Biokinetics and dosimetry of 18 F-PSMA-1007 in patients with prostate cancer.

PURPOSE: Positron emission tomography-computed tomography (PET-CT) using prostate-specific membrane antigen (PSMA) ligands is a method for imaging prostate cancer. A recent tracer, 18 F-PSMA-1007, offers advantages concerning production and biokinetics compared to the standard tracer (68 Ga-PSMA-11). Until now, radiation dosimetry data for this ligand was limited to the material of three healthy volunteers. The purpose of this study is to study the biokinetics and dosimetry of 18 F-PSMA-1007. METHODS: Twelve patients with prostate cancer were injected with 4 MBq/kg 18 F-PSMA-1007. Eight PET-CT scans with concomitant blood sampling were performed up to 330 min after injection. Urine was collected until the following morning. Volumes of interest for radiation-sensitive organs and organs with high uptake of 18 F-PSMA-1007 were drawn in the PET images. A biokinetic compartment model was developed using activity data from PET images and blood and urine samples. Time-activity curves and time-integrated activity coefficients for all delineated organs were calculated. The software IDAC-dose 2.1 was used to calculate the absorbed and effective doses. RESULTS: High concentrations of activity were noted in the liver, kidneys, parts of the small intestine, spleen, salivary glands, and lacrimal glands. The elimination through urine was 8% of injected activity in 20 h. The highest absorbed doses coefficients were in the lacrimal glands, kidneys, salivary glands, liver, and spleen (98-66 µGy/MBq). The effective dose coefficient was 25 µSv/MBq. CONCLUSION: The effective dose of 18 F-PSMA-1007 is 6.0-8.0 mSv for a typical patient weighing 80 kg injected with 3-4 MBq/kg.

Dose-reduced [18F]PSMA-1007 PET is feasible for functional imaging of the renal cortex.

BACKGROUND: In Prostate-specific membrane antigen (PSMA) positron emission tomography with computed tomography (PET-CT), there is significant renal uptake. The standard in renal cortical functional imaging is scintigraphy with technetium-99m labeled dimercaptosuccinic acid (DMSA). Using [68Ga]Ga-PSMA-11 PET for renal imaging has been suggested, but using [18F]PSMA-1007 has not been explored. The aims of this study were to establish the optimal time point for renal imaging after [18F]PSMA-1007 injection, to investigate the reproducibility of split renal uptake measurements, and to determine the margin for reduction in administered activity. METHODS: Twelve adult male patients with prostate cancer underwent [18F]PSMA-1007 PET-CT at 8 time points up to 5.5 h post-injection (p.i.). List-mode data were binned to durations of 10 to 120 s per bed position (bp). Left renal percentage of total renal uptake (LRU%) was measured, and the difference between highest and lowest measurement per patient ("delta max") was calculated. Images acquired at 1 h, 2 h, and 5.5 h p.i. with durations of 10 to 120 s/bp were rated regarding image quality. RESULTS: Imaging at 2 h p.i. with 60 s/bp yielded acceptable quality in all cases. Increasing acquisition time to 15 min for a single bp would allow reducing administered activity to 0.27 MBq/kg, resulting in an effective dose of 0.4 mSv for a 1-year old child weighing 10 kg. The median delta max of LRU% measurements was 2.7% (range 1.8-7.3%). CONCLUSIONS: Renal [18F]PSMA-1007 PET-CT is feasible, with imaging 2 h p.i., acceptable split renal uptake variability, and effective dose and acquisition time comparable to those of [99mTc]Tc-DMSA scintigraphy.

Head-to-head comparison of a Si-photomultiplier-based and a conventional photomultiplier-based PET-CT system.

