Acquisitions of the energy spectrum and a cylindrical phantom image to determine energy window settings and collimator choice for Ra-223 SPECT imaging (basic study A)
The energy spectra of Ra-223 with low-energy high-resolution (LEHR), MEGP or HEGP collimators and without any collimator were obtained using a dual-headed SPECT system (Discovery NM630, GE Healthcare, Milwaukee, WI). The thickness of the detector crystal was 3/8 in. Hole diameter, hole length and lead thickness of the collimator were 3.0, 58 and 1.1 mm for MEGP and 4.0, 66 and 1.8 mm for HEGP, respectively. Each of the two vials containing Ra-223 solution (1.1 MBq, 2.0 mL) was carefully placed at a distance of 100 mm from the detector under the different conditions where the vials were set around the air or in the chamber filled with iodine contrast media (CT value, 350 HU), and each energy spectrum was then obtained (Fig. 1). The energy spectrum < 500 keV was obtained for 30 min.
Image quality was assessed using a cylindrical phantom filled with water (diameter, 200 mm; height, 210 mm) in which a cylindrical rod (diameter, 45 mm; height, 200 mm) filled with 2.0 kBq/mL of Ra-223 was embedded along the phantom axis (Additional file 1: Figure S1). The radio concentration of the rod was determined based on the phantom study by Hindorf et al. [12]. SPECT/CT scans were performed with MEGP and HEGP collimators using the same protocol (matrix, 64 × 64; pixel size, 8.8 mm; scan orbit, body contour; frames per detector, 30 (6° steps); acquisition time per frame, 60 s; total acquisition time, 30 min). Total acquisition time was determined based on the balance of count statistics and patient durability in our clinical study described later.
First, the energy window setting around 84 keV was evaluated. We focused on image noise and contrast in image quality of Ra-223 SPECT because of the limited injected dose. As studied in Sr-89 imaging [17], we evaluated the impact of characteristic X-rays of lead (75 keV (Kα) and 85 keV (Kβ) [18]) on image quality of Ra-223 SPECT by comparing the energy window widths between ± 20% and ± 10%. The latter width has been used so far [9, 12], although these characteristic X-rays have not been fully included.
The SPECT data with the two energy window widths were reconstructed using 3-dimensional ordered subset expectation maximisation (3D OSEM) algorithm (five subsets, 10 iterations). Butterworth filter was used for image noise reduction (cutoff frequency, 0.20 cycle/cm; order, 10). Attenuation or scatter correction was not performed. Circular regions-of-interest (ROIs) (diameter, 45 mm) were carefully placed on the hot rod in a transaxial slice (slice thickness, 8.8 mm) with a reference of the corresponding CT (Additional file 1: Figure S1). Background counts (BKG) were also measured using the same 8 ROIs, avoiding high activity around the hot rod. Then, the quality of SPECT images was assessed with the following parameters:
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Hr = ROI counts in the hot rod
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BKG = averaged ROI counts in the background
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SD = standard deviation of BKG
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Hot rod-to-background ratio (HBR) = Hr/BKG
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Contrast-to-noise ratio (CNR) = (Hr–BKG)/SD
Second, the energy window regarding the other peaks was set at 154 keV ± 10% and 269 keV ± 5% according to previous reports [9, 12]. Similarly, Hr, BKG, HBR and CNR were measured. The procedure of the parameter measurement was repeated 10 times (i.e. 10 arbitrary transaxial slices) obtained with the two collimators.
SPECT acquisition of a modified body phantom simulating bowel activity and lumbar spine metastases compared to planar imaging for clinical Ra-223 SPECT (basic study B)
A modified body phantom simulating bowel activity and lumbar spine metastases was developed and scanned. The configuration of the phantom is shown in Fig. 2a. The phantom was filled with water, and two identical 28 mm spheres (11.5 cm3) with 15.0 kBq/mL of Ra-223 and attenuation medium (350 HU) and a tube-shaped chamber with 15.0 kBq/mL of Ra-223 were embedded. The spheres were set in the same longitudinal axis. One of them (sphere 1) was set in the same anteroposterior axis as a tube-shaped chamber so that uptake of the sphere is overlaid by uptake of the chamber on the planar image. The other sphere (sphere 2) was used as reference. Planar static data were obtained for 30 min in a 128 × 128 matrix. Image acquisition and reconstruction for SPECT were the same as those for a cylindrical phantom.
