Early lesion detection with 18F-DCFPyL PET/CT in 248 patients with biochemically recurrent prostate cancer

Purpose Prostate-specific membrane antigen (PSMA) PET/CT is increasingly used in patients with biochemically recurrent prostate cancer (BCR), mostly using gallium-68 (168Ga)-labelled radiotracers. Alternatively, fluorine-18 (18F)-labelled PSMA tracers are available, such as 18F-DCFPyL, which offer enhanced image quality and therefore potentially increased detection of small metastases. In this study we evaluate the lesion detection efficacy of 18F-DCFPyL PET/CT in patients with BCR and determine the detection efficacy as a function of their PSA value. Methods A total of 248 consecutive patients were evaluated and underwent scanning with 18F-DCFPyL PET/CT for BCR between November 2016 and 2018 in two hospitals in the Netherlands. Patients were examined after radical prostatectomy (52%), external-beam radiation therapy (42%) or brachytherapy (6%). Imaging was performed 120 min after injection of a median dose of 311 MBq 18F-DCFPyL. Results In 214 out of 248 PET/CT scans (86.3%), at least one lesion suggestive of cancer recurrence was detected (‘positive scan’). Scan positivity increased with higher PSA values: 17/29 scans (59%) with PSA values <0.5 ng/ml; 20/29 (69%) with PSA 0.5 to <1.0 ng/ml; 35/41 (85%) with PSA 1.0 to <2.0 ng/ml; 69/73 (95%) with PSA 2.0 to <5.0 ng/ml; and 73/76 (96%) with PSA ≥5.0 ng/ml. Interestingly, suspicious lesions outside the prostatic fossa were detected in 39–50% of patients with PSA <1.0 ng/ml after radical prostatectomy (i.e. candidates for salvage radiotherapy). Conclusion 18F-DCFPyL PET/CT offers early detection of lesions in patients with BCR, even at PSA levels <0.5 ng/ml. These results appear to be comparable to those reported for 68Ga-PSMA and 18F-PSMA-1007, with potentially increased detection efficacy compared to 68Ga-PSMA for patients with PSA <2.0. Electronic supplementary material The online version of this article (10.1007/s00259-019-04385-6) contains supplementary material, which is available to authorized users.


Introduction
Prostate cancer (PCa) is the most common cancer in men in the Western world [1,2]. Initial therapy includes local intervention with curative intent, such as radical prostatectomy (RP), external-beam radiation therapy (EBRT), or brachytherapy (BT). However, between 28% and 53% of all such treated patients will develop biochemically recurrent prostate cancer (BCR) [3]. BCR is defined as two consecutive prostatespecific antigen (PSA) values ≥0.2 ng/ml after RP, or any PSA increase of 2.0 ng/ml above the nadir following EBRT and BT [4][5][6]. Accurate imaging studies are important for patients with BCR, as early lesion localisation directs further treatment, which might include stereotactic metastasisdirected radiotherapy, salvage radiotherapy, salvage lymph node dissection, or the initiation of systemic treatment [3].
Positron emission tomography/computed tomography (PET/CT) using radiotracers that bind to the prostate-specific membrane antigen (PSMA) is increasingly used for PCa diagnostics. PSMA is a class II transmembrane glycoprotein that provides a valuable target for radiolabelled imaging, as it is significantly overexpressed in malignant prostate cells [7]. So far, studies have primarily investigated gallium-68 ( 68 Ga)labelled PSMA tracers ( 68 Ga-PSMA-HBED-CC), which have demonstrated promising results in patients with BCR [8]. Alternatively, fluorine-18 ( 18 F)-labelled PSMA tracers are available, most notably 18 F-DCFPyL [9,10] and 18 F-PSMA-1007 [11]. Because of a shorter positron range and higher positron yield, the 18 F radionuclide provides higher PET image resolution than 68 Ga, which may improve the detection of small metastases (e.g. at low PSA values) [12]. Although 18 F-DCFPyL PET/CT is increasingly used in clinical practice, only minimal data are yet available on the diagnostic efficacy in patients with BCR [13]. Hence, the aim of this study was to determine the lesion detection efficacy of 18 F-DCFPyL PET/ CT in patients with BCR and establish the efficacy as a function of patients' current PSA values.

Material and methods
This retrospective analysis consists of 248 patients with BCR consecutively scanned with 18  Imaging 18 F-DCFPyL was synthesised under good manufacturing practice (GMP) conditions at the on-site cyclotron facilities of both hospitals [14]. PET acquisitions were made 120 min after injection of a median dose of 311 MBq 18 F-DCFPyL (interquartile range 284-325 MBq). Imaging was performed with a Philips Ingenuity TF (Philips Healthcare, the Netherlands/USA) and a Siemens Biograph TruePoint-16 (Siemens Healthineers, Germany) PET/CT scanner. The scan trajectory included mid-thigh to skull vertex, with 4 min (Philips scanner) and 5 min (Siemens scanner) per bed position. PET acquisitions were combined with a low-dose CT or contrast-enhanced CT scan (30-110 mAs, 110-130 kV). All images were corrected for decay, scatter, and random coincidences; photon attenuation correction was performed using CT images. Images were reconstructed with the vendor-provided BLOB-based ordered-subset expectation maximisation algorithm on the Philips system (3 iterations; 33 subsets) [15] and the ordered-subset expectation maximisation algorithm on the Siemens system (4 iterations; 16 subsets, including a 5-mm Gaussian filter). The reconstructed images had a maximum image matrix size of 256 × 256, voxel size 2.67 × 2.67 × 4 mm (Siemens data) and matrix size 288 × 288, voxel size 2 × 2 × 2 mm (Philips data).