BACKGROUND: A novel generation of PET scanners based on silicon (Si)-photomultiplier (PM) technology has recently been introduced. Concurrently, there has been development of new reconstruction methods aimed at increasing the detectability of small lesions without increasing image noise. The combination of new detector technologies and new reconstruction algorithms has been found to increase image quality. However, it is unknown to what extent the demonstrated improvement of image quality is due to scanner hardware development or improved reconstruction algorithms. To isolate the contribution of the hardware, this study aimed to compare the ability to detect small hotspots in phantoms using the latest generation SiPM-based PET/CT scanner (GE Discovery MI) relative to conventional PM-based PET/CT scanner (GE Discovery 690), using identical reconstruction protocols. MATERIALS AND METHODS: Two different phantoms (NEMA body and Jasczcak) with fillable spheres (31 µl to 26.5 ml) and varying sphere-to-background-ratios (SBR) were scanned in one bed position for 15-600 s on both scanners. The data were reconstructed using identical reconstruction parameters on both scanners. The recovery-coefficient (RC), noise level, contrast (spherepeak/backgroundpeak-value), and detectability of each sphere were calculated and compared between the scanners at each acquisition time. RESULTS: The RC-curves for the NEMA phantom were near-identical for both scanners at SBR 10:1. For smaller spheres in the Jaszczak phantom, the contrast was 1.22 higher for the DMI scanner at SBR 15:1. The ratio decreased for lower SBR, with a ratio of 1.03 at SBR 3.85:1. Regarding the detectability of spheres, the sensitivity was 98% and 88% for the DMI and D690, respectively, for SBR 15:1. For SBR 7.5, the sensitivity was 75% and 83% for the DMI and D690, respectively. For SBR 3.85:1, the sensitivity was 43% and 30% for the DMI and D690, respectively. CONCLUSION: Marginally higher contrast in small spheres was seen for the SiPM-based scanner but there was no significant difference in detectability between the scanners. It was difficult to detect differences between the scanners, suggesting that the SiPM-based detectors are not the primary reason for improved image quality.

Feasibility of Thorium-227/Radium-223 Gamma-Camera Imaging During Radionuclide Therapy.

Thorium-227 (227Th) is a long-lived (T1/2 = 18.7 d) α-emitter that has emerged as candidate for radioimmunotherapy. Imaging of patients treated with thorium-227 conjugates is challenging due to the low activity administered and to photon emissions with low yields. In addition, the radioactive daughter radium-223 (223Ra) have photon emissions in the same energy range as 227Th. The long half-life of 223Ra (T1/2 = 11.4 d) and the possibility of redistribution motivates efforts to separate 227Th and 223Ra. The aim of this study was to investigate the feasibility of imaging of patients treated with 227Th-labeled-monoclonal antibody (mAb) and to determine acquisition and image processing parameters to enable discrimination between 227Th and 223Ra. Imaging was performed with a GE Discovery 670 NM/CT γ-camera. Radionuclide separation with different energy windows (EW) and collimators was studied in images of vials with either 227Th or 223Ra. Phantom acquisitions with clinically relevant activities were performed to assess image quality and the usefulness of background subtraction and spatial filtering. Two patients treated with 227Th-labeled-mAb were imaged. Imaging of vials showed that 223Ra can be distinguished from 227Th using multiple energy windows. Medium- and high-energy collimators showed similar performance of sensitivity and spatial resolution, whereas the low-energy collimator had higher sensitivity but poor resolution due to collimator penetration. Visually, the image quality was improved with background subtraction and spatial filtering. The patient images exhibited the expected image quality and a possibility to separate 227Th and 223Ra. γ-Camera imaging of patients treated with 227Th-mAb is feasible and 223Ra can be distinguished from 227Th. Image quality is substantially improved using background subtraction and a spatial smoothing filter. Acquisition settings recommended for planar images are: high-energy general purpose or medium-energy general purpose collimator, 40 min acquisition time and energy windows: (1) 70-100 keV (227Th and 223Ra); (2) 215-260 keV (227Th); (3) 260-290 keV (223Ra); (4) 350-420 keV (223Ra).

Optimization of [18F]PSMA-1007 PET-CT using regularized reconstruction in patients with prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) radiotracers such as [18F]PSMA-1007 used with positron emission tomography-computed tomography (PET-CT) is promising for initial staging and detection of recurrent disease in prostate cancer patients. The block-sequential regularization expectation maximization algorithm (BSREM) is a new PET reconstruction algorithm, which provides higher image contrast while also reducing noise. The aim of the present study was to evaluate the influence of different acquisition times and different noise-suppressing factors in BSREM (ß values) in [18F]PSMA-1007 PET-CT regarding quantitative data as well as a visual image quality assessment. We included 35 patients referred for clinical [18F]PSMA-1007 PET-CT. Four megabecquerels per kilogramme were administered and imaging was performed after 120 min. Eighty-four image series per patient were created with combinations of acquisition times of 1-4 min/bed position and ß values of 300-1400. The noise level in normal tissue and the contrast-to-noise ratio (CNR) of pathological uptakes versus the local background were calculated. Image quality was assessed by experienced nuclear medicine physicians. RESULTS: The noise level in the liver, spleen, and muscle was higher for low ß values and low acquisition times (written as activity time products (ATs = administered activity × acquisition time)) and was minimized at maximum AT (16 MBq/kg min) and maximum ß (1400). There was only a small decrease above AT 10. The median CNR increased slowly with AT from approximately 6 to 12 and was substantially lower at AT 4 and higher at AT 14-16. At AT 4-6, many images were regarded as being of unacceptable quality. For AT 8, ß values of 700-900 were considered of acceptable quality. CONCLUSIONS: An AT of 8 (for example as in our study, 4 MB/kg with an acquisition time of 2 min) with a ß value of 700 performs well regarding noise level, CNR, and visual image quality assessment.