In this phantom study, the following parameters were evaluated; first, using the data of sphere 2, the threshold for spherical volume of interest (VOI) of bone metastasis for clinical Ra-223 SPECT was determined by comparing the sphere volumes on CT and SPECT. Second, the uptake ratio of sphere 1 to sphere 2 was assessed using a 28-mm circular ROI in the anteroposterior view of the planar image and using the threshold method in SPECT. Third, the sphere-to-background ratio for sphere 2 (SBR) was compared between the planar and SPECT images using 48-mm circular background ROIs for the planar image and 48-mm spherical background VOIs for the SPECT (Fig. 2a). Finally, the phantom was repeatedly scanned to evaluate the linearity between radio-concentration and SPECT count in sphere 2.
Direct comparison of clinical Ra-223 and Tc-99m HMDP SPECT images
Both Ra-223 treatment and image acquisition of Ra-223 in patients with prostate cancer were approved by the institutional review board in Keio University Hospital (approval number 20160203). The study was conducted in accordance with the Declaration of Helsinki. The study protocol was registered at the University Hospital Medical Information Network (UMIN000024274). Written informed consent was obtained from 10 patients with prostate cancer who had a bone metastasis diagnosis confirmed with Tc-99m HMDP SPECT/CT.
Injection dose of Ra-223 dichloride solution was 55 kBq/kg per cycle. Image acquisition was performed after the first injection during six cycles of Ra-223 treatment in all patients. One-bed Ra-223 SPECT scanning was performed in an area where the greatest bone metabolism was revealed in Tc-99m HMDP SPECT. SPECT data were collected 2 h after Ra-223 injection successively with the MEGP and HEGP collimators for 30 min each. Since the difference in uptake time from injection to image acquisition could affect image contrast between the two successive SPECT acquisitions (120 vs 150 min), image acquisition was performed first with the MEGP collimator for five patients and with the HEGP collimator for the remaining five. The energy windows were set at 84 keV ± 20% according to the results of the phantom study. Acquisition and reconstruction parameters were identical to those used for the phantom images.
Tc-99m HMDP SPECT/CT was performed 3 h after injection using the LEHR collimator at 141 keV ± 10%. Tc-99m HMDP SPECT data were also reconstructed on a 128 × 128 matrix (pixel size, 4.4 mm) with 3D OSEM (five subsets; 10 iterations) and Butterworth filter (cutoff frequency, 0.33 cycle/cm; order, 10) using attenuation and scatter correction (dual-energy window method) and resolution recovery with Evolution for Bone (GE Healthcare).
With a reference of CT images, the LBR was calculated for metastatic lesions showing increased Ra-223 uptake at least two times greater than uptake in the normal spine with both the MEGP (LBRme) and HEGP (LBRhe) collimators. The LBR for Tc-99m HMDP SPECT was also calculated (LBRtc). VOIs were placed on the metastatic lesions to encompass the selected metastasis at a contour level of 60% of the highest count. For background VOIs, spherical VOIs (50 cm3) were carefully drawn within the liver parenchyma with reference to the corresponding CT images, avoiding the large hepatic vein. Then, the LBR was measured as mean counts in the lesion ROI divided by mean counts in the background ROI.
Statistical analysis
All statistical analyses were performed using JMP 12.0.1 software (SAS Institute Inc., Cary, NC). All data were expressed as median and range (minimum to maximum) and analysed with non-parametric methods. Comparisons of Hr, BKG, HBR and CNR for the cylindrical phantom between the energy window of 84 keV ± 20% and ± 10% were performed using the Wilcoxon signed-rank test. After selecting the optimal energy window, around 84 keV, comparisons of Hr, BKG, HBR and CNR among the three energy windows were performed using Friedman’s test, and when significant differences were found, the Steel-Dwass test was performed on each pair. Comparisons of SBR for the modified body phantom between planar vs SPECT or MEGP vs HEGP were also performed using the Wilcoxon signed-rank test.
Regarding the clinical study, detection of bone metastasis was compared between Ra-223 SPECT and Tc-99m HMDP SPECT using the Wilcoxon signed-rank test. The relationships between LBRme or LBRhe vs LBRtc were assessed using linear regression analysis. The comparison between LBRme and LBRhe was performed using paired t test. The differences at the 95% confidence level (p < 0.05) were considered to be statistically significant.