Early Injection of Furosemide Increases Detection Rate of Local Recurrence in Prostate Cancer Patients with Biochemical Recurrence Referred for ⁶⁸Ga-PSMA-11 PET/CT

DISCUSSION

In ⁶⁸Ga-PSMA-11 PET/CT, usually conducted 60 min after tracer injection, LR may be overlooked when it is located adjacent to the urinary bladder, mainly due to the masking effect of overlaying urinary bladder activity (11). In addition, there are cases in which it is almost impossible to discriminate LR from urinary activity within the urethra or the bladder neck, especially at the site of anastomosis after RP (8), as displayed in an example in Figure 2.

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 2.

Example of an equivocal finding in prostate fossa on ⁶⁸Ga-PSMA-11 PET/CT with maximum-intensity-projection (A), fused axial (B), fused coronal (C), and fused sagittal (D) images of a PC patient with BR after radical prostatectomy and salvage radiation therapy (PSA: 1.34 ng/mL), receiving no preparation before imaging. Intense focal uptake is present in midline at level of vesicourethral anastomosis (red arrow). Clear distinction between LR and urinary activity within urethra is not possible (SUV_max of focal uptake in midline: 10.3 and SUV_max of urinary bladder: 118.0).

Administration of furosemide is recommended in the joint EANM/SNMMI procedure guideline for ⁶⁸Ga-PSMA-11 PET/CT (6). In a recently published study by our group, we demonstrated that forced diuresis with 20 mg of furosemide, injected simultaneously with the radiotracer, significantly reduced tracer accumulation in the urinary bladder compared with patients receiving no preparation or hydration alone (19).

The primary objective of the present study was to investigate whether the afore-described furosemide-induced reduction of urinary bladder activity also improved detection rates of LR and enhanced diagnostic certainty in the prostate fossa. Indeed, our study revealed a significantly higher number of PSMA-positive LRs in the furosemide group than in the group of patients without preparation, with 56 and 38 cases judged positive for LR, respectively (25.5% vs. 17.3% of patients). The effect of furosemide-induced tracer washout of the urinary bladder on detectability of LR is illustrated in Figure 3. Furthermore, the number of equivocal findings in the prostate fossa was lower in patients undergoing forced diuresis in comparison with patients without furosemide, with 27 and 37 unclear cases, respectively (12.3% vs. 16.8% of patients). However, the difference in this respect did not reach statistical significance. This may be attributable to the fact that tracer activity does not vanish completely from the urinary routes after furosemide administration, and in a small number of cases a relatively high amount of tracer remains within the bladder and urethra despite forced diuresis (15,21,24). Of note, our data suggest that patients who have undergone radical prostatectomy (RPE) profit most from furosemide. The number of unclear findings after RPE was significantly lower in the furosemide group and a clear tendency in the positivity rate of LR was found after furosemide, although these did not reach statistical significance. In contrast, the detection rate of LR in both groups was almost the same in patients who underwent primary radiation therapy without RPE (as presented in Table 3). Our results are in line with the findings of a study conducted by Fennessy et al., using a similar preparation protocol with early administration of furosemide (15). Fennessy et al. reported that diagnostic confidence in the pelvic area on ⁶⁸Ga-PSMA-11 PET/CT could be improved in patients injected with furosemide. However, the number of patients in the patient subset with BR was relatively low in this analysis (n = 44) and the analysis was probably underpowered to detect a positive effect of the furosemide protocol on detection rates of LR.

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 3.

⁶⁸Ga-PSMA-11 PET/CT with maximum-intensity-projection (A), fused axial (B), fused coronal (C), and fused sagittal (D) images of a PC patient with BR after radical prostatectomy (PSA: 1.18 ng/mL), who received forced diuresis with 20 mg of furosemide simultaneously with radiotracer injection. Focal uptake of high intensity with SUV_max of 9.6 is present in area of vesicourethral anastomosis (red arrow) that can be clearly distinguished from adjacent urinary activity in bladder (SUV_max of 9.4), representing case consistent with LR. Malignant origin of finding was confirmed on subsequent MRI.

There are concerns whether injection of furosemide at the time of radiotracer injection is appropriate. Injection of furosemide early in the uptake phase of the tracer might lead to an increased renal washout of ⁶⁸Ga-PSMA-11 before it binds to PSMA, possibly resulting in a reduced tracer uptake in tumor lesions and in lower sensitivity of the examination. We tried to address this issue by comparing intensity of tracer accumulation in organs and tissues with physiologic ⁶⁸Ga-PSMA-11 uptake in patients receiving furosemide and patients without preparation. We hypothesized that if a significant increase of renal tracer excretion was induced by early injection of furosemide, it would result in a lower tracer uptake in organs with physiologic uptake. However, our results clearly showed that, apart from the urinary bladder, tracer accumulation in all organs and tissues investigated was not lower in the patient group receiving furosemide than in the patient group without preparation. Calculated SUVs are comparable to those of previous studies dealing with biodistribution of ⁶⁸Ga-PSMA-11 (7,10,25). Taken together, our findings can be interpreted as sufficient evidence that administration of furosemide shortly after tracer injection does not have a relevant negative influence on organ distribution of ⁶⁸Ga-PSMA-11.