Monte Carlo-based SPECT reconstruction within the SIMIND framework.

This paper presents the development and validation of a Monte Carlo-based singe photon emission computed tomography reconstruction program for parallel-hole collimation contained within the SIMIND Monte Carlo framework. The Monte Carlo code is used as an accurate forward-projector and is combined with a simplified back-projector to perform iterative tomographic reconstruction using the Maximum Likelihood Expectation Maximization and Ordered Subsets Expectation Maximization algorithms, together forming a program called SIMREC. The Monte Carlo simulation transforms the estimated source distribution directly from activity to counts in its projections. Hence, the reconstructed image is expressed in activity without reference to an external calibration. The program is tested using phantom measurements of spheres filled with 99mTc, 177Lu and 131I placed in air and centrally and peripherally in a water-filled elliptical phantom. The feasibility of applying the reconstruction to patients is also demonstrated for a range of radiopharmaceuticals. The deviation in total activity in the spheres ranged between -4.1% and 6.2% compared with the activity determined when preparing the phantom. The SIMREC program was found to be accurate with respect to activity estimation and to reconstruct visually acceptable images within a few hours when applied to patient examples.

Feasibility of simplifying renal dosimetry in 177Lu peptide receptor radionuclide therapy.

BACKGROUND: Recently, 177Lu-dotatate therapy for neuroendocrine tumours has received regulatory approval. Dosimetry can be used to optimize treatment on an individual basis, but there is no international consensus as to how it should be done. The aim of this study is to determine a feasible and accurate dosimetry method to guide individualized peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumours. As part of a clinical trial on 177Lu-dotatate therapy, renal dosimetry was performed for all patients in each treatment cycle, using a hybrid planar-SPECT/CT method. In the present study, we use the image data acquired from 22 patients and 119 cycles and define a set of alternative treatment planning strategies, each representing a simplification in terms of image acquisition and dosimetric calculations. The results from the simplified strategies are compared to the results from the protocol-prescribed hybrid planar-SPECT/CT-based method by analysing differences both in per-cycle and total cumulative absorbed dose (AD) analyses. RESULTS: In general, the SPECT-based methods gave results that were largely consistent with the protocol-specified hybrid method, both in the per-cycle and cumulative AD analyses. Notably, performing one SPECT/CT per cycle at 96 h yielded ADs that were very similar to the protocol method. The methods using planar dosimetry resulted in larger variations, as expected, while giving 4 cycles to all patients resulted in the largest inter-individual differences in cumulative AD. CONCLUSIONS: Performing one SPECT/CT at 96 h in every treatment cycle gives sufficiently reliable dosimetric results to base individualized treatment planning on, with a reasonable demand on resources.

The accuracy of quantitative parameters in (99m) Tc-MAG3 dynamic renography: a national audit based on virtual image data.

Assessment of image analysis methods and computer software used in (99m) Tc-MAG3 dynamic renography is important to ensure reliable study results and ultimately the best possible care for patients. In this work, we present a national multicentre study of the quantification accuracy in (99m) Tc-MAG3 renography, utilizing virtual dynamic scintigraphic data obtained by Monte Carlo-simulated scintillation camera imaging of digital phantoms with time-varying activity distributions. Three digital phantom studies were distributed to the participating departments, and quantitative evaluation was performed with standard clinical software according to local routines. The differential renal function (DRF) and time to maximum renal activity (Tmax ) were reported by 21 of the 28 Swedish departments performing (99m) Tc-MAG3 studies as of 2012. The reported DRF estimates showed a significantly lower precision for the phantom with impaired renal uptake than for the phantom with normal uptake. The Tmax estimates showed a similar trend, but the difference was only significant for the right kidney. There was a significant bias in the measured DRF for all phantoms caused by different positions of the left and right kidney in the anterior-posterior direction. In conclusion, this study shows that virtual scintigraphic studies are applicable for quality assurance and that there is a considerable uncertainty associated with standard quantitative parameters in dynamic (99m) Tc-MAG3 renography, especially for patients with impaired renal function.

