LatticeOpt: An automatic tool for planning optimisation of spatially fractionated stereotactic body radiotherapy.

PURPOSE: Lattice radiotherapy (LRT) is a three dimensional (3D) implementation of spatially fractionated radiation therapy, based on regular spatial distribution of high dose spheres (vertices) inside the target. Due to tumour shape heterogeneity, finding the best lattice arrangement is not trivial. The aim of this study was to develop the LatticeOpt tool to generate the best lattice structures on clinical cases for treatment planning. METHODS: Developed in MATLAB, LatticeOpt finds the 3D-spatial configurations that maximize the number of vertices within the gross target volume (GTV). If organs at risk (OARs) are considered, it chooses the solution that minimizes the overlapping volume histograms (OVH). Otherwise, the lattice structure with the minimum Hausdorff distance between vertices and GTV boundary is chosen to avoid unpopulated regions. Different lattice structures were created for 20 patients, with (OVHopt) and without (OVHunopt) OVH minimization. Imported into TPS (Eclipse, Varian), corresponding plans were generated and evaluated in terms of OAR mean and maximum doses, GTV vertex coverage and dose gradients, as well as pre-clinical plan dosimetry. RESULTS: Plans based on an optimized lattice structure (OVHopt, OVHunopt) had similar dose distributions in terms of vertex coverage and gradient index score. OAR sparing was observed in all patients, with a 4 % and 9 % difference for mean and max dose (both p-values <0.01), respectively. The best vertices dimensions and their relative distances were patient dependent. CONCLUSIONS: LatticeOpt was able to reduce the time-consuming procedures of LRT, as well as to achieve standardized and reproducible results, useful for multicentre studies.

Safety injections of nuclear medicine radiotracers: towards a new modality for a real-time detection of extravasation events and 18F-FDG SUV data correction.

BACKGROUND: 18F-FDG PET/CT imaging allows to study oncological patients and their relative diagnosis through the standardised uptake value (SUV) evaluation. During radiopharmaceutical injection, an extravasation event may occur, making the SUV value less accurate and possibly leading to severe tissue damage. The study aimed to propose a new technique to monitor and manage these events, to provide an early evaluation and correction to the estimated SUV value through a SUV correction coefficient. METHODS: A cohort of 70 patients undergoing 18F- FDG PET/CT examinations was enrolled. Two portable detectors were secured on the patients' arms. The dose-rate (DR) time curves on the injected DRin and contralateral DRcon arm were acquired during the first 10 min of injection. Such data were processed to calculate the parameters ΔpinNOR = (DRinmax- DRinmean)/DRinmax and ΔRt = (DRin(t) - DRcon(t)), where DRinmax is the maximum DR value, DRinmean is the average DR value in the injected arm. OLINDA software allowed dosimetric estimation of the dose in the extravasation region. The estimated residual activity in the extravasation site allowed the evaluation of the SUV's correction value and to define an SUV correction coefficient. RESULTS: Four cases of extravasations were identified for which ΔRt [(390 ± 26) µSv/h], while ΔRt [(150 ± 22) µSv/h] for abnormal and ΔRt [(24 ± 11) µSv/h] for normal cases. The ΔpinNOR showed an average value of (0.44 ± 0.05) for extravasation cases and an average value of (0.91 ± 0.06) and (0.77 ± 0.23) in normal and abnormal classes, respectively. The percentage of SUV reduction (SUV%CR) ranges between 0.3% and 6%. The calculated self-tissue dose values range from 0.027 to 0.573 Gy, according to the segmentation modality. A similar correlation between the inverse of ΔpinNOR and the normalised ΔRt with the SUV correction coefficient was found. CONCLUSIONS: The proposed metrics allowed to characterised the extravasation events in the first few minutes after the injection, providing an early SUV correction when necessary. We also assume that the characterisation of the DR-time curve of the injection arm is sufficient for the detection of extravasation events. Further validation of these hypotheses and key metrics is recommended in larger cohorts.

On the use of solid 133Ba sources as surrogate for liquid 131I in SPECT/CT calibration: a European multi-centre evaluation.

INTRODUCTION: Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using 133Ba as a surrogate for 131I imaging. MATERIALS AND METHODS: Two sets of four traceable 133Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68-107.4 mL). Corresponding hollow cylinders to be filled with liquid 131I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of 133Ba sources and liquid 131I. RESULTS: As anticipated, the 131I pseudo-image calibration factors (cps/MBq) were higher than those for 133Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12-1.5%. The site-specific cross-calibration method also showed agreement between 133Ba and 131I for all cylinder volumes, which highlights the potential use of 133Ba sources to calculate recovery coefficients for partial volume correction. CONCLUSION: This comparison exercise demonstrated that traceable solid 133Ba sources can be used as surrogate for liquid 131I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with 131I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals.

