Multicentre quantitative ⁶⁸Ga PET/CT performance harmonisation

Abstract

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 ⁶⁸Gallium (⁶⁸Ga)-labelled peptides for PET imaging has increased in the past years with the market authorisation for ⁶⁸Ga/⁶⁸Ge-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 ⁶⁸Ga-PET/CT is mainly based on visual assessment, quantitative measures should be used to evaluate or predict therapy response.

Previous experience with ¹⁸Fluorine (¹⁸F) 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 ¹⁸F-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 ⁸⁹Zirconium (⁸⁹Zr) 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 ¹⁸F performance study showed that post-reconstruction filtering is not required for state-of-the-art PET/CT systems in relation to this isotope [5]. However, for ⁶⁸Ga, such studies are not yet available.

In general, PET quantification accuracy depends on reconstructions, noise, and spatial resolution [6]. For ⁶⁸Ga, 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 ¹⁸F [7]. Therefore, the aim of this study was to assess ⁶⁸Ga-PET/CT quantification accuracy and reproducibility in a multicentre setting based on EARL standards.

Materials and methods

Clinical protocol evaluation

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

¹⁸F and ⁶⁸Ga 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.

¹⁸F and ⁶⁸Ga 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 ¹⁸F and ⁶⁸Ga. 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 ¹⁸F and ⁶⁸Ga 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 ⁶⁸Ga 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 semi-automatic 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 cm³ 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.

Table 1 Acquisition and reconstruction settings of clinical ⁶⁸Ga PET/CT imaging for prostate cancer and neuroendocrine tumours. One hospital per row is presented

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). The median [IQR] ratio was 0.93 [0.91–0.98] and 0.99 [0.97–1.01] for ⁶⁸Ga and ¹⁸F, respectively. Two systems showed identical calibration accuracy for both isotopes (system 2 and 11), all other show a consistent underestimation for ⁶⁸Ga. The ⁶⁸Ga CoV in the centre of the cylindrical phantom was below 10% (Fig. 2).

Table 2 PET/CT reconstruction settings for phantom measurements

Fig. 1

Accuracy of the measured activity by the PET/CT system and local dose calibrator, based on the average between the cylindrical and IQ phantom. Numbers correspond to Table 2

Fig. 2

Noise across the cylindrical phantom filled with ⁶⁸Ga, visualized as coefficient of variation (CoV)

The ¹⁸F RC-curves of all PET/CT systems satisfied the current EARL specifications (Fig. 3a–c). However, for ⁶⁸Ga the RC-curves were located around the lower limit of the EARL specifications (Figure 3d-f). In addition, ⁶⁸Ga showed a reduced mean recovery and larger variation between PET/CT systems compared to the ¹⁸F. The variation for all spheres of the RC_mean, RC_max and RC_peak for ¹⁸F was 6%, 6% and 8%, respectively. For ⁶⁸Ga, 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 ¹⁸F. The mean ⁶⁸Ga/¹⁸F calibration difference within one scanner was 7% (range 1–13%).

Fig. 3

RC for ¹⁸F with the current EARL standards and RC of ⁶⁸Ga. Solid lines: maximum and minimum values according to EARL limits as applicable before 2019

After correction for the local difference between ⁶⁸Ga/¹⁸F cross-calibration (Fig. 1), the ⁶⁸Ga RC curve was within EARL limits for all but two scanners (Figure 4). The mean ⁶⁸Ga RC_max and RC_mean were accordingly 5% lower compared to mean EARL standards.

Fig. 4

⁶⁸Ga RC-curves corrected for the ¹⁸F/⁶⁸Ga calibration mismatch according to local cross-calibration. Solid lines: maximum and minimum values according to EARL limits as applicable before 2019

Discussion

In this study, quantitative ⁶⁸Ga 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. Although 11 out of the 13 PET/CT systems were EARL accredited, all systems showed ¹⁸F recovery performance within EARL standards. For this reason, all systems were included for ⁶⁸Ga evaluation.

