31 consecutive patients). At every third treatment fraction, continuous portal images were acquired. The time-resolved chest wall position during treatment was compared with the planned position to determine the inter-fraction setup errors and the intra-fraction motion of the chest wall. RESULTS: The DIBH compliance was 95% during both recruitment periods. A tendency of smaller inter-fraction setup errors and intra-fraction motion was observed for group 2 (medial marker block position). However, apart from a significantly reduced inter-field random shift (σ = 1.7 mm vs. σ = 0.9 mm, p = 0.005), no statistically significant differences between the groups were found. In a combined analysis, the group mean inter-fraction setup error was M = - 0.1 mm, with random and systematic errors of σ = 1.7 mm and Σ = 1.4 mm. The group mean inter-field shift was M = 0.0 (σ = 1.3 mm and Σ = 1.1 mm) and the group mean standard deviation of the intra-field motion was 0.5 mm. The absolute setup error had a maximum of 16.3 mm, exceeding 5 mm in 2.2% of the imaged fields. CONCLUSION: Compared to free breathing treatments, the primary benefit of the DIBH technique was the separation of the heart from the target rather than more accurate targeting. Despite a small gating window, occasional large errors in the chest wall position were observed for some patients, illustrating limitations of the external marker block as surrogate in a broad patient population.

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.

Two-dimensional time-resolved scintillating sheet monitoring of proton pencil beam scanning FLASH mouse irradiations.

BACKGROUND: Dosimetry in pre-clinical FLASH studies is essential for understanding the beam delivery conditions that trigger the FLASH effect. Resolving the spatial and temporal characteristics of proton pencil beam scanning (PBS) irradiations with ultra-high dose rates (UHDR) requires a detector with high spatial and temporal resolution. PURPOSE: To implement a novel camera-based system for time-resolved two-dimensional (2D) monitoring and apply it in vivo during pre-clinical proton PBS mouse irradiations. METHODS: Time-resolved 2D beam monitoring was performed with a scintillation imaging system consisting of a 1 mm thick transparent scintillating sheet, imaged by a CMOS camera. The sheet was placed in a water bath perpendicular to a horizontal PBS proton beam axis. The scintillation light was reflected through a system of mirrors and captured by the camera with 500 frames per second (fps) for UHDR and 4 fps for conventional dose rates. The raw images were background subtracted, geometrically transformed, flat field corrected, and spatially filtered. The system was used for 2D spot and field profile measurements and compared to radiochromic films. Furthermore, spot positions were measured for UHDR irradiations. The measured spot positions were compared to the planned positions and the relative instantaneous dose rate to equivalent fiber-coupled point scintillator measurements. For in vivo application, the scintillating sheet was placed 1 cm upstream the right hind leg of non-anaesthetized mice submerged in the water bath. The mouse leg and sheet were both placed in a 5 cm wide spread-out Bragg peak formed from the mono-energetic proton beam by a 2D range modulator. The mouse leg position within the field was identified for both conventional and FLASH irradiations. For the conventional irradiations, the mouse foot position was tracked throughout the beam delivery, which took place through repainting. For FLASH irradiations, the delivered spot positions and relative instantaneous dose rate were measured. RESULTS: The pixel size was 0.1 mm for all measurements. The spot and field profiles measured with the scintillating sheet agreed with radiochromic films within 0.4 mm. The standard deviation between measured and planned spot positions was 0.26 mm and 0.35 mm in the horizontal and vertical direction, respectively. The measured relative instantaneous dose rate showed a linear relation with the fiber-coupled scintillator measurements. For in vivo use, the leg position within the field varied between mice, and leg movement up to 3 mm was detected during the prolonged conventional irradiations. CONCLUSIONS: The scintillation imaging system allowed for monitoring of UHDR proton PBS delivery in vivo with 0.1 mm pixel size and 2 ms temporal resolution. The feasibility of instantaneous dose rate measurements was demonstrated, and the system was used for validation of the mouse leg position within the field.