Predictive and Prognostic Role of Pre-Therapy and Interim 68Ga-DOTATOC PET/CT Parameters in Metastatic Advanced Neuroendocrine Tumor Patients Treated with PRRT.

Peptide receptor radionuclide therapy (PRRT) is an effective therapeutic option in patients with metastatic neuroendocrine tumor (NET). However, PRRT fails in about 15-30% of cases. Identification of biomarkers predicting the response to PRRT is essential for treatment tailoring. We aimed to evaluate the predictive and prognostic role of semiquantitative and volumetric parameters obtained from the 68Ga-DOTATOC PET/CT before therapy (bPET) and after two cycles of PRRT (iPET). A total of 46 patients were included in this retrospective analysis. The primary tumor was 78% gastroenteropancreatic (GEP), 13% broncho-pulmonary and 9% of unknown origin. 35 patients (76.1%) with stable disease or partial response after PRRT were classified as responders and 11 (23.9%) as non-responders. Logistic regression analysis identified that baseline total volume (bTV) was associated with therapy outcome (OR 1.17; 95%CI 1.02-1.32; p = 0.02). No significant association with PRRT response was observed for other variables. High bTV was confirmed as the only variable independently associated with OS (HR 12.76, 95%CI 1.53-107, p = 0.01). In conclusion, high bTV is a negative predictor for PRRT response and is associated with worse OS rates. Early iPET during PRRT apparently does not provide information useful to change the management of NET patients.

A multicentre and multi-national evaluation of the accuracy of quantitative Lu-177 SPECT/CT imaging performed within the MRTDosimetry project.

PURPOSE: Patient-specific dosimetry is required to ensure the safety of molecular radiotherapy and to predict response. Dosimetry involves several steps, the first of which is the determination of the activity of the radiopharmaceutical taken up by an organ/lesion over time. As uncertainties propagate along each of the subsequent steps (integration of the time-activity curve, absorbed dose calculation), establishing a reliable activity quantification is essential. The MRTDosimetry project was a European initiative to bring together expertise in metrology and nuclear medicine research, with one main goal of standardizing quantitative 177Lu SPECT/CT imaging based on a calibration protocol developed and tested in a multicentre inter-comparison. This study presents the setup and results of this comparison exercise. METHODS: The inter-comparison included nine SPECT/CT systems. Each site performed a set of three measurements with the same setup (system, acquisition and reconstruction): (1) Determination of an image calibration for conversion from counts to activity concentration (large cylinder phantom), (2) determination of recovery coefficients for partial volume correction (IEC NEMA PET body phantom with sphere inserts), (3) validation of the established quantitative imaging setup using a 3D printed two-organ phantom (ICRP110-based kidney and spleen). In contrast to previous efforts, traceability of the activity measurement was required for each participant, and all participants were asked to calculate uncertainties for their SPECT-based activities. RESULTS: Similar combinations of imaging system and reconstruction lead to similar image calibration factors. The activity ratio results of the anthropomorphic phantom validation demonstrate significant harmonization of quantitative imaging performance between the sites with all sites falling within one standard deviation of the mean values for all inserts. Activity recovery was underestimated for total kidney, spleen, and kidney cortex, while it was overestimated for the medulla. CONCLUSION: This international comparison exercise demonstrates that harmonization of quantitative SPECT/CT is feasible when following very specific instructions of a dedicated calibration protocol, as developed within the MRTDosimetry project. While quantitative imaging performance demonstrates significant harmonization, an over- and underestimation of the activity recovery highlights the limitations of any partial volume correction in the presence of spill-in and spill-out between two adjacent volumes of interests.

Comparison of different calculation techniques for absorbed dose assessment in patient specific peptide receptor radionuclide therapy.

