Multicentre quantitative 68Ga PET/CT performance harmonisation

Purpose Performance standards for quantitative 18F-FDG PET/CT studies are provided by the EANM Research Ltd. (EARL) to enable comparability of quantitative PET in multicentre studies. Yet, such specifications are not available for 68Ga. Therefore, our aim was to evaluate 68Ga-PET/CT quantification variability in a multicentre setting. Methods A survey across Dutch hospitals was performed to evaluate differences in clinical 68Ga PET/CT study protocols. 68Ga and 18F phantom acquisitions were performed by 8 centres with 13 different PET/CT systems according to EARL protocol. The cylindrical phantom and NEMA image quality (IQ) phantom were used to assess image noise and to identify recovery coefficients (RCs) for quantitative analysis. Both phantoms were used to evaluate cross-calibration between the PET/CT system and local dose calibrator. Results The survey across Dutch hospitals showed a large variation in clinical 68Ga PET/CT acquisition and reconstruction protocols. 68Ga PET/CT image noise was below 10%. Cross-calibration was within 10% deviation, except for one system to overestimate 18F and two systems to underestimate the 68Ga activity concentration. RC-curves for 18F and 68Ga were within and on the lower limit of current EARL standards, respectively. After correction for local 68Ga/18F cross-calibration, mean 68Ga performance was 5% below mean EARL performance specifications. Conclusions 68Ga PET/CT quantification performs on the lower limits of the current EARL RC standards for 18F. Correction for local 68Ga/18F cross-calibration mismatch is advised, while maintaining the EARL reconstruction protocol thereby avoiding multiple EARL protocols.


Introduction
The use of 68 Gallium ( 68 Ga)-labelled peptides for PET imaging has increased in the past years with the market authorisation for 68 Ga/ 68 Ge-generators. The main applications include imaging of neuroendocrine tumours using somatostatin analogues and prostate cancer imaging using the prostate-specific membrane antigen [1,2]. Though the interpretation of 68 Ga-PET/CT is mainly based on visual assessment, quantitative measures should be used to evaluate or predict therapy response.
Previous experience with 18 Fluorine ( 18 F) expressed the need for standardisation of acquisition and reconstruction protocols in order to retrieve comparable quantitative imaging data. The EANM Research Ltd. (EARL) provides an accreditation programme to ensure PET/CT system harmonisation in multicentre 18 F-FDG PET/CT studies [3]. This approach is based on standardizing the recovery coefficient (RC) for six phantom spheres with different sizes, thereby minimising inter-and intra-institute variability. For other isotopes, quantification should be evaluated separately as isotope characteristics can result in different image quality and quantification accuracy. For example, Makris et al. studied 89 Zirconium ( 89 Zr) PET and showed the need for a specific harmonisation step including post-reconstruction smoothing to enable comparable quantitative measures among PET/CT systems [4]. In contrast, a recent 18 F performance study showed that postreconstruction filtering is not required for state-of-the-art PET/CT systems in relation to this isotope [5]. However, for 68 Ga, such studies are not yet available.
In general, PET quantification accuracy depends on reconstructions, noise, and spatial resolution [6]. For 68 Ga, the lower positron yield (89%), long positron range due to high initial positron energy (max 1.90 MeV, mean 0.84 MeV), short physical half-life (68 min) and small prompt gamma branching (3.2%, 1.077 MeV) may result in an inferior image quality compared to 18 F [7]. Therefore, the aim of this study was to assess 68 Ga-PET/CT quantification accuracy and reproducibility in a multicentre setting based on EARL standards.

Clinical protocol evaluation
A survey among eight Dutch hospitals was performed to evaluate factors that affect quantification and to assess variability in clinical 68 Ga-PET/CT acquisition protocols. Questions focussed on administered activity, PET/CT system, and acquisition-and reconstruction settings.

