Four-dimensional treatment planning strategies for dynamic tumor tracking.

INTRODUCTION: Dynamic tumor tracking (DTT) is a motion management technique where the radiation beam follows a moving tumor in real time. Not modelling DTT beam motion in the treatment planning system leaves an organ at risk (OAR) vulnerable to exceeding its dose limit. This work investigates two planning strategies for DTT plans, the "Boolean OAR Method" and the "Aperture Sorting Method," to determine if they can successfully spare an OAR while maintaining sufficient target coverage. MATERIALS AND METHODS: A step-and-shoot intensity modulated radiation therapy (sIMRT) treatment plan was re-optimized for 10 previously treated liver stereotactic ablative radiotherapy patients who each had one OAR very close to the target. Two planning strategies were investigated to determine which is more effective at sparing an OAR while maintaining target coverage: (1) the "Boolean OAR Method" created a union of an OAR's contours from two breathing phases (exhale and inhale) on the exhale phase (the planning CT) and protected this combined OAR during plan optimization, (2) the "Aperture Sorting Method" assigned apertures to the breathing phase where they contributed the least to an OAR's maximum dose. RESULTS: All 10 OARs exceeded their dose constraints on the original plan four-dimensional (4D) dose distributions and average target coverage was V100% = 91.3% ± 2.9% (ranging from 85.1% to 94.8%). The "Boolean OAR Method" spared 7/10 OARs, and mean target coverage decreased to V100% = 87.1% ± 3.8% (ranging from 80.7% to 93.7%). The "Aperture Sorting Method" spared 9/10 OARs and the mean target coverage remained high at V100% = 91.7% ± 2.8% (ranging from 84.9% to 94.5%). CONCLUSIONS: 4D planning strategies are simple to implement and can improve OAR sparing during DTT treatments. The "Boolean OAR Method" improved sparing of OARs but target coverage was reduced. The "Aperture Sorting Method" further improved sparing of OARs and maintained target coverage.

Markerless dynamic tumor tracking (MDTT) radiotherapy using diaphragm as a surrogate for liver targets.

PURPOSE: To assess the feasibility of using the diaphragm as a surrogate for liver targets during MDTT. METHODS: Diaphragm as surrogate for markers: a dome-shaped phantom with implanted markers was fabricated and underwent dual-orthogonal fluoroscopy sequences on the Vero4DRT linac. Ten patients participated in an IRB-approved, feasibility study to assess the MDTT workflow. All images were analyzed using an in-house program to back-project the diaphragm/markers position to the isocenter plane. ExacTrac imager log files were analyzed. Diaphragm as tracking structure for MDTT: The phantom "diaphragm" was contoured as a markerless tracking structure (MTS) and exported to Vero4DRT/ExacTrac. A single field plan was delivered to the phantom film plane under static and MDTT conditions. In the patient study, the diaphragm tracking structure was contoured on CT breath-hold-exhale datasets. The MDTT workflow was applied until just prior to MV beam-on. RESULTS: Diaphragm as surrogate for markers: phantom data confirmed the in-house 3D back-projection program was functioning as intended. In patients, the diaphragm/marker relative positions had a mean ± RMS difference of 0.70 ± 0.89, 1.08 ± 1.26, and 0.96 ± 1.06 mm in ML, SI, and AP directions. Diaphragm as tracking structure for MDTT: Building a respiratory-correlation model using the diaphragm as surrogate for the implanted markers was successful in phantom/patients. During the tracking verification imaging step, the phantom mean ± SD difference between the image-detected and predicted "diaphragm" position was 0.52 ± 0.18 mm. The 2D film gamma (2%/2 mm) comparison (static to MDTT deliveries) was 98.2%. In patients, the mean difference between the image-detected and predicted diaphragm position was 2.02 ± 0.92 mm. The planning target margin contribution from MDTT diaphragm tracking is 2.2, 5.0, and 4.7 mm in the ML, SI, and AP directions. CONCLUSION: In phantom/patients, the diaphragm motion correlated well with markers' motion and could be used as a surrogate. MDTT workflows using the diaphragm as the MTS is feasible using the Vero4DRT linac and could replace the need for implanted markers for liver radiotherapy.

In-vivo quality assurance of dynamic tumor tracking (DTT) for liver SABR using EPID images.

PURPOSE: To assess dynamic tumor tracking (DTT) target localization uncertainty for in-vivo marker-based stereotactic ablative radiotherapy (SABR) treatments of the liver using electronic-portal-imaging-device (EPID) images. The Planning Target Volume (PTV) margin contribution for DTT is estimated. METHODS: Phantom and patient EPID images were acquired during non-coplanar 3DCRT-DTT delivered on a Vero4DRT linac. A chain-code algorithm was applied to detect Multileaf Collimator (MLC)-defined radiation field edges. Gold-seed markers were detected using a connected neighbor algorithm. For each EPID image, the absolute differences between the measured center-of-mass (COM) of the markers relative to the aperture-center (Tracking Error, (ET )) was reported in pan, tilt, and 2D-vector directions at the isocenter-plane. PHANTOM STUDY: An acrylic cube phantom implanted with gold-seed markers was irradiated with non-coplanar 3DCRT-DTT beams and EPID images collected. Patient Study: Eight liver SABR patients were treated with non-coplanar 3DCRT-DTT beams. All patients had three to four implanted gold-markers. In-vivo EPID images were analyzed. RESULTS: Phantom Study: On the 125 EPID images collected, 100% of the markers were identified. The average ± SD of ET were 0.24 ± 0.21, 0.47 ± 0.38, and 0.58 ± 0.37 mm in pan, tilt and 2D directions, respectively. Patient Study: Of the 1430 EPID patient images acquired, 78% had detectable markers. Over all patients, the average ± SD of ET was 0.33 ± 0.41 mm in pan, 0.63 ± 0.75 mm in tilt and 0.77 ± 0.80 mm in 2D directions The random 2D-error, σ, for all patients was 0.79 mm and the systematic 2D-error, Σ, was 0.20 mm. Using the Van Herk margin formula 1.1 mm planning target margin can represent the marker based DTT uncertainty. CONCLUSIONS: Marker-based DTT uncertainty can be evaluated in-vivo on a field-by-field basis using EPID images. This information can contribute to PTV margin calculations for DTT.

Four-dimensional dose calculations for dynamic tumour tracking with a gimbal-mounted linear accelerator.

PURPOSE: In this study we present a novel method for re-calculating a treatment plan on different respiratory phases by accurately modeling the panning and tilting beam motion during DTT (the "rotation method"). This method is used to re-calculate the dose distribution of a plan on multiple breathing phases to accurately assess the dosimetry. METHODS: sIMRT plans were optimized on a breath hold computed tomography (CT) image taken at exhale (BHexhale ) for 10 previous liver stereotactic ablative radiotherapy patients. Our method was used to re-calculate the plan on the inhale (0%) and exhale (50%) phases of the four-dimensional CT (4DCT) image set. The dose distributions were deformed to the BHexhale CT and summed together with proper weighting calculated from the patient's breathing trace. Subsequently, the plan was re-calculated on all ten phases using our method and the dose distributions were deformed to the BHexhale CT and accumulated together. The maximum dose for certain organs at risk (OARs) was compared between calculating on two phases and all ten phases. RESULTS: In total, 26 OARs were examined from 10 patients. When the dose was calculated on the inhale and exhale phases six OARs exceeded their dose limit, and when all 10 phases were used five OARs exceeded their limit. CONCLUSION: Dynamic tumor tracking plans optimized for a single respiratory phase leave an OAR vulnerable to exceeding its dose constraint during other respiratory phases. The rotation method accurately models the beam's geometry. Using deformable image registration to accumulate dose from all 10 breathing phases provides the most accurate results, however it is a time consuming procedure. Accumulating the dose from two extreme breathing phases (exhale and inhale) and weighting them properly provides accurate results while requiring less time. This approach should be used to confirm the safety of a DTT treatment plan prior to delivery.

Liver toxicity prediction with stereotactic body radiation therapy: The impact of accounting for fraction size.

PURPOSE: Current liver SBRT protocols rely on the calculation of "effective volume" without accounting for the biologic effect of fraction size to estimate the risk of liver toxicity, which subsequently defines tumor prescription doses. This study compared effective volume and liver toxicity predictions with and without correction for fraction size. METHODS AND MATERIALS: The effective volume was determined for 18 liver SBRT plans with and without biologic normalization using the linear quadratic formula. Lyman-Kutcher-Burman normal tissue complication probability models estimated the risk of liver toxicity. Effective volumes and corresponding toxicity predictions were compared with and without biologic normalization. RESULTS: Accounting for the biologic difference of larger fraction size reduced the effective volume in all treatment plans compared with the unadjusted effective volume (median effective volume 0.21 vs 0.32). The lower effective volume with biologic normalization substantially reduced the estimated risk of liver toxicity (average risk of toxicity 32% vs 4.5%). CONCLUSIONS: This study demonstrates that accounting for the biologic effect of fraction size with effective volume significantly decreases predicted hepatic toxicity, which suggests that the risk of liver toxicity may be overestimated in clinical practice if biologic normalization is omitted. The effective volume toxicity model has proven safe in prospective clinical trials, though safe dose escalation with liver SBRT may be feasible.

Monte Carlo modelling of singles-mode transmission data for small animal PET scanners.

The attenuation corrections factors (ACFs), which are necessary for quantitatively accurate PET imaging, can be obtained using singles-mode transmission scanning. However, contamination from scatter is a largely unresolved problem for these data. We present an extension of the Monte Carlo simulation tool, GATE, for singles-mode transmission data and its validation using experimental data from the microPET R4 and Focus 120 scanners. We first validated our simulated PET scanner for coincidence-mode data where we found that experimental resolution and scatter fractions (SFs) agreed well for simulations that included positron interactions and scatter in the source material. After modifying GATE to model singles-mode data, we compared simulated and experimental ACFs and SFs for three different sized water cylinders using 57Co (122 keV photon emitter) and 68Ge (positron emitter) transmission sources. We also propose a simple correction for a large background contamination we identified in the 68Ge singles-mode data due to intrinsic 176Lu radioactivity present in the detector crystals. For simulation data, the SFs agreed to within 1.5% and 2.5% of experimental values for background-corrected 68Ge and 57Co transmission data, respectively. This new simulation tool accurately models the photon interactions and data acquisition for singles-mode transmission scans.

A scatter-corrected list-mode reconstruction and a practical scatter/random approximation technique for dynamic PET imaging.

We describe an ordinary Poisson list-mode expectation maximization (OP-LMEM) algorithm with a sinogram-based scatter correction method based on the single scatter simulation (SSS) technique and a random correction method based on the variance-reduced delayed-coincidence technique. We also describe a practical approximate scatter and random-estimation approach for dynamic PET studies based on a time-averaged scatter and random estimate followed by scaling according to the global numbers of true coincidences and randoms for each temporal frame. The quantitative accuracy achieved using OP-LMEM was compared to that obtained using the histogram-mode 3D ordinary Poisson ordered subset expectation maximization (3D-OP) algorithm with similar scatter and random correction methods, and they showed excellent agreement. The accuracy of the approximated scatter and random estimates was tested by comparing time activity curves (TACs) as well as the spatial scatter distribution from dynamic non-human primate studies obtained from the conventional (frame-based) approach and those obtained from the approximate approach. An excellent agreement was found, and the time required for the calculation of scatter and random estimates in the dynamic studies became much less dependent on the number of frames (we achieved a nearly four times faster performance on the scatter and random estimates by applying the proposed method). The precision of the scatter fraction was also demonstrated for the conventional and the approximate approach using phantom studies.

In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD.

This is the first in vivo determination of the vesicular monoamine transporter (VMAT2) density (B(max)) and ligand-transporter affinity (K(d)(app)) in six unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats using micro-positron emission tomography (PET) imaging with [(11)C]-(+)-alpha-dihydrotetrabenazine (DTBZ). A multiple ligand concentration transporter assay (MLCTA) was used to determine a B(max) value of 178+/-32 pmol/mL and a K(d)(app) of 47.7+/-9.3 pmol/mL for the non-lesioned side and 30.52+/-5.84 and 43.4+/-15.52 pmol/mL for the lesioned side, respectively. While B(max) was significantly different between the two sides, no significant difference was observed for the K(d)(app). In addition to demonstrating the feasibility of in vivo Scatchard analysis in rats, these data confirm the expectation that a 6-OHDA lesion does not affect the affinity; a much simpler binding potential (BP) measure can thus be used as a marker of lesion severity (LS) in this rat model of Parkinson's disease. A transporter occupancy curve demonstrated negligible transporter occupancy ( approximately 1%) at a specific activity (SA) of 1100 nCi/pmol (assuming an injected dose of 100 microCi/100 g), while 10% occupancy was estimated at 100 nCi/pmol. An indirect measurement indicated that the degree of occupancy as a function of SA is independent of LS. Finally, BP measurement reproducibility was assessed and found to be 11%+/-7% for the healthy and 8%+/-12% for the lesioned side. Quantitative PET results can thus be obtained even for severely lesioned animals with the striatum on one side not clearly visible provided accurate image analysis methods are used.

The influence of measurement uncertainties on the evaluation of the distribution volume ratio and binding potential in rat studies on a microPET R4: a phantom study.

In small animal positron emission tomography (PET) imaging, the injectable radiotracer dose is often limited by the tracer mass which, together with the tracer kinetics and scanner sensitivity, dictates the statistical quality of the time activity curves (TACs) used to extract biological parameters. We investigated the effect of measurement uncertainty on the determination of the distribution volume ratio (DVR) and binding potential (BP) as estimated using the tissue input Logan (DVR(L), BP(L)) and the ratio (DVRr, BPr) methods for two tracers, with the Concorde microPET R4 camera. Parameters' coefficients of variation (COV) were estimated from a combination of rat and phantom data. For 11C-dihydrotetrabenazine, the COV was 11% for the BP(L) and 13.4% for the BPr when using TACs obtained from individual regions of interest (ROIs) and segmented attenuation correction. The COVs were reduced to 7.5% (BP(L)) and 8.6% (BPr) when the striatal and cerebellar TACs were estimated as averages of 3 and 2 ROIs respectively. Results obtained for 11C-methylphenidate (MP) yielded approximately 30% higher COVs. With measured attenuation correction, the COVs were on average 100% higher. The presented method can be used to examine the contribution of a variety of imaging conditions to the uncertainty of biologically meaningful parameters.