Organ absorbed doses in the IORT treatment of breast cancer with the INTRABEAM device: a Monte-Carlo study.

Purpose: The current prescription and the assessment of the delivered absorbed dose in intraoperative radiation therapy (IORT) with the INTRABEAM system rely mainly on depth-dose measurements in water. The accuracy of this approach is limited because tissue heterogeneity is ignored. It is also difficult to accurately determine the dose delivered to the patient experimentally as the steep dose gradient is highly sensitive to geometric errors. Our goal is to determine the dose to the target volume and the organs at risk of a clinical breast cancer patient from treatment with the system.Methods: A homogeneous water-equivalent CT dataset was derived from the preoperative CT scan of a patient by setting all materials in the patient volume as water-equivalent. This homogeneous CT data represents the current assumption of a homogenous patient, while the original CT data is considered the ground truth. An in-house Monte Carlo algorithm was used to simulate the delivered dose in both setups for a prescribed treatment dose of 20 Gy to the surface of the 3.5 cm diameter spherical applicator.Results: The doses received by 2% (D2%) of the target volume for the homogeneous and heterogeneous geometries are 16.26 Gy and 9.33 Gy, respectively. The D2% for the heart are 0.035 Gy and 0.119 Gy for the homogeneous and heterogeneous geometries, respectively. This trend is also observed for the other organs at risk.Conclusions: The assumption of a homogeneous patient overestimates the dose to the target volume and underestimates the doses to the organs at risk.

Performance assessment of the ALBIRA II pre-clinical SPECT S102 system for 99mTc imaging.

OBJECTIVE: The performance characteristics of the SPECT sub-system S102 of the ALBIRA II PET/SPECT/CT are analyzed for the 80 mm field of view (FOV) to evaluate the potential in-vivo imaging in rats, based on measurements of the system response for the commonly used Technetium-99 m (99mTc) in small animal imaging. METHODS: The ALBIRA II tri-modal µPET/SPECT/CT pre-clinical system (Bruker BioSpin, Ettlingen, Germany) was used. The SPECT modality is made up of two opposite gamma cameras (Version S102) with Sodium doped Cesium Iodide (CsI(Na)) single continuous crystal detectors coupled to position-sensitive photomultipliers (PSPMTs). Imaging was performed with the NEMA NU-4 image quality phantom (Data Spectrum Corporation, Durham, USA). Measurements were performed with a starting activity concentration of 4.76 MBq/mL 99mTc. An energy window of 20% at 140 keV was selected in this study. The system offers a 20 mm, 40 mm, 60 mm and an 80 mm field of view (FOV) and in this study the 80 mm FOV was used for all the acquisitions. The data were reconstructed with an ordered subset expectation maximization (OSEM) algorithm. Sensitivity, spatial resolution, count rate linearity, convergence of the algorithm and the recovery coefficients (RC) were analyzed. All analyses were performed with PMOD and MATLAB software. RESULTS: The sensitivities measured at the center of the 80 mm FOV with the point source were 23.1 ± 0.3 cps/MBq (single pinhole SPH) and 105.6 ± 5.5 cps/MBq (multi pinhole MPH). The values for the axial, tangential and radial full width at half maximum (FWHM) were 2.51, 2.54, and 2.55 mm with SPH and 2.35, 2.44 and 2.32 mm with MPH, respectively. The corresponding RC values for the 5 mm, 4 mm, 3 mm and 2 mm rods were 0.60 ± 0.28, 0.61 ± 0.24, 0.29 ± 0.11 and 0.20 ± 0.06 with SPH and 0.56 ± 0.20, 0.50 ± 0.18, 0.38 ± 0.09 and 0.23 ± 0.06 with MPH. To obtain quantitative imaging data, the image reconstructions should be performed with 12 iterations. CONCLUSION: The ALBIRA II preclinical SPECT sub-system S102 has a favorable sensitivity and spatial resolution for the 80 mm FOV setting for both the SPH and MPH configurations and is a valuable tool for small animal imaging.

A single-source photon source model of a linear accelerator for Monte Carlo dose calculation.