AIM: The present work concerns the comparison of the performances of three systems for dosimetry in RPT that use different techniques for absorbed dose calculation (organ-level dosimetry, voxel-level dose kernel convolution and Monte Carlo simulations). The aim was to assess the importance of the choice of the most adequate calculation modality, providing recommendations about the choice of the computation tool. METHODS: The performances were evaluated both on phantoms and patients in a multi-level approach. Different phantoms filled with a 177Lu-radioactive solution were used: a homogeneous cylindrical phantom, a phantom with organ-shaped inserts and two cylindrical phantoms with inserts different for shape and volume. A total of 70 patients with NETs treated by PRRT with 177Lu-DOTATOC were retrospectively analysed. RESULTS: The comparisons were performed mainly between the mean values of the absorbed dose in the regions of interest. A general better agreement was obtained between Dose kernel convolution and Monte Carlo simulations results rather than between either of these two and organ-level dosimetry, both for phantoms and patients. Phantoms measurements also showed the discrepancies mainly depend on the geometry of the inserts (e.g. shape and volume). For patients, differences were more pronounced than phantoms and higher inter/intra patient variability was observed. CONCLUSION: This study suggests that voxel-level techniques for dosimetry calculation are potentially more accurate and personalized than organ-level methods. In particular, a voxel-convolution method provides good results in a short time of calculation, while Monte Carlo based computation should be conducted with very fast calculation systems for a possible use in clinics, despite its intrinsic higher accuracy. Attention to the calculation modality is recommended in case of clinical regions of interest with irregular shape and far from spherical geometry, in which Monte Carlo seems to be more accurate than voxel-convolution methods.

Uncertainty analysis of tumour absorbed dose calculations in molecular radiotherapy.

BACKGROUND: Internal dosimetry evaluation consists of a multi-step process ranging from imaging acquisition to absorbed dose calculations. Assessment of uncertainty is complicated and, for that reason, it is commonly ignored in clinical routine. However, it is essential for adequate interpretation of the results. Recently, the EANM published a practical guidance on uncertainty analysis for molecular radiotherapy based on the application of the law of propagation of uncertainty. In this study, we investigated the overall uncertainty on a sample of a patient following the EANM guidelines. The aim of this study was to provide an indication of the typical uncertainties that may be expected from performing dosimetry, to determine parameters that have the greatest effect on the accuracy of calculations and to consider the potential improvements that could be made if these effects were reduced. RESULTS: Absorbed doses and the relative uncertainties were calculated for a sample of 49 patients and a total of 154 tumours. A wide range of relative absorbed dose uncertainty values was observed (14-102%). Uncertainties associated with each quantity along the absorbed dose calculation chain (i.e. volume, recovery coefficient, calibration factor, activity, time-activity curve fitting, time-integrated activity and absorbed dose) were estimated. An equation was derived to describe the relationship between the uncertainty in the absorbed dose and the volume. The largest source of error was the VOI delineation. By postulating different values of FWHM, the impact of the imaging system spatial resolution on the uncertainties was investigated. DISCUSSION: To the best of our knowledge, this is the first analysis of uncertainty in molecular radiotherapy based on a cohort of clinical cases. Wide inter-lesion variability of absorbed dose uncertainty was observed. Hence, a proper assessment of the uncertainties associated with the calculations should be considered as a basic scientific standard. A model for a quick estimate of uncertainty without implementing the entire error propagation schema, which may be useful in clinical practice, was presented. Ameliorating spatial resolution may be in future the key factor for accurate absorbed dose assessment.

Partial volume effect of SPECT images in PRRT with 177Lu labelled somatostatin analogues: A practical solution.

BACKGROUND: At present activity quantification is one of the most critical step in dosimetry calculation, and Partial Volume Effect (PVE) one of the most important source of error. In recent years models based upon phantoms that incorporate hot spheres have been used to establish recovery models. In this context the goal of this study was to point out the most critical issues related to PVE and to establish a model closer to a biological imaging environment. METHODS: Two different phantoms, filled with a 177Lu solution, were used to obtain the PVE Recovery Coefficients (RCs): a phantom with spherical inserts and a phantom with organ-shaped inserts. Two additional phantoms with inserts of various geometrical shapes and an anthropomorphic phantom were acquired to compare the real activities to predicted values after PVE correction. RESULTS: The RCs versus volume of the inserts produced two different curves, one for the spheres and one for the organs. After PVE correction, accuracy on activity quantification averaged over all inserts of three test phantoms passed from -26% to 1.3% (from 26% to 10% for absolute values). CONCLUSION: RCs is a simple method for PVE correction easily applicable in clinical routine. The use of two different models for organs and lesions has permitted to closely mimic the situation in a living subject. A marked improvement in the quantification of activity was observed when PVE correction was adopted, even if further investigations should be performed for more accurate models of PVE corrections.