A negative impact of early furosemide injection on lesion detectability could not be observed either. The patient-based overall detection rate of at least 1 ⁶⁸Ga-PSMA-11–avid lesion consistent with recurrent PC was even higher in the group receiving furosemide than in patients without preparation (66.8% vs. 60.5% of cases). In comparison with other studies, a somewhat lower overall detection rate in our analysis may be noticed. In a study by Afshar-Oromieh et al. including 1,007 PC patients with BR referred for ⁶⁸Ga-PSMA-11 PET/CT, a PET positivity in 79.5% of patients is described (1). In a recently published study by Chevalme et al. on the performance of ⁶⁸Ga-PSMA-11 PET/CT after a negative or equivocal ¹⁸F-fluorocholine PET/CT (including 1,084 PC patients with BR), an overall PET positivity rate of 68% of patients was found (26), revealing no significant difference between subgroups of patients with furosemide administered at the time of tracer injection and patients without furosemide. The lower percentage of PET-positive patients in our analysis may be due to relatively low PSA values of patients in both groups (median PSA: 1.3 ng/mL and 0.82 ng/mL, respectively). It is well known that detection efficacy of ⁶⁸Ga-PSMA-11 PET/CT increases with higher PSA levels (1,4).

Although with the present study we could demonstrate that furosemide administered at the time of tracer injection has a major impact on assessment of LR in PC patients with BR, a debate on the best time point for injection of furosemide in ⁶⁸Ga-PSMA-11 PET/CT may remain. Applying a biphasic scan protocol, Afshar-Oromieh et al. described that a reduction of radioactivity in the urinary bladder between scans 1 h after injection and 3 h after injection was more intense after injection of furosemide, assuming a better visibility of PC lesions in the vicinity of the urinary bladder (17). Another approach with late furosemide injection is described by Haupt et al. (16). Compared with a standard protocol without furosemide and scan acquisition 60 min after injection, a slightly higher detection rate of LR was demonstrated in patients orally hydrated with 1 L of water 30 min after injection and injected with furosemide 60 min after injection followed by a single PET examination 90 min after injection (LR present in 42.9% of patients with furosemide vs. 42.0% of patients without furosemide). Haupt et al. demonstrated that urinary bladder activity was significantly lower with furosemide than with the standard protocol, resulting also in a significantly better contrast between LR and urinary bladder activity. The high percentage of LR in both groups in this study is striking and may be explained by the relatively high overall PSA levels of patients analyzed (39.2% of patients with PSA > 4.0 ng/mL). In a study by Derlin et al. using ⁶⁸Ga-PSMA I&T, a different PSMA-ligand with high urinary bladder accumulation, the authors showed that furosemide injected simultaneously with radiotracer significantly reduced urinary bladder activity on PET scans at 60 min after injection compared with patients without furosemide, resulting also in a significant improvement in assessment of the prostatic fossa (18). However, with respect to evaluation of the prostate bed, best results were obtained with delayed imaging 180 min after injection, performed after oral hydration and injection of furosemide after a PET/CT scan at 60 min after injection.

Despite the favorable results of these furosemide protocols, the described procedures require either a longer waiting time for the patients or additional scans. For institutions with high throughput of PET examinations and limited camera availability a protocol with an uptake time of only 60 min and a single image acquisition as presented in this study is clearly advantageous.

There are some limitations within this study. First, the data were collected retrospectively. We are aware that some parameters in the patient population differed significantly between both preparation groups, such as median radiotracer uptake time, number of patients with primary radiotherapy, and initial T-stage. We cannot exclude that this heterogeneity may have influenced the results. With respect to median uptake time, a difference of 2 min does not, in our view, have a relevant negative effect on results. In particular, Q1 and Q3 demonstrate that most participants had an uptake time between quite a small time window of 60 and 77 min. A major drawback of the current study is that no histologic verification of lesions rated as LR was performed. Usually, biopsy of PSMA-positive LR is not part of our standard clinical work-up of PC patients with BR. However, interpretation of findings was done by 2 experienced readers in a standardized way following published guidelines (8,22). Therefore, we are strongly convinced that PSMA-positive local findings in the prostate fossa, that were not verified by other imaging modalities or on follow-up, can be regarded as true-positive.