Correlation between local instantaneous dose rate and oxygen pressure reduction during proton pencil beam scanning irradiation.

Background and purpose: Oxygen dynamics may be important for the tissue-sparing effect observed at ultra-high dose rates (FLASH sparing effect). This study investigated the correlation between local instantaneous dose rate and radiation-induced oxygen pressure reduction during proton pencil beam scanning (PBS) irradiations of a sample and quantified the oxygen consumption g-value. Materials and methods: A 0.2 ml phosphorescent sample (1 µM PtG4 Oxyphor probe in saline) was irradiated with a 244 MeV proton PBS beam. Four irradiations were performed with variations of a PBS spot pattern with 5 × 7 spots. During irradiation, the partial oxygen pressure (pO2) was measured with 4.5 Hz temporal resolution with a phosphorometer (Oxyled) that optically excited the probe and recorded the subsequently emitted light. A calibration was performed to calculate the pO2 level from the measured phosphorescence lifetime. A fiber-coupled scintillator simultaneously measured the instantaneous dose rate in the sample with 50 kHz sampling rate. The oxygen consumption g-value was determined on a spot-by-spot level and using the total pO2 change for full spot pattern irradiation. Results: A high correlation was found between the local instantaneous dose rate and pO2 reduction rate, with a correlation coefficient of 0.96-0.99. The g-vales were 0.18 ± 0.01 mmHg/Gy on a spot-by-spot level and 0.17 ± 0.01 mmHg/Gy for full spot pattern irradiation. Conclusions: The pO2 reduction rate was directly related to the local instantaneous dose rate per delivered spot in PBS deliveries. The methodology presented here can be applied to irradiation at ultra-high dose rates with modifications in the experimental setup.

Oxygen Enhancement Ratio-Weighted Dose Quantitatively Describes Acute Skin Toxicity Variations in Mice After Pencil Beam Scanning Proton FLASH Irradiation With Changing Doses and Time Structures.

PURPOSE: The aim of this work was to investigate the ability of a biological oxygen enhancement ratio-weighted dose, DOER, to describe acute skin toxicity variations observed in mice after proton pencil beam scanning irradiations with changing doses and beam time structures. METHODS AND MATERIALS: In five independent experiments, the right hind leg of a total of 621 CDF1 mice was irradiated previously in the entrance plateau of a pencil beam scanning proton beam. The incidence of acute skin toxicity (of level 1.5-2.0-2.5-3.0-3.5) was scored for 47 different mouse groups that mapped toxicity as function of dose for conventional and FLASH dose rate, toxicity as function of field dose rate with and without repainting, and toxicity when splitting the treatment into 1 to 6 identical deliveries separated by 2 minutes. DOER was calculated for all mouse groups using a simple oxygen kinetics model to describe oxygen depletion. The three independent model parameters (oxygen-depletion rate, oxygen-recovery rate, oxygen level without irradiation) were fitted to the experimental data. The ability of DOER to describe the toxicity variations across all experiments was investigated by comparing DOER-response curves across the five independent experiments. RESULTS: After conversion from the independent variable tested in each experiment to DOER, all five experiments had similar MDDOER50 (DOER giving 50% toxicity incidence) with standard deviations of 0.45 - 1.6 Gy for the five toxicity levels. DOER could thus describe the observed toxicity variations across all experiments. CONCLUSIONS: DOER described the varying FLASH-sparing effect observed for a wide range of conditions. Calculation of DOER for other irradiation conditions can quantitatively estimate the FLASH-sparing effect for arbitrary irradiations for the investigated murine model. With appropriate fitting parameters DOER also may be able to describe FLASH effect variations with dose and dose rate for other assays and endpoints.

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.

Spread-out Bragg peak FLASH: quantifying normal tissue toxicity in a murine model.

Objective: A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model. Material/Methods: Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment. Results: Comparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4). Conclusion: Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

Dosimetric impact of respiratory motion, interfraction baseline shifts, and anatomical changes in radiotherapy of non-small cell lung cancer.