PURPOSE: To introduce a new method of deriving a virtual source model (VSM) of a linear accelerator photon beam from a phase space file (PSF) for Monte Carlo (MC) dose calculation. MATERIALS AND METHODS: A PSF of a 6 MV photon beam was generated by simulating the interactions of primary electrons with the relevant geometries of a Synergy linear accelerator (Elekta AB, Stockholm, Sweden) and recording the particles that reach a plane 16 cm downstream the electron source. Probability distribution functions (PDFs) for particle positions and energies were derived from the analysis of the PSF. These PDFs were implemented in the VSM using inverse transform sampling. To model particle directions, the phase space plane was divided into a regular square grid. Each element of the grid corresponds to an area of 1 mm2 in the phase space plane. The average direction cosines, Pearson correlation coefficient (PCC) between photon energies and their direction cosines, as well as the PCC between the direction cosines were calculated for each grid element. Weighted polynomial surfaces were then fitted to these 2D data. The weights are used to correct for heteroscedasticity across the phase space bins. The directions of the particles created by the VSM were calculated from these fitted functions. The VSM was validated against the PSF by comparing the doses calculated by the two methods for different square field sizes. The comparisons were performed with profile and gamma analyses. RESULTS: The doses calculated with the PSF and VSM agree to within 3% /1 mm (>95% pixel pass rate) for the evaluated fields. CONCLUSION: A new method of deriving a virtual photon source model of a linear accelerator from a PSF file for MC dose calculation was developed. Validation results show that the doses calculated with the VSM and the PSF agree to within 3% /1 mm.

Quantitative and qualitative assessment of Yttrium-90 PET/CT imaging.

Yttrium-90 is known to have a low positron emission decay of 32 ppm that may allow for personalized dosimetry of liver cancer therapy with (90)Y labeled microspheres. The aim of this work was to image and quantify (90)Y so that accurate predictions of the absorbed dose can be made. The measurements were performed within the QUEST study (University of Sydney, and Sirtex Medical, Australia). A NEMA IEC body phantom containing 6 fillable spheres (10-37 mm ∅) was used to measure the 90Y distribution with a Biograph mCT PET/CT (Siemens, Erlangen, Germany) with time-of-flight (TOF) acquisition. A sphere to background ratio of 8:1, with a total (90)Y activity of 3 GBq was used. Measurements were performed for one week (0, 3, 5 and 7 d). he acquisition protocol consisted of 30 min-2 bed positions and 120 min-single bed position. Images were reconstructed with 3D ordered subset expectation maximization (OSEM) and point spread function (PSF) for iteration numbers of 1-12 with 21 (TOF) and 24 (non-TOF) subsets and CT based attenuation and scatter correction. Convergence of algorithms and activity recovery was assessed based on regions-of-interest (ROI) analysis of the background (100 voxels), spheres (4 voxels) and the central low density insert (25 voxels). For the largest sphere, the recovery coefficient (RC) values for the 30 min -2-bed position, 30 min-single bed and 120 min-single bed were 1.12 ± 0.20, 1.14 ± 0.13, 0.97 ± 0.07 respectively. For the smaller diameter spheres, the PSF algorithm with TOF and single bed acquisition provided a comparatively better activity recovery. Quantification of Y-90 using Biograph mCT PET/CT is possible with a reasonable accuracy, the limitations being the size of the lesion and the activity concentration present. At this stage, based on our study, it seems advantageous to use different protocols depending on the size of the lesion.

A fast method for rescaling voxel S values for arbitrary voxel sizes in targeted radionuclide therapy from a single Monte Carlo calculation.