Uncertainty propagation for SPECT/CT-based renal dosimetry in (177)Lu peptide receptor radionuclide therapy.

A computer model of a patient-specific clinical (177)Lu-DOTATATE therapy dosimetry system is constructed and used for investigating the variability of renal absorbed dose and biologically effective dose (BED) estimates. As patient models, three anthropomorphic computer phantoms coupled to a pharmacokinetic model of (177)Lu-DOTATATE are used. Aspects included in the dosimetry-process model are the gamma-camera calibration via measurement of the system sensitivity, selection of imaging time points, generation of mass-density maps from CT, SPECT imaging, volume-of-interest delineation, calculation of absorbed-dose rate via a combination of local energy deposition for electrons and Monte Carlo simulations of photons, curve fitting and integration to absorbed dose and BED. By introducing variabilities in these steps the combined uncertainty in the output quantity is determined. The importance of different sources of uncertainty is assessed by observing the decrease in standard deviation when removing a particular source. The obtained absorbed dose and BED standard deviations are approximately 6% and slightly higher if considering the root mean square error. The most important sources of variability are the compensation for partial volume effects via a recovery coefficient and the gamma-camera calibration via the system sensitivity.

Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in (177)Lu-DOTATATE peptide receptor radionuclide therapy.

Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with (177)Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for (177)Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in (177)Lu PRRT.

Long-Term Retention of 177Lu/177mLu-DOTATATE in Patients Investigated by γ-Spectrometry and γ-Camera Imaging.

UNLABELLED: Dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE is based on patient imaging during the first week after administration and determination of the activity retention as a function of time for different tissues. For calculation of the absorbed dose, it is generally assumed that the long-term activity retention follows the pattern determined from the first week. This work aimed to investigate the validity of this assumption by performing additional patient measurements between 5 and 10 wk after administration. A further aim was to investigate to what extent absorbed dose values were affected when including these measurements, also taking into account the radionuclide impurity of (177m)Lu and build-up of secondary (177)Lu from the (177m)Lu decay. METHODS: A combination of methods was used: planar γ-camera imaging as part of the clinical dosimetry protocol, determination of the whole-body activity between 5 and 9 wk after injection using spectrometric NaI(Tl) and HPGe detectors, and imaging between 5 and 10 wk after injection for assessment of the activity distribution. From these measurements the long-term retention of activity was determined and the relative influence on absorbed doses calculated. RESULTS: The most important finding was a clearly visualized tumor uptake in images from between 5 and 7 wk after injection and in 1 patient also kidney and spleen uptake in images acquired on day 33. As a consequence, the total-body time-activity curve had a tail, which was not completely captured by imaging during the first week. The absorbed doses to total body and tumors obtained when including these late time points were on average 5%-6% higher than those obtained when using data acquired during the first week. The contributions to the absorbed dose from (177m)Lu and secondary (177)Lu were negligible. CONCLUSION: At approximately 5-7 wk after injection, there was a measureable amount of (177)Lu-DOTATATE in patients, which is mainly governed by retention in tumors. For tumor dosimetry, imaging at a later time than the routinely used 7 d may be warranted. The contribution to the absorbed dose from the radionuclide impurity of (177m)Lu was negligible.

Dynamic (99m)Tc-MAG3 renography: images for quality control obtained by combining pharmacokinetic modelling, an anthropomorphic computer phantom and Monte Carlo simulated scintillation camera imaging.

In dynamic renal scintigraphy, the main interest is the radiopharmaceutical redistribution as a function of time. Quality control (QC) of renal procedures often relies on phantom experiments to compare image-based results with the measurement setup. A phantom with a realistic anatomy and time-varying activity distribution is therefore desirable. This work describes a pharmacokinetic (PK) compartment model for (99m)Tc-MAG3, used for defining a dynamic whole-body activity distribution within a digital phantom (XCAT) for accurate Monte Carlo (MC)-based images for QC. Each phantom structure is assigned a time-activity curve provided by the PK model, employing parameter values consistent with MAG3 pharmacokinetics. This approach ensures that the total amount of tracer in the phantom is preserved between time points, and it allows for modifications of the pharmacokinetics in a controlled fashion. By adjusting parameter values in the PK model, different clinically realistic scenarios can be mimicked, regarding, e.g., the relative renal uptake and renal transit time. Using the MC code SIMIND, a complete set of renography images including effects of photon attenuation, scattering, limited spatial resolution and noise, are simulated. The obtained image data can be used to evaluate quantitative techniques and computer software in clinical renography.