BACKGROUND: The survival rates for patients with non-small cell lung cancer (NSCLC) may be improved by dose escalation; however, margin reduction may be required in order to keep the toxicity at an acceptable level. In this study we have investigated the dosimetric impact of tumor motion and anatomical changes during intensity-modulated radiotherapy (IMRT) of patients with NSCLC. MATERIAL AND METHODS: Sixteen NSCLC patients received IMRT with concomitant chemotherapy. The tumor and lymph node targets were delineated in the mid-ventilation phase of a planning 4DCT scan (CT1). Typically 66 Gy was delivered in 33 fractions using daily CBCT with bony anatomy match for patient setup. The daily baseline shifts of the mean tumor position relative to the spine were extracted from the CBCT scans. A second 4DCT scan (CT2) was acquired halfway through the treatment course and the respiratory tumor motion was extracted. The plan was recalculated on CT2 with and without inclusion of the respiratory tumor motion and baseline shifts in order to investigate the impact of tumor motion and anatomical changes on the tumor dose. RESULTS: Respiratory tumor motion was largest in the cranio-caudal (CC) direction (range 0-13.1 mm). Tumor baseline shifts up to 18 mm (CC direction) and 24 mm (left-right and anterior-posterior) were observed. The average absolute difference in CTV mean dose to the primary tumor (CTV-t) between CT1 and CT2 was 1.28% (range 0.1-4.0%) without motion. Respiratory motion and baseline shifts lead to average absolute CTV-t mean dose changes of 0.46% (0-1.9%) and 0.65% (0.0-2.1%), respectively. For most patients, the changes in the CTV-t dose were caused by anatomical changes rather than internal target motion. CONCLUSION: Anatomical changes had larger impact on the target dose distribution than internal target motion. Adaptive radiotherapy could be used to achieve better target coverage throughout the treatment course.

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.

Time-resolved dose rate measurements in pencil beam scanning proton FLASH therapy with a fiber-coupled scintillator detector system.

BACKGROUND: The spatial and temporal dose rate distribution of pencil beam scanning (PBS) proton therapy is important in ultra-high dose rate (UHDR) or FLASH irradiations. Validation of the temporal structure of the dose rate is crucial for quality assurance and may be performed using detectors with high temporal resolution and large dynamic range. PURPOSE: To provide time-resolved in vivo dose rate measurements using a scintillator-based detector during proton PBS pre-clinical mouse experiments with dose rates ranging from conventional to UHDR. METHODS: All irradiations were performed at the entrance plateau of a 250 MeV PBS proton beam. A detector system with four fiber-coupled ZnSe:O inorganic scintillators and 20 µs temporal resolution was used for dose rate measurements. The system was first characterized in terms of precision and stem signal. The detector precision was determined through repeated irradiations with the same field. The stem signal contribution was quantified by irradiating two of the detector probes alongside a bare fiber (fiber without a coupled scintillator). Next, the detector system was calibrated against an ionization chamber (IC) with all four detector probes and the IC placed in a water bath at 2 cm depth. A scan pattern covering 9.6 × 9.6 cm was used. Multiple irradiations with different requested nozzle currents provided instantaneous dose rates at the detector positions in the range of 7-1270 Gy/s. The correspondence of the detector signal (in Volts) to the instantaneous dose rate (in Gy/s) was found. The instantaneous dose rate was calculated from the beam current and the spot-to-detector distance assuming a Gaussian beam profile at distances up to 8 mm from the spot. Afterwards, the calibrated system was used in vivo, in mouse experiments, where mouse legs were irradiated with a constant dose and varying field dose rates of 0.7-87.5 Gy/s. The instantaneous dose rate was measured for each delivered spot and the delivered dose was determined as the integrated instantaneous dose rate. The spot dose profile and PBS dose rate map were calculated. The dose contamination to neighbouring mice were measured together with the upper limit of the dose to the mouse body. RESULTS: The detectors showed high precision with ≤0.4% fluctuations in the measured dose. The stem signal exceeded 10% for spots <5 mm from the optical fiber and >18 mm from the scintillator. It contributed up to 0.2% to the total dose, which was considered negligible. All four detectors showed a non-linear relation between signal and instantaneous dose rate, which was modelled with a polynomial response function. In the mouse experiments, the measured scintillator dose showed 1.8% fluctuations, independent of the field dose rate. The in vivo measured spot dose profile had tails that deviated from a Gaussian profile with measurable dose contributions from spots up to 85 mm from the detector. Neighbour mouse irradiation contributed ∼1% of the total mouse dose. The upper limit of the mouse body dose was 6% of the mouse leg dose. CONCLUSIONS: A fiber-coupled inorganic scintillator-based detector system can provide high precision in vivo measurements of the instantaneous dose rate if correction for the non-linear dose rate dependency is applied.