PURPOSE: In targeted radionuclide therapy, patient-specific dosimetry based on voxel S values (VSVs) is preferable to dosimetry based on mathematical phantoms. Monte-Carlo (MC) simulations are necessary to deduce VSVs for those voxel sizes required by quantitative imaging. The aim of this study is, starting from a single set of high-resolution VSVs obtained by MC simulations for a small voxel size along one single axis perpendicular to the source voxel, to present a suitable method to accurately calculate VSVs for larger voxel sizes. METHODS: Accurate sets of VSVs for target voxel to source voxel distances up to 10 cm were obtained for high-resolution voxel sizes (0.5 mm for electrons and 1.0 mm for photons) from MC simulations for Y-90, Lu-177, and I-131 using the radiation transport code MCNPX v.2.7a. To make these values suitable to any larger voxel size, different analytical methods (based on resamplings, interpolations, and fits) were tested and compared to values obtained by direct MC simulations. As a result, an optimal calculation procedure is proposed. This procedure consisted of: (1) MC simulation for obtaining of a starting set of VSVs along a single line of voxels for a small voxel size for each radionuclide and type of radiation; (2) interpolation within the values obtained in point (1) for obtaining the VSVs for voxels within a spherical volume; (3) resampling of the data obtained in (1) and (2) for obtaining VSVs for voxels sizes larger than the one used for the MC calculation for integer voxel ratios (voxel ratio=new voxel size∕voxel size MC simulation); (4) interpolation on within the data obtained in (3) for integer voxel ratios. The results were also compared to results from other authors. RESULTS: The results obtained with the method proposed in this work show deviations relative to the source voxel below 1% for I-131 and Lu-177 and below 1.5% for Y-90 as compared with values obtained by direct MC simulations for voxel sizes ranging between 1.0 and 10.0 cm. The results obtained in this work show differences between the scored deposited energy and the emitted energy lower than 2% for electron radiation. Higher differences, attributable to the short considered radius of 10 cm in comparison with their penetration, can be found for photons. The authors' results agree well with previously published data obtained by other authors using different methods. CONCLUSIONS: A reliable and fast approach for obtaining accurate VSVs for voxel sizes larger than the voxel size used for the MC calculation of the starting set of high-resolution VSVs was developed and successfully tested for three different radionuclides of interest for targeted radiotherapy: one pure beta (Y-90) and 2 beta-gamma emitters (Lu-177 und I-131). Applying the method of this work allows any interested reader to repeat the calculations for arbitrary radionuclides of interest and∕or smaller high-resolution voxel sizes, provided the means for running MC simulations are available.

A Monte Carlo based source model for dose calculation of endovaginal TARGIT brachytherapy with INTRABEAM and a cylindrical applicator.

PURPOSE: To generate and validate a source model of a miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany) for endovaginal TARGeted Intra-operative radioTherapy (TARGIT) brachytherapy a Geant4-based Monte Carlo (MC) tool was developed. The model was used to calculate the accurate relative dose distribution for the source combined with a cylindrical applicator which was developed for endovaginal treatment. METHODS AND MATERIALS: Geometries with given materials of the X-ray source and applicator were implemented in a Geant4-based dose calculation framework. To reduce the calculation time, phase space files for a set of circular electron beam foci and different beam radii were precalculated. Different beam radii had to be considered because the exact electron beam path on the target is not known in advance. To estimate the electron beam radius distribution of the system, a least squares minimization between the EBT film measured relative dose distribution and the simulation was performed. RESULTS: Relative dose distributions were calculated and compared with Gafchromic EBT film measurements to validate the MC method. In a region of interest around the source, the 2%/2mm gamma criterion matched with 98%. Profiles showed excellent agreement between measurement and simulation. The calculation time to simulate an entire treatment was twelve minutes. CONCLUSIONS: The method was able to predict the radius and width of the trajectory where the electrons impact on the target. This enables the complete simulation. The developed method allows calculating relative dose distributions for endovaginal TARGIT brachytherapy matching measured relative dose distributions within clinically acceptable limits.

Cost-effectiveness of hybrid PET/CT for staging of non-small cell lung cancer.

UNLABELLED: Although the diagnostic effectiveness of integrated PET/CT for staging of non-small cell lung cancer (NSCLC) has already been proven, it remains to be determined if tumor staging with combined metabolic and anatomic imaging is also cost-effective. The objective of this study was to evaluate from a payers' perspective the cost-effectiveness of staging NSCLC with CT alone (representing the mainstay diagnostic test) and with integrated PET/CT. METHODS: The study is based on 172 NSCLC patients from a prospective clinical study who underwent diagnostic, contrast-enhanced helical CT and integrated PET/CT. Imaging was performed at the University Hospital Ulm between May 2002 and December 2004. To calculate treatment costs, we differentiated among cost for diagnosis, cost for nonsurgical treatment according to the clinical diagnosis, and cost for surgical procedures according to the clinical tumor stage. RESULTS: The diagnostic effectiveness in terms of correct TNM staging was 40% (31/77) for CT alone and 60% (46/77) for PET/CT. For the assessment of resectability (tumor stages Ia-IIIa vs. IIIb-IV), 65 of 77 patients (84%) were staged correctly by PET/CT (CT alone, 70% [54/77]). The incremental cost-effectiveness ratios per correctly staged patient were $3,508 for PET/CT versus CT alone. The incremental cost-effectiveness ratios per quality-adjusted life year gained were $79,878 for PET/CT vs. CT alone, decreasing to $69,563 assuming a reduced loss of utility (0.10 quality-adjusted life years) due to surgical morbidity. CONCLUSION: Cost-effectiveness analyses showed that costs for PET/CT are within the commonly accepted range for diagnostic tests or therapies. Therefore, reimbursement of PET/CT for NSCLC staging can be also recommended from an economic point of view.

Model selection for time-activity curves: the corrected Akaike information criterion and the F-test.

Data analysis often requires a multi model approach, i.e. the best model or models are selected from a well chosen set of candidate models and subsequent parameter inference is conducted. The selection of the model or models which are best supported by the data can be accomplished using various criteria. The present work focuses on the comparison of two approaches namely the corrected Akaike information criterion (AICc) and the F-test for sparse data sets, which are common in medical research. The selection of the true model and the determination of relevant pharmacokinetic parameters as the clearance, the volume of distribution and the mean residence time are examined using Monte Carlo simulations with 10000 replications. The data (N = 10 per replication) are generated from a sum of two exponentials, which parameters were determined by fitting to time-concentration data of 111In labelled anti-CD66 antibody in blood serum. Four different normal distributed multiplicative statistical errors (0.05, 0.1, 0.15, 0.2) were examined. The set of candidate models consists of sums of up to 3 exponentials. Comparisons with two different model set sizes were conducted. All candidate models are fitted to the generated data and selected according to the AICc and the F-test. Both selection criteria perform well for our data. The selection frequency of functions of lower dimension increases proportionally to the statistical error for both criteria, while for higher errors, the AICc tends to choose a model of lower dimension more frequently than the F-test. In addition, the overfitted fraction decreases proportionally to the statistical error for both methods but selection frequency of function of higher dimension is larger using the F-test. The choice of the adequate model set is important for the positive effect of model averaging concerning the bias and the variability of the estimated parameters. It is in general assumed and has been confirmed in this study that parameter estimation using the AICc has clear advantages over the F-test.

Early assessment of therapy response in malignant lymphoma with the thymidine analogue [18F]FLT.

PURPOSE: The aim of this study was to determine whether the thymidine analogue 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) is adequate for early evaluation of the response of malignant lymphoma to antiproliferative treatment in a mouse xenotransplant model. METHODS: Immunodeficient mice bearing a follicular lymphoma xenotransplant were treated with high-dose chemotherapy (cyclophosphamide, n = 10), immunotherapy (CD20 mAb, ibritumomab-tiuxetan, n = 10) or radioimmunotherapy ([(90)Y]CD20 mAb, Zevalin, n = 10). Forty-eight hours after treatment, antiproliferative effects were assessed with [(18)F]FLT. Ninety minutes after i.v. injection of 5-10 MBq [(18)F]FLT, mice were sacrificed and radioactivity within the tumour and normal organs was measured using a gamma counter and calculated as % ID/g. The proliferation fraction in tissue samples derived from treated and untreated tumours was evaluated by Ki-67 immunohistochemistry, which served as the reference for proliferative activity. RESULTS: In untreated lymphoma, the mean proliferation fraction was 83.6%. After chemotherapy, the mean proliferation fraction decreased to 39.3% (p = 0.0001), after immunotherapy to 77.6% (p = 0.0078) and after radioimmunotherapy to 78.8% (p = 0.014). In none of the animals was a significant change in tumour size observed. In untreated lymphoma, tumoural [(18)F]FLT uptake was 5.4% ID/g, after chemotherapy it was 1.5% (p = 0.0005), after immunotherapy, 3.9% (non-significant), and after radioimmunotherapy, 5.8% (non-significant). CONCLUSION: In a lymphoma xenotransplant model, [(18)F]FLT detects early antiproliferative drug activity before changes in tumour size are visible. These findings further support the use of [(18)F]FLT-PET for imaging early response to treatment in malignant lymphoma.

F-18 NaF PET for detection of bone metastases in lung cancer: accuracy, cost-effectiveness, and impact on patient management.

UNLABELLED: As bone metastases might be present in lung cancer despite a normal bone scan, we examined various alternatives prospectively. Positron emission tomography using F-18 sodium fluoride (PET) and single photon emission tomography (SPECT) were more sensitive than a planar bone scan. PET was more accurate with a shorter examination time than SPECT but had higher incremental costs. INTRODUCTION: Previous studies have shown that vertebral bone metastases not seen on planar bone scans may be present on F-18 fluoride positron emission tomography (PET) scan or single photon emission computed tomography (SPECT). The purpose of this study was to measure the accuracy, clinical value and cost-effectiveness of tomographic bone imaging. MATERIALS AND METHODS: A total of 103 patients with initial diagnosis of lung cancer was prospectively examined with planar bone scintigraphy (BS), SPECT of the vertebral column and PET using F-18 sodium fluoride (F-18 PET). Receiver operating characteristic (ROC) curve analysis was used for determination of the diagnostic accuracy. A decision-analysis model and the national charge schedule of the German Hospital Association were used for determination of the cost-effectiveness. RESULTS: Thirteen of 33 patients with bone metastases were false negative on BS, 4 on SPECT, and 2 on F-18 PET. The area under the ROC curve was 0.771 for BS, 0.875 for SPECT, and 0.989 for F-18 PET (p < 0.05). As a result of SPECT and F-18 PET imaging, clinical management was changed in 8 (7.8%) and 10 (9.7%) patients. Compared with BS, the costs per additional correctly diagnosed patient were 1272 Euro with SPECT and 2861 Euro with F-18 PET. The threshold for the costs of F-18 PET being more cost-effective than SPECT was 345 EUR. CONCLUSION: Routine performance of tomographic bone imaging improves the therapeutic strategy because of detection of otherwise missed metastases. F-18 PET is more effective than SPECT but is associated with higher incremental costs.

ROC analysis for assessment of lesion detection performance in 3D PET: influence of reconstruction algorithms.

Image quality in positron emission tomography (PET) can be assessed with physical parameters, as spatial resolution and signal-to-noise ratio, or using psychophysical approaches, which include the observer performance and the considered task (ROC analysis). For PET in oncology, such a task is the detection of hot lesions. The aim of the present study was to assess the lesion detection performance due to adequate modeling of the scanner and the measurement process in the image reconstruction process. We compared the standard OSEM software of the manufacturer with a sophisticated fully 3D iterative reconstruction technique (USC MAP). A rectangular phantom with 6 oblique line sources in a homogeneous background (2.6 kBq/ml 18F) was imaged dynamically with an ECAT EXACT HR+ scanner in 3D mode. Reconstructed activity contrasts varied between 15 and 0, as the line sources were filled with 11C (3.2 MBq/ml). Measured attenuation and standard randoms, dead time, and scatter corrections of the manufacturer were employed. For the ROC analysis, a software tool presented a cut-out of the phantom (15 x 15 pixels) to two observers. These cut-outs were rated (5 classes) and the area Az under the ROC curve was determined as a measure of detection performance. The improvement for Az with USC MAP compared to the OSEM reconstructions ranged between 0.02 and 0.23 for signal-to-noise ratios of the background between 2.8 and 3.1 and lesion contrast between 2.1 and 4.2. This study demonstrates that adequate modeling of the measurement process in the reconstruction algorithm improves the detection of small hot lesions markedly.

3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules.

We investigated whether uptake of the thymidine analogue 3-deoxy-3-[(18)F]fluorothymidine ([(18)F]FLT) reflects proliferation in solitary pulmonary nodules (SPNs). Thirty patients with SPNs were prospectively examined with positron emission tomography. Standardized uptake values were calculated for quantification of FLT uptake. Histopathology revealed 22 malignant and 8 benign lesions. Proliferation was evaluated by Ki-67 immunostaining and showed a mean proliferation fraction of 30.9% (range, 1-65%) in malignant SPNs and <5% in benign lesions. Linear regression analysis indicated a significant correlation between FLT-standardized uptake values and proliferative activity (P < 0.0001; r = 0.87). FLT uptake was specific for malignant lesions and may be used for differential diagnosis of SPNs, assessment of proliferation, and estimation of prognosis.