Image interpretation
Scan interpretation was performed in the participating centres by four nuclear medicine physicians in total, with ample experience in PCa PET reading (>200 scans). Dual-reading was performed for all scans, the final conclusion was drawn up in consensus, recording the localisation of detected lesions (i.e. prostate/prostatic fossa, loco-regional lymph nodes, distant lymph nodes, bones, visceral organs). A scan was considered 'positive' if at least one lesion suggestive of PCa recurrence was detected. Prostate lesions and lymph nodes were considered positive when the activity in those lesions exceeded blood pool activity. Bone lesions were considered positive if the activity was higher than general bone marrow activity, without CT findings clearly demarcating benign lesions such as hemangioma.

Statistical analysis
Numerical variables were summarised as medians and interquartile ranges; categorical variables with proportions (%). Scan positivity was calculated for the following PSA strata (<0.5; 0.5 to <1.0; 1.0 to <2.0; 2.0 to <5.0; ≥5.0 ng/ml) and includes a 95% confidence interval (CI). Binary logistic regression analyses were performed to identify predictors of scan positivity (e.g. PSA value at the time of PET/CT, PSA doubling time, Gleason score, tumour stage, use of androgen deprivation therapy (ADT) at the time of PET/CT). Differences in the distribution of detected lesions (e.g. local recurrence, regional lymph nodes) between PSA strata were tested using Fisher's exact test with Holm-Bonferroni correction.

Results
In 214 out of 248 18  Excluding patients with incomplete clinical history (e.g. Gleason score, see Table 1) for the evaluation revealed similar results (Supplementary data 1). Aside from current PSA value, no other parameter (Gleason score, tumour stage, current ADT use, PSA-doubling time, previous salvage radiotherapy) was a significant predictor of 18 F-DCFPyL PET/CT scan positivity in regression analysis (Supplementary data 2).
A subgroup analysis was performed for patients with BCR after RP and low PSA values (<1.0 ng/ml) (n = 43), as they may be candidates for curative salvage radiotherapy to the prostate bed [3]. In our cohort, 18 F-DCFPyL PET/CT revealed suspicious lesions outside of the prostatic fossa in 39-50% of these patients (Figs. 2, 3).