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.

The dosimetric error due to uncorrected tumor rotation during real-time adaptive prostate stereotactic body radiation therapy.

BACKGROUND: During prostate stereotactic body radiation therapy (SBRT), prostate tumor translational motion may deteriorate the planned dose distribution. Most of the major advances in motion management to date have focused on correcting this one aspect of the tumor motion, translation. However, large prostate rotation up to 30° has been measured. As the technological innovation evolves toward delivering increasingly precise radiotherapy, it is important to quantify the clinical benefit of translational and rotational motion correction over translational motion correction alone. PURPOSE: The purpose of this work was to quantify the dosimetric impact of intrafractional dynamic rotation of the prostate measured with a six degrees-of-freedom tumor motion monitoring technology. METHODS: The delivered dose was reconstructed including (a) translational and rotational motion and (b) only translational motion of the tumor for 32 prostate cancer patients recruited on a 5-fraction prostate SBRT clinical trial. Patients on the trial received 7.25 Gy in a treatment fraction. A 5 mm clinical target volume (CTV) to planning target volume (PTV) margin was applied in all directions except the posterior direction where a 3 mm expansion was used. Prostate intrafractional translational motion was managed using a gating strategy, and any translation above the gating threshold was corrected by applying an equivalent couch shift. The residual translational motion is denoted as T r e s $T_{res}$ . Prostate intrafractional rotational motion R u n c o r r $R_{uncorr}$ was recorded but not corrected. The dose differences from the planned dose due to T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ , ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) and due to T r e s $T_{res}$ alone, ΔD( T r e s $T_{res}$ ), were then determined for CTV D98, PTV D95, bladder V6Gy, and rectum V6Gy. The residual dose error due to uncorrected rotation, R u n c o r r $R_{uncorr}$ was then quantified: Δ D R e s i d u a l $\Delta D_{Residual}$ = ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) - ΔD( T res ${T}_{\textit{res}}$ ). RESULTS: Fractional data analysis shows that the dose differences from the plan (both ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) and ΔD( T r e s $T_{res}$ )) for CTV D98 was less than 5% in all treatment fractions. ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) was larger than 5% in one fraction for PTV D95, in one fraction for bladder V6Gy, and in five fractions for rectum V6Gy. Uncorrected rotation, R u n c o r r $R_{uncorr}$ induced residual dose error, Δ D R e s i d u a l $\Delta D_{Residual}$ , resulted in less dose to CTV and PTV in 43% and 59% treatment fractions, respectively, and more dose to bladder and rectum in 51% and 53% treatment fractions, respectively. The cumulative dose over five fractions, ∑D( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) and ∑D( T r e s $T_{res}$ ), was always within 5% of the planned dose for all four structures for every patient. CONCLUSIONS: The dosimetric impact of tumor rotation on a large prostate cancer patient cohort was quantified in this study. These results suggest that the standard 3-5 mm CTV-PTV margin was sufficient to account for the intrafraction prostate rotation observed for this cohort of patients, provided an appropriate gating threshold was applied to correct for translational motion. Residual dose errors due to uncorrected prostate rotation were small in magnitude, which may be corrected using different treatment adaptation strategies to further improve the dosimetric accuracy.

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.

Time structure of pencil beam scanning proton FLASH beams measured with scintillator detectors and compared with log files.

PURPOSE: Key factors in FLASH treatments are the ultra-high dose rate (UHDR) and the time structure of the beam delivery. Measurement of the time structure in pencil beam scanning (PBS) proton FLASH treatments is challenging for many types of detectors since high temporal resolution is needed. In this study, a fast scintillator detector system was developed and used to measure the individual spot durations as well as the time when the beam moves between two positions (transition duration) during PBS proton FLASH and UHDR treatments. The spot durations were compared with machine log-file recordings. METHODS: A detector system based on inorganic scintillating crystals was developed. The system consisted of four detector probes made of a sub-millimeter ZnSe:O crystal that was coupled via an optical fiber to an optical reader with 50 kHz sampling rate. The detector system was used in two experiments, both performed with a PBS proton beam with 250 MeV beam energy and 215 nA requested nozzle beam current. The sampling rate enabled multiple measurements during each spot delivery and during the beam transition between spots. First, the detector was tested in a phantom experiment, where a total of 305 scan sequences were delivered to the four detectors. The number of spots delivered without beam interruption in a single scan sequence ranged from one to 35. The spot duration and transition duration were measured for each individual spot. Secondly, the detector system was used in vivo in preclinical experiments with FLASH irradiation of mouse legs placed in the entrance plateau of the beam. A single detector was placed 1 cm downstream of the irradiated mouse leg. The mouse dose ranged from 30.5 to 44.2 Gy and the field consisted of 35 spots. The spot durations as well as the mean dose rate (field dose divided by the measured field duration) for each mouse were determined using the detector and then compared with the corresponding log files. RESULTS: The phantom experiment showed that the logged total duration of an uninterrupted spot sequence was consistently shorter than the measured duration with a difference of -0.252 ms (95% confidence interval: [-0.255, -0.249 ms]). This corresponded to 0.05%-0.07% of the spot sequence duration in the mice experiments. For individual spots, the mean ± 1SD difference between logged and measured spot duration was -0.39 ± 0.05 ms for the first spot in a sequence, 0.13 ± 0.04 ms for the last spot in a sequence, and -0.0017 ± 0.09 ms for the intermediate spots in a sequence. The measured spot transition durations were 0.20 ± 0.04 ms (5.1 mm horizontal steps) and 0.50 ± 0.04 ms (5.0 mm vertical steps). For the mouse experiments, the mean dose rate calculated from the measured field duration was 84.1-92.5 Gy/s. It agreed with log files with a root mean square difference of 0.02 Gy/s. CONCLUSIONS: Fiber-coupled scintillator detectors were designed with sufficient temporal resolution to measure the spot and transition duration during PBS proton UHDR deliveries. Their small volume makes them feasible for in vivo use in preclinical FLASH studies. The logged spot durations were in excellent agreement with measurements but showed small systematic errors in the logged duration for the first and last spot in a sequence.

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.

A method for robust segmentation of arbitrarily shaped radiopaque structures in cone-beam CT projections.

PURPOSE: Implanted markers are commonly used in radiotherapy for x-ray based target localization. The projected marker position in a series of cone-beam CT (CBCT) projections can be used to estimate the three dimensional (3D) target trajectory during the CBCT acquisition. This has important applications in tumor motion management such as motion inclusive, gating, and tumor tracking strategies. However, for irregularly shaped markers, reliable segmentation is challenged by large variations in the marker shape with projection angle. The purpose of this study was to develop a semiautomated method for robust and reliable segmentation of arbitrarily shaped radiopaque markers in CBCT projections. METHODS: The segmentation method involved the following three steps: (1) Threshold based segmentation of the marker in three to six selected projections with large angular separation, good marker contrast, and uniform background; (2) construction of a 3D marker model by coalignment and backprojection of the threshold-based segmentations; and (3) construction of marker templates at all imaging angles by projection of the 3D model and use of these templates for template-based segmentation. The versatility of the segmentation method was demonstrated by segmentation of the following structures in the projections from two clinical CBCT scans: (1) Three linear fiducial markers (Visicoil) implanted in or near a lung tumor and (2) an artificial cardiac valve in a lung cancer patient. RESULTS: Automatic marker segmentation was obtained in more than 99.9% of the cases. The segmentation failed in a few cases where the marker was either close to a structure of similar appearance or hidden behind a dense structure (data cable). CONCLUSIONS: A robust template-based method for segmentation of arbitrarily shaped radiopaque markers in CBCT projections was developed.

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.

Six degrees of freedom dynamic motion-including dose reconstruction in a commercial treatment planning system.

PURPOSE: Intrafractional motion during radiotherapy delivery can deteriorate the delivered dose. Dynamic rotational motion of up to 38 degrees has been reported during prostate cancer radiotherapy, but methods to determine the dosimetric consequences of such rotations are lacking. Here, we create and experimentally validate a dose reconstruction method that accounts for dynamic rotations and translations in a commercial treatment planning system (TPS). Interplay effects are quantified by comparing dose reconstructions with dynamic and constant rotations. METHODS: The dose reconstruction accumulates the dose in points of interest while the points are moved in six degrees of freedom (6DoF) in a precalculated time-resolved four-dimensional (4D) dose matrix to emulate dynamic motion in a patient. The required 4D dose matrix was generated by splitting the original treatment plan into multiple sub-beams, each representing 0.4 s dose delivery, and recalculating the dose of the split plan in the TPS (Eclipse). The dose accumulation was performed via TPS scripting by querying the dose of each sub-beam in dynamically moving points, allowing dose reconstruction with any dynamic motion. The dose reconstruction was validated with film dosimetry for two prostate dual arc VMAT plans with intra-prostatic lesion boosts. The plans were delivered to a pelvis phantom with internal dynamic rotational motion of a film stack (21 films with 2.5 mm separation). Each plan was delivered without motion and with three prostate motion traces. Motion-including dose reconstruction was performed for each motion experiment using the actual dynamic rotation as well as a constant rotation equal to the mean rotation during the experiment. For each experiment, the 3%/2 mm γ failure rate of the TPS dose reconstruction was calculated with the film measurement being the reference. For each motion experiment, the motion-induced 3%/2 mm γ failure rate was calculated using the static delivery as the reference and compared between film measurements and TPS dose reconstruction. DVH metrics for RT structures fully contained in the film volume were also compared between film and TPS. RESULTS: The mean γ failure rate of the TPS dose reconstructions when compared to film doses was 0.8% (two static experiments) and 1.7% (six dynamic experiments). The mean (range) of the motion-induced γ failure rate in film measurements was 35.4% (21.3-59.2%). The TPS dose reconstruction agreed with these experimental γ failure rates with root-mean-square errors of 2.1% (dynamic rotation dose reconstruction) and 17.1% (dose reconstruction assuming constant rotation). By DVH metrics, the mean (range) difference between dose reconstructions with dynamic and constant rotation was 4.3% (-0.3-10.6%) (urethra D 2 % ), -0.6% (-5.6%-2.5%) (urethra D 99 % ), 1.1% (-7.1-7.7%) (GTV D 2 % ), -1.4% (-17.4-7.1%) (GTV D 95 % ), -1.2% (-17.1-5.7%) (GTV D 99 % ), and -0.1% (-3.2-7.6%) (GTV mean dose). Dose reconstructions with dynamic motion revealed large interplay effects (cold and hot spots). CONCLUSIONS: A method to perform dose reconstructions for dynamic 6DoF motion in a TPS was developed and experimentally validated. It revealed large differences in dose distribution between dynamic and constant rotations not identifiable through dose reconstructions with constant rotation.