Effects of furosemide and tracer selection on urinary activity and peri-bladder artefacts in PSMA PET/CT: a single-centre retrospective study

PSMA PET/CT has proven to be a valuable tool in staging of primary and recurrent PCa [1, 2]. The commonly used PSMA-ligands 68Ga-PSMA-11 and 18F-DCFPyL are excreted mainly via the urine. Difficulties in the assessment of structures adjacent to the urinary bladder and ureters have been recognized early in the clinical use of these tracers [3,4,5, 12]. In a recent study by Uprimny et al., it was shown in 220 patients that patient preparation with hydration and forced diuresis using furosemide prior to 68Ga-PSMA-11 PET/CT significantly increased the detection rate of local recurrence of PCa [9]. This strategy to improve clearance of accumulated tracer from the ureters and bladder was already advocated by the joint EANM and SNMMI procedure guideline for PCa imaging using 68Ga-PSMA-ligands [10]. It is likely that imaging using 18F-based PSMA tracers with high urinary excretion, such as 18F-DCFPyL, would benefit from such strategies as well. However, to date there are neither reports assessing the effects of forced diuresis in 18F-DCFPyL PET/CT nor reports describing a direct comparison between 68Ga and 18F-based PSMA tracers on urinary activity and peri-bladder artefacts in a large patient cohort.

The present data show that administration of intravenous furosemide concurrent with tracer injection considerably reduces tracer concentration in the urinary bladder in patients staged with PSMA PET/CT for prostate cancer, which is true for both 68Ga-PSMA-11 as well as 18F-DCFPyL. For 68Ga-PSMA-11, similar findings have been described in earlier studies [4, 7,8,9]]. In addition, extreme SUVmax bladder values (e.g. SUVmax bladder > 100) were not noted in the furosemide cohorts, but not infrequent in the other cohorts. Significantly higher urinary bladder activities were found in 18F-DCFPyL compared to 68Ga-PSMA-11 for the respective subgroups with and without furosemide. Theoretically the difference in timepoint of acquisition between the 18F-DCFPyL cohorts and the 68Ga-PSMA-11 cohorts (60 and 45 min PI, respectively) could, by continuing urinary excretion of tracer in that timeframe, contribute to higher urinary activity in the 18F-DCFPyL cohorts [13]. However, the observed differences in biodistribution time did not lead to a significant effect in the multivariate analysis, leaving choice of tracer and furosemide as independent factors influencing urinary bladder activity. A stronger effect of furosemide on urinary bladder activity was found in 18F-DCFPyL compared to 68Ga-PSMA-11, although the relative reduction by furosemide for both tracers was of the same magnitude (+/- 70%). Comparable reductions in urinary bladder activity for 68Ga-PSMA-11 were found by Fennesy et al. and Uprimny et al. administering 20mg intravenous furosemide concurrent with the tracer [4, 7]. Uprimny et al. reported an even greater reduction compared to a protocol without any patient preparation (no hydration, no furosemide). Therefore, hydration, which is already a standard procedure in many centres, seems a sensible measure to decrease urinary bladder activity [4, 7]. If there is a net benefit of intravenous compared to oral hydration is not clear.

Given the comparable noise levels for the G- and F cohorts, reported differences in SUVmax between these cohorts may not be explained by differences in tracer dosages and acquisition time. The G+ cohort, however, displayed larger SUV_SD values which may have led to increased SUVmax values of urinary tracer activity as well. However, the G+ cohort already displayed the lowest SUVmax values compared to the other cohorts, and these may have even been lower; therefore, reported effects and correlations in this study may even have been underestimated.

The effects of furosemide and choice of tracer on the ureteral activity were comparable to the effects on urinary bladder activity, although less pronounced. Visual ureteral activity was significantly different on the overall cohort level, but a clear relation of the incidence of visual ureter activity with administration of furosemide or choice of tracer was not found. On the other hand, SUVmax ureter was significantly influenced by both furosemide and choice of tracer and was shown to be significantly higher in the 18F-DCFPyL cohort without furosemide. These results are in line with earlier studies reporting a significant reduction of ureteral activity after administration of furosemide using 68Ga-PSMA-11 [4, 7] or 68Ga-PSMA-I&T as tracer [5].

Peri-bladder artefacts with a photopenic ‘halo-like’ area surrounding the bladder or kidneys were first described in 68Ga-PSMA-11 PET/MRI and recognized as impairing image interpretation [14]. This phenomenon is present in PET/CT as well and has also been described using 18F-DCFPyL as tracer [6]. In an experimental setting, these artefacts were found to be related to high contrast to background ratios and not tracer- or modality-dependent (PET/CT vs. PET/MRI) [15]. In this study, we found peri-bladder artefacts in up to fifty per cent of patients in the 18F-DCFPyL without furosemide cohort, though remarkably lower percentages in the 68Ga-PSMA-11 cohorts which is in line with earlier studies [4, 7]. We found a great overlap in occurrence and severity of halo- and flare-type peri-bladder artefacts, and this may well be explained by a common cause: erroneous scatter correction [15, 16]. This study confirms in a clinical setting that peri-bladder artefacts are encountered in 68Ga-PSMA-11 as well as 18F-DCFPyL PET/CT and that they are solely dependent on urinary bladder activity. Although the occurrence and severity of peri-bladder artefacts may be diminished by improved PET scatter correction algorithms [15, 16], these usually are an integrated part of the reconstruction algorithms provided by the manufacturers and not easily adjusted [7]. Therefore, strategies to decrease urinary bladder activity are also sensible to decrease the occurrence of peri-bladder artefacts. Late pelvic imaging has been reported as a strategy to decrease urinary bladder activity as well; however, this strategy lacks a clear benefit, while it complicates logistics [5, 6, 8].

The administration of furosemide concurrent with the tracer has no effect on physiologic uptake in 68Ga-PSMA-11 PET/CT, and thus, a negative impact of early furosemide injection on targeting properties and biodistribution of 68Ga-PSMA-11 seems unlikely [9]. Given the similarities in biodistribution of 68Ga-PSMA-11 and 18F-DCFPyL, these findings probably apply to 18F-DCFPyL as well. In our study, the effects on urinary activity and peri-bladder artefacts were observed using a relatively low dose of 10mg intravenous furosemide, whereas earlier studies used 20–40 mg furosemide as standard dose [4,5,6,7,8,9]. The frequency and severity of urinary urge complaints are likely related to the furosemide dose, whereas a higher dose may not increase the aimed effects of forced diuresis (7). Therefore, the optimal furosemide dose should be a balance of maximizing the aimed effects of forced diuresis on the one hand and minimizing the urinary urgency complaints on the other hand.

A limitation of this study is its retrospective nature. Different protocols have been used sequentially, and patient population may have varied over time. However, we assume these factors may have had only limited influence on the measured urinary activity and occurrence of peri-bladder artefacts. Furthermore, the clinical outcome of patients has not been evaluated in this study.

This study shows that in patients undergoing PSMA PET/CT stimulating forced diuresis through a combination of hydration and 10mg intravenous furosemide is an effective strategy to increase clearance of urinary activity and decrease peri-bladder artefacts, especially in 18F-DCFPyL PET/CT, whereas the benefit in 68Ga-PSMA-11 PET/CT is lower and should be balanced to a possible increase in urge complaints when longer scanning protocols are used to maintain image quality with limited availability of generator-produced 68Ga isotope. Based on the results of this study, forced diuresis using furosemide was reintroduced at our department for 18F-DCFPyL PET/CT.

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