F and 68 Ga PET/CT phantom acquisitions
Eight European hospitals with 13 PET/CT systems performed phantom acquisitions, of which 11 systems were EARL accredited, but all had recoveries within the published EARL specifications. Six Biograph mCT systems (Siemens Healthineers, Erlangen, Germany), three Discovery systems (GE Healthcare, Milwaukee, WI, USA) and four Philips systems (Philips Healthcare, Eindhoven, The Netherlands) were included. 18 F and 68 Ga acquisitions were performed at the end of 2017 and beginning of 2018 with two phantoms which were prepared using a standardised procedure by experienced staff from each centre. First, the NEMA PET cylindrical phantom was filled with 6-13 kBq/ml of 18 F and 68 Ga. Second, the NEMA NU-2 Image Quality (IQ) phantom was imaged using a 1:10 ratio with 2.0 and 20.0 kBq/ml of 18 F and 68 Ga in background compartment and spheres (37, 28, 21, 17, 13, and 10 mm diameter), respectively. Acquisitions of both phantoms were performed with minimal two bed positions and at least 5 min per bed position. Images were reconstructed according to local settings, including corrections for decay, randoms, dead time, CT-based attenuation, and scatter.

Data analysis
Image noise was characterized for 68 Ga only using the coefficient of variation (CoV) along a 30 × 30 × 160 mm bar in the centre of the cylindrical phantom.
Image quality was based on the RC of all six spheres, analysed by the EARL semiautomatic tool [5,8]. The RC max , RC peak and RC mean were determined as a function of sphere size based on the maximum voxel value (RC max ), the 1.0 cm 3 volume with the maximised average value (RC peak ) and the mean value of 50% isocontour of the maximum voxel value (RC mean ) with contrast correction, respectively. A spherical volume-of-interest (VOI) of~300 ml in the centre of the cylindrical phantom and ten VOIs in the background of the IQ phantom were used for local PET and dose calibrator cross-calibration. IQ phantom background volume was 9400 ml, unless specified otherwise by the institute.

Results
Eight Dutch hospitals provided their clinical acquisition-and reconstruction protocols (Table 1), which showed to be different. An overview of all PET/CT systems and reconstruction settings is provided in Table 2. For local cross-calibration, most systems performed within 10% deviation of the dose calibrator ( Fig. 1 (Fig. 2). The 18 F RC-curves of all PET/CT systems satisfied the current EARL specifications (Fig. 3a-c). However, for 68 Ga the RC-curves were located around the lower limit of the EARL specifications (Figure 3d-f). In addition, 68 Ga showed a reduced mean recovery and larger variation between PET/CT systems compared to the 18 F. The variation for all spheres of the RC mean, RC max and RC peak for 18 F was 6%, 6% and 8%, respectively. For 68 Ga, the mean range was 11%, 11% and 15% (largest variation was 19%). Furthermore, the mean RC max and RC mean were both 11% lower compared to the mean EARL specifications for 18 F. The mean 68 Ga/ 18 F calibration difference within one scanner was 7% (range 1-13%).
After correction for the local difference between 68 Ga/ 18 F cross-calibration (Fig. 1), the 68 Ga RC curve was within EARL limits for all but two scanners (Figure 4). The mean 68 Ga RC max and RC mean were accordingly 5% lower compared to mean EARL standards.

Discussion
In this study, quantitative 68 Ga PET/CT performance was evaluated in a multicentre setting. In a survey across Dutch hospitals, differences in clinical acquisition and reconstruction protocols were observed, underlining the need for clinical harmonisation. The absence of local and central dose calibrator cross-calibration for 68 Ga is a limitation in this study. This would increase local calibrator harmonisation and improves PET/CT comparability across sites. Most institutes use a long-lived ( 137 Ceasium) source to assess constancy and accuracy of the dose calibrator on a daily basis, and perform actual cross-calibration with the PET/CT system at least once a year using 18 F. Still, in all but three PET/CT systems the measured 18 F and 68 Ga activity concentrations were within 10% deviation from the local dose calibrator. High energy prompt gammas emitted by 68 Ga are likely detected by the dose calibrator causing a disconcordance, yet in fewer extent by the PET system. Because of this, the dose calibrator overestimates 68 Ga-activity, and a persistent underestimation for 68 Ga compared to 18 F is seen in Fig. 1. A recent study by Bailey et al. also showed an underestimation of ± 15% for 68 Ga, which was primarily related to an inaccurate scaling factor for the dose calibrator of a specific vendor [9]. To avoid these issues, they calibrated the dose calibrator towards the PET, after verifying that the scanner has a good response for 18 F. These results are also supported by the fact that on specific Siemens scanners (scanners 1 and 2), a traceable 68 Germanium ( 68 Ge) source was used to verify absolute PET response independent of a dose calibrator. When imaging the 68 Ge-source, the PET/ CT system did not show the same offset as was observed when imaging the 68 Ga crosscalibration phantom (roughly a deviation of < 1% vs. 6% and 7%, respectively). For the sake of simplicity, we would suggest to correct the RC curve for the local 68 Ga/ 18 F discrepancy, as after correction for this 68 Ga/ 18 F difference (Fig. 4) all but two scanners were within EARL specifications. This correction has to be performed offline in multicentre quantitative studies. The 68 Ga used for this study was produced either locally or by a pharmaceutical institution and was therefore not traceable to a central dose calibrator. We expect that the response between the dose calibrator and the PET-system could be uniform in future clinical 68 Ga-PET/CT studies if a traceable (NIST) source is used to harmonise protocols between centres. 68 Ga image noise was below 10% for all PET/CT systems which is in concordance with the EANM/EARL guidelines [3,8]. The RC variation is larger for 68 Ga compared to 18 F (Fig. 3). However, 68 Ga performance nearly reached EARL performance specifications after correction for the local 68 Ga/ 18 F ratio. Surprisingly, the RC peak variation (8% and 15%) is larger in contrast to RC max and RC mean (both 6% and 11%) for both 18 F and 68 Ga, respectively. The study of Kaalep et al. showed the opposite result in RC peak variation [5]. The RC peak is expected to be less prone to noise compared to RC max ; therefore, it was expected to be more comparable over all PET-systems. The difference could be explained by the fact that the standard deviation of RC max and RC peak are similar: 8.4% and 8.6% for 68 Ga and 4.8% and 5.0% for 18 F, respectively. Yet, the mean RC peak value is lower; therefore, resulting in a higher CoV. Next to that, the larger 68 Ga variation in the RC-curves compared to 18 F is likely related to the higher positron energy of 68 Ga and thereby revealing a lower signal-to-noise ratio. This effect is enhanced by post-reconstruction filtering. Finally, previous single-centre studies show 68 Ga RC-curves similar [10] or somewhat better due to point spread function reconstruction [11] as observed in the current study. The EARL limits as applicable before 2019 (EARL1) are shown in Figs. 3 and 4, as all acquisitions were acquired before 2019 and therefore site-specific acquisition and reconstruction protocols are designed to meet the EARL1 limits. RC peak specifications are not available for EARL1 and are therefore not shown in Figs. 3 and 4. EARL2 limits (applicable from 2019) for RC max and RC mean increased with~25% in comparison to EARL1. We expect that the gap between 18 F and 68 Ga recoveries will further increase with these new limits, as already for EARL1 not all scanners agreed to EARL1 limits after 68 Ga/ 18 F correction (Fig. 4). Based on the results, we propose to correct 68 Ga recovery towards the 18 F recovery to correct for the current dose calibrator deviation. We suggest, therefore, to apply the EARL acquisition and reconstruction protocol and to correct for 68 Ga/ 18 F crosscalibration mismatch. One can assume that 68 Ga recovery is steady if 18 F specifications of a PET-system are stable during regular yearly assessment. Unless the acquisition and reconstruction protocol is changed or major maintenance is performed to the PET/CTsystem, we recommend to perform additional 68 Ga IQ acquisitions only when regular 18 F evaluations are deviating. An EARL accreditation programme for 68 Ga can thus be based on the 18 F accreditation but extended with a cross-calibration verification between 68 Ga measured by the dose calibrator and PET/CT system only, similarly as proposed by Kaalep et al. for 89 Zr [12]. In addition, frequent 18 F cross-calibration acquisitions using the cylindrical phantom are advised, especially after PET/CT system maintenance.