Discussion
In this study we evaluated the lesion detection efficacy of 18 F-DCFPyL PET/CT in 248 patients with BCR. Suspected metastases were identified in the majority of PET examinations and even at PSA values <0.5 ng/ml, lesions were observed in 59% of patients. These results show clear improvement over the results with conventional imaging modalities, as well as choline PET/CT [16][17][18]. Compared to a recent meta-analysis on 68 Ga-PSMA PET/CT [8], our study demonstrates equivalent results in patients with PSA values >2.0 ng/ml (i.e. 95% lesion detection with both tracers). Potentially improved detection is observed compared to 68 Ga-PSMA in all PSA strata <2.0 ng/ml (most notably, 59% detection with 18 F-DCFPyL when PSA <0.5 ng/ml vs. 45% with 68 Ga-PSMA; Table 2) [8].
Recently revised European Association of Urology guidelines recommend performing PSMA PET/CT at BCR after RP if the PSA level is >0.2 ng/ml and if the results will influence subsequent treatment decisions [19]. PSMA PET/CT is recommended in case of BCR after EBRT in patients fit for curative salvage treatment. The guidelines also recommend offering a PSMA PET to men with a persistent PSA >0.2 ng/ml after prostatectomy to exclude metastatic disease. Those recommendations are in line with our findings that even at the lowest PSA values, sites of PCa recurrence could be detected with 18 F-DCFPyL PET/CT in the majority of patients.
Further, 18 F-DCFPyL PET/CT revealed lesions outside the prostatic fossa even at very low PSA levels (e.g. 39% with PSA <0.5 ng/ml) (Figs. 2, 3). These findings are clinically relevant, because patients with BCR after RP are candidates for local salvage radiation treatment to the prostatic fossa, and such treatment is likely to be ineffective in the presence of (lymph node) metastases. Indeed, Emmett et al. recently demonstrated that 68 Ga-PSMA PET/CT may be effective for stratification of patients into groups with a high probability of response to salvage radiotherapy (negative PET or detection of local recurrence only) versus lower probability of response (detected lesions outside the prostatic fossa). In that study (n = 164), PSMA PET findings predicted salvage therapy outcomes better than established predictors, most notably current PSA values [20].
To our knowledge, there is only one prior study on 18 F-DCFPyL PET/CT for patients with BCR, analysing n = 62 18 F-DCFPyL PET/CT scans in direct comparison with 68 Ga-PSMA PET/CT [13]. Dietlein et al. [13] found higher sensitivity with 18 F-DCFPyL in patients with PSA values between 0.5-3.5 ng/ml (88% with 18 F-DCFPyL versus 66% with 68 Ga- PSMA, p = 0.042). Compared to Dietlein et al., we observed a higher detection efficacy, especially at PSA values <0.5 ng/ml (59% versus 13%, respectively). This difference might be due to the image interpretation protocol applied by Dietlein et al., which required corresponding findings on CT for all PETpositive lesions. Based on current standardised reporting systems, such a requirement is no longer applied for PSMA PET interpretation at our institutions [21,22].
Recently, another 18 F-labelled PSMA tracer was introduced: 18 F-PSMA-1007 [23]. 18 F-PSMA-1007 is only minimally excreted via the urinary tract, which potentially improves visualisation of tumour deposits adjacent to the urinary bladder (mainly local recurrence). Our results with 18  results (e.g. included patient population, PET scanner technique, image reconstruction methods, experience of the PET readers). In particular for cohorts including patients treated with EBRT, such as our cohort, somewhat higher detection rates are generally found in comparison with populations treated with RP only.
In terms of detection of local recurrence, no evident benefit of 18 F-PSMA-1007 over 18 F-DCFPyL is seen. Giesel et al. included only patients with BCR after RP and detected local recurrence in 25% of patients. Rahbar et al. noted local recurrence in 37% of all patients (treated with either EBRT or RP) [24,25]. In our study, local recurrence was detected in 24% of all patients treated with RP and in 37% of the entire population.
Contrary to our finding that PSA at PET/CT is the only predictor of scan positivity, a recent study by Rauscher et al. found that concurrent ADT was also a predictor of a positive scan in multivariable analysis [26]. It should be noted that in our cohort, only 20 patients were receiving ADT at the time of PET/CT, the majority of whom received ADT in combination with EBRT; Rauscher et al. included only patients after RP, all with a PSA <1.0 ng/ml. Overall, the role of ADT in scan outcomes remains incompletely understood, for ADT may upregulate PSMA expression initially [27], but reduce lesion detection efficacy upon longer exposure [28]. Patients who received ADT after prostatectomy due to known metastatic disease without salvage options-in other words, in a palliative setting-were not included in this cohort. Although there is no definition as to where BCR ends in the course of prostate cancer progression, in our opinion, a cohort of patients with BCR should only include patients who are candidates for salvage options before PSMA PET/CT is performed.
Accurate identification of patients with oligometastatic disease is of current interest [29], although the definition of oligometastatic disease remains unclear (either ≤3 or ≤5 metastases). The clinical benefit of (oligo)metastases-directed  treatment has not yet been established [3]. Nevertheless, it seems evident that any success of metastases-directed strategies will depend on accurate imaging studies, as well as adequate timing of diagnostic procedures. From our data it can be observed that performing 18 F-DCFPyL PET/CT soon after diagnosis of BCR (i.e. at lower PSA values) favours detection of oligometastases (Fig. 4). At higher PSA levels (>5.0 ng/ml), more patients are diagnosed with polymetastases (>5). Yet even in these patients, a substantial proportion had oligometastastic disease on 18 F-DCFPyL PET/CT (Fig. 4). An important limitation of the present study, and studies on PSMA PET for BCR in general, is the lack of histopathologic confirmation of PET results [8,12,30]. PSMA PET-detected lesions are often smaller than 1 cm, making biopsy procedures difficult and burdensome for patients. In our study, histologic confirmation of PET findings (CT-guided biopsy, lymph node dissection, prostate biopsy) had been performed in only 15 of our patients, although follow-up of patients from outside our PET centres was often lacking. In 12 of these patients (80%), the malignant nature of detected lesions was confirmed. Overall, these numbers are insufficient to assess the extent of false-positive outcomes (the specificity) in our study. High specificity of PSMA PET has been demonstrated in primary PCa patients, however, where imaging findings can be correlated to histopathology from lymph node dissection (96% specificity with 68 Ga-PSMA [30]; 96-99% specificity with 18 F-DCFPyL [31]). We were also unable to evaluate the sensitivity of 18 F-DCFPyL on a lesion basis, since the true number of PCa metastases remains unknown. PET is inherently limited by its image resolution to the detection of small metastases (<2-4 mm). We should therefore assume that 18 F-DCFPyL PET/CT still underestimates the extent of disease.
Clinically, it is important to realise that improved detection of metastases is only of benefit to patients if followed by appropriate, proven-effective therapeutic strategies. The identification of additional metastases may delay treatment of local recurrences, trigger metastasis-directed treatment, or result in initiation of systemic therapy. None of the clinical outcomes of these (PSMA PