Herman, Michael G.

PurposeThe presence of respiratory motion during radiation treatment leads to degradation of the expected dose distribution, both for target coverage and healthy tissue sparing, particularly for techniques like pencil beam scanning proton therapy which have dynamic delivery systems. While tools exist to estimate this degraded four‐dimensional (4D) dose, they typically have one or more deficiencies such as not including the particular effects from a dynamic delivery, using analytical dose calculations, and/or using nonphysical dose‐accumulation methods. This work presents a clinically useful 4D‐dose calculator that addresses each of these shortcomings.MethodsTo quickly compute the 4D dose, the three main tasks of the calculator were run on graphics processing units (GPUs). These tasks were (a) simulating the delivery of the plan using measured delivery parameters to distribute the plan amongst 4DCT phases characterizing the patient breathing, (b) using an in‐house Monte Carlo simulation (MC) dose calculator to determine the dose delivered to each breathing phase, and (c) accumulating the doses from the various breathing phases onto a single phase for evaluation. The accumulation was performed by individually transferring the energy and mass of dose‐grid subvoxels, a technique that models the transfer of dose in a more physically realistic manner. The calculator was run on three test cases, with lung, esophagus, and liver targets, respectively, to assess the various uncertainties in the beam delivery simulation as well as to characterize the dose‐accumulation technique.ResultsFour‐dimensional doses were successfully computed for the three test cases with computation times ranging from 4–6 min on a server with eight NVIDIA Titan X graphics cards; the most time‐consuming component was the MC dose engine. The subvoxel‐based dose‐accumulation technique produced stable 4D‐dose distributions at subvoxel scales of 0.5–1.0 mm without impairing the total computation time. The uncertainties in the beam delivery simulation led to moderate variations of the dose–volume histograms for these cases; the variations were reduced by implementing repainting or phase‐gating motion mitigation techniques in the calculator.ConclusionsA MC‐based and GPU‐accelerated 4D‐dose calculator was developed to estimate the effects of respiratory motion on pencil beam scanning proton therapy treatments. After future validation, the calculator could be used to assess treatment plans and its quick runtime would make it easily usable in a future 4D‐robust optimization system.

PurposeAccuracy of dose calculation models and robustness under various uncertainties are key factors influencing the quality of intensity modulated proton therapy (IMPT) plans. To mitigate the effects of uncertainties and to improve the dose calculation accuracy, an all‐scenario robust IMPT optimization based on accurate Monte Carlo (MC) dose calculation was developed.MethodsIn the all‐scenario robust IMPT optimization, dose volume histograms (DVHs) were computed for the nominal case and for each uncertainty scenario. All scenarios were weighted by DVH values dynamically throughout optimization iterations. In contrast, probabilistic approach weighted scenarios with fixed scenario weights and worst case optimizations picked one single scenario — the worst scenario for each iteration. Uncertainties in patient setup and proton range were considered in all clinical cases studied. Graphics processing unit (GPU) computation was employed to reduce the computational time in both the MC dose calculation and optimization stages. A previously published adaptive quasi‐Newton method for proton optimization was extended to include robustness. To validate the all‐scenario algorithm extension, it was compared with the single scenario optimization target volume (OTV) based approach in clinical cases of three different disease sites. Additional comparisons with worst case optimization methods were conducted to evaluate the performance of the all‐scenario robust optimization against other robust optimizations.ResultsThe all‐scenario robust IMPT optimization spared organs at risk (OARs) better than the OTV‐based method while maintaining target coverage and improving the robustness of targets and OARs. Compared with composite and voxel‐wise worst case optimization, the all‐scenario robust optimization converged faster, and arrived at solutions of tighter DVH robustness spread, better target coverage and lower OAR dose.ConclusionAn all‐scenario robust IMPT treatment planning system was developed using an adaptive quasi‐Newton optimization method. The optimization system was GPU‐accelerated and based on MC dose calculation. Improved performance was observed in clinical cases when compared with worst case optimization methods.

PurposeMicrodosimetry is a vital tool for assessing the microscopic patterns of energy deposition by radiation, which ultimately govern biological effect. Solid‐state, silicon‐on‐insulator microdosimeters offer an approach for making microdosimetric measurements with high spatial resolution (on the order of tens of micrometers). These high‐resolution, solid‐state microdosimeters may therefore play a useful role in characterizing proton radiotherapy fields, particularly for making highly resolved measurements within the Bragg peak region. In this work, we obtain microdosimetric measurements with a solid‐state microdosimeter (MicroPlus probe) in a clinical, spot‐scanning proton beam of small spot size.MethodsThe MicroPlus probe had a 3D single sensitive volume on top of silicon oxide. The sensitive volume had an active cross‐sectional area of 250 μm × 10 μm and thickness of 10 μm. The proton facility was a synchrotron‐based, spot‐scanning system with small spot size (σ ≈ 2 mm). We performed measurements with the clinical beam current (≈1 nA) and had no detected pulse pile‐up. Measurements were made in a water‐equivalent phantom in water‐equivalent depth (WED) increments of 0.25 mm or 1.0 mm along pristine Bragg peaks of energies 71.3 MeV and 159.9 MeV, respectively. For each depth, we measured lineal energy distributions and then calculated the dose‐weighted mean lineal energy, . The measurements were repeated for two field sizes: 4 × 4 cm2 and 20 × 20 cm2.ResultsFor both 71.3 MeV and 159.9 MeV and for both field sizes, increased with depth toward the distal edge of the Bragg peak, a result consistent with Monte Carlo calculations and measurements performed elsewhere. For the 71.3 MeV, 4 × 4 cm2 beam (range at 80% distal falloff, R80 = 3.99 cm), we measured keV/μm at WED = 2 cm, and keV/μm at WED = 3.95 cm. For the 71.3 MeV, 20 × 20 cm2 beam, we measured keV/μm at WED = 2.6 cm, and keV/μm at WED = 3 cm. For the 159.9 MeV, 4 × 4 cm2 beam (R80 = 17.7 cm), keV/μm at WED = 5 cm, and keV/μm at WED = 17.6 cm. For the 159.9 MeV, 20 × 20 cm2 beam, keV/μm at WED = 5 cm, and keV/μm at WED = 17.6 cm.ConclusionsWe performed microdosimetric measurements with a novel solid‐state, silicon‐on‐insulator microdosimeter in a clinical spot‐scanning proton beam of small spot size and unmodified beam current. For all of the proton field sizes and energies considered, the measurements of were in agreement with expected trends. Furthermore, we obtained measurements with a spatial resolution of 10 μm in the beam direction. This spatial resolution greatly exceeded that possible with a conventional gaseous tissue‐equivalent proportional counter and allowed us to perform a high‐resolution investigation within the Bragg peak region. The MicroPlus probe is therefore suitable for applications in proton radiotherapy.

PurposeTo accurately model the beam delivery time (BDT) for a synchrotron‐based proton spot scanning system using experimentally determined beam parameters.MethodsA model to simulate the proton spot delivery sequences was constructed, and BDT was calculated by summing times for layer switch, spot switch, and spot delivery. Test plans were designed to isolate and quantify the relevant beam parameters in the operation cycle of the proton beam therapy delivery system. These parameters included the layer switch time, magnet preparation and verification time, average beam scanning speeds in x‐ and y‐directions, proton spill rate, and maximum charge and maximum extraction time for each spill. The experimentally determined parameters, as well as the nominal values initially provided by the vendor, served as inputs to the model to predict BDTs for 602 clinical proton beam deliveries. The calculated BDTs (TBDT) were compared with the BDTs recorded in the treatment delivery log files (TLog): ∆t = TLog−TBDT.ResultsThe experimentally determined average layer switch time for all 97 energies was 1.91 s (ranging from 1.9 to 2.0 s for beam energies from 71.3 to 228.8 MeV), average magnet preparation and verification time was 1.93 ms, the average scanning speeds were 5.9 m/s in x‐direction and 19.3 m/s in y‐direction, the proton spill rate was 8.7 MU/s, and the maximum proton charge available for one acceleration is 2.0 ± 0.4 nC. Some of the measured parameters differed from the nominal values provided by the vendor. The calculated BDTs using experimentally determined parameters matched the recorded BDTs of 602 beam deliveries (∆t = −0.49 ± 1.44 s), which were significantly more accurate than BDTs calculated using nominal timing parameters (∆t = −7.48 ± 6.97 s).ConclusionsAn accurate model for BDT prediction was achieved by using the experimentally determined proton beam therapy delivery parameters, which may be useful in modeling the interplay effect and patient throughput. The model may provide guidance on how to effectively reduce BDT and may be used to identifying deteriorating machine performance.

Background— This study sought to investigate external photon beam radiation for catheter-free ablation of the atrioventricular junction in intact pigs. Methods and Results— Ten pigs were randomized to either sham irradiation or irradiation of the atrioventricular junction (55, 50, 40, and 25 Gy). Animals underwent baseline electrophysiological evaluation, cardiac gated multi-row computed tomographic imaging for beam delivery planning, and intensity-modulated radiation therapy. Doses to the coronary arteries were optimized. Invasive follow-up was conducted ≤4 months after the irradiation. A mean volume of 2.5±0.5 mL was irradiated with target dose. The mean follow-up length after irradiation was 124.8±30.8 days. Out of 7 irradiated animals, complete atrioventricular block was achieved in 6 animals of all 4 dose groups (86%). Using the same targeting margins, ablation lesion size notably increased with the delivered dose because of volumetric effects of isodose lines around the target volume. The mean macroscopically calculated atrial lesion volume for all 4 dose groups was 3.8±1.1 mL, lesions extended anteriorly into the interventricular septum. No short-term side effects were observed. No damage was observed in the tissues of the esophagus, phrenic nerves, or trachea. However, histology revealed in-field beam effects outside of the target volume. Conclusions— Single-fraction doses as low as 25 Gy caused a lesion with interruption of cardiac impulse propagation using this respective target volume. With doses of ≤55 Gy, maximal point-doses to coronary arteries could be kept <7Gy, but target conformity of lesions was not fully achieved using this approach.

ABSTRACT Various types of radiation are utilized in the treatment of cancer. Equal physical doses of different radiation types do not always result in the same amount of biological damage. In order to account for these differences, a scaling factor known as the relative biological effectiveness (RBE) can be used. 137Cesium (137Cs) has been used as a source of radiation in a significant body of radiation therapy research. However, high-energy X-rays, such as 6 MV X-rays, are currently used clinically to treat patients. To date, there is a gap in the literature regarding the RBE comparison of these two types of radiation. Therefore, the purpose of this study was to investigate the RBE of 137Cs relative to that of 6 MV X-rays. To determine the RBE, five cell lines were irradiated [Chinese hamster ovary (CHO); human lung adenocarcinoma (A549); human glioma (U251); human glioma (T98); and human osteosarcoma (U2OS)] by both types of radiation and assessed for cell survival using a clonogenic assay. Three of the five cell lines resulted in RBE values of ~1.00 to within 11% for all survival fractions, showing the physical and biological dose for these two types of radiation were equivalent. The other two cell lines gave RBE values differing from 1.00 by up to 36%. In conclusion, the results show the range in biological effect seen between cell lines, and therefore cell type must be considered when characterizing RBE.

Background— Particle therapy, with heavy ions such as carbon-12 ( 12 C), delivered to arrhythmogenic locations of the heart could be a promising new means for catheter-free ablation. As a first investigation, we tested the feasibility of in vivo atrioventricular node ablation, in Langendorff-perfused porcine hearts, using a scanned 12C beam. Methods and Results— Intact hearts were explanted from 4 (30–40 kg) pigs and were perfused in a Langendorff organ bath. Computed tomgraphic scans (1 mm voxel and slice spacing) were acquired and 12 C ion beam treatment planning (optimal accelerator energies, beam positions, and particle numbers) for atrioventricular node ablation was conducted. Orthogonal x-rays with matching of 4 implanted clips were used for positioning. Ten Gray treatment plans were repeatedly administered, using pencil beam scanning. After delivery, positron emission tomography-computed tomgraphic scans for detection of β + ( 11 C) activity were obtained. A 12 C beam with a full width at half maximum of 10 mm was delivered to the atrioventricular node. Delivery of 130 Gy caused disturbance of atrioventricular conduction with transition into complete heart block after 160 Gy. Positron emission computed tomgraphy demonstrated dose delivery into the intended area. Application did not induce arrhythmias. Macroscopic inspection did not reveal damage to myocardium. Immunostaining revealed strong γH2AX signals in the target region, whereas no γH2AX signals were detected in the unirradiated control heart. Conclusions— This is the first report of the application of a 12 C beam for ablation of cardiac tissue to treat arrhythmias. Catheter-free ablation using 12C beams is feasible and merits exploration in intact animal studies as an energy source for arrhythmia elimination.