The absence of local and central dose calibrator cross-calibration for ⁶⁸Ga 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 (¹³⁷Ceasium) 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 ¹⁸F. Still, in all but three PET/CT systems the measured ¹⁸F and ⁶⁸Ga activity concentrations were within 10% deviation from the local dose calibrator. High energy prompt gammas emitted by ⁶⁸Ga 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 ⁶⁸Ga-activity, and a persistent underestimation for ⁶⁸Ga compared to ¹⁸F is seen in Fig. 1. A recent study by Bailey et al. also showed an underestimation of ± 15% for ⁶⁸Ga, 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 ¹⁸F. These results are also supported by the fact that on specific Siemens scanners (scanners 1 and 2), a traceable ⁶⁸Germanium (⁶⁸Ge) source was used to verify absolute PET response independent of a dose calibrator. When imaging the ⁶⁸Ge-source, the PET/CT system did not show the same offset as was observed when imaging the ⁶⁸Ga cross-calibration 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 ⁶⁸Ga/¹⁸F discrepancy, as after correction for this ⁶⁸Ga/¹⁸F difference (Fig. 4) all but two scanners were within EARL specifications. This correction has to be performed offline in multicentre quantitative studies. The ⁶⁸Ga 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 ⁶⁸Ga-PET/CT studies if a traceable (NIST) source is used to harmonise protocols between centres.

⁶⁸Ga 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 ⁶⁸Ga compared to ¹⁸F (Fig. 3). However, ⁶⁸Ga performance nearly reached EARL performance specifications after correction for the local ⁶⁸Ga/¹⁸F 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 ¹⁸F and ⁶⁸Ga, 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 ⁶⁸Ga and 4.8% and 5.0% for ¹⁸F, respectively. Yet, the mean RC_peak value is lower; therefore, resulting in a higher CoV. Next to that, the larger ⁶⁸Ga variation in the RC-curves compared to ¹⁸F is likely related to the higher positron energy of ⁶⁸Ga and thereby revealing a lower signal-to-noise ratio. This effect is enhanced by post-reconstruction filtering. Finally, previous single-centre studies show ⁶⁸Ga 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 ¹⁸F and ⁶⁸Ga recoveries will further increase with these new limits, as already for EARL1 not all scanners agreed to EARL1 limits after ⁶⁸Ga/¹⁸F correction (Fig. 4).

Based on the results, we propose to correct ⁶⁸Ga recovery towards the ¹⁸F recovery to correct for the current dose calibrator deviation. We suggest, therefore, to apply the EARL acquisition and reconstruction protocol and to correct for ⁶⁸Ga/¹⁸F cross-calibration mismatch. One can assume that ⁶⁸Ga recovery is steady if ¹⁸F 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/CT-system, we recommend to perform additional ⁶⁸Ga IQ acquisitions only when regular ¹⁸F evaluations are deviating. An EARL accreditation programme for ⁶⁸Ga can thus be based on the ¹⁸F accreditation but extended with a cross-calibration verification between ⁶⁸Ga measured by the dose calibrator and PET/CT system only, similarly as proposed by Kaalep et al. for ⁸⁹Zr [12]. In addition, frequent ¹⁸F cross-calibration acquisitions using the cylindrical phantom are advised, especially after PET/CT system maintenance.

Conclusion

This evaluation of multicentre ⁶⁸Ga PET/CT performance showed that ⁶⁸Ga RCs perform at the lower limits of current ¹⁸F EARL standards. For practical reasons, we recommend to use the ¹⁸F EARL approved reconstruction settings and to correct for ⁶⁸Ga/¹⁸F calibration mismatch based on local cross-calibration. Finally, we suggest to evaluate ⁶⁸Ga PET/CT recovery performance once and repeat only when ¹⁸F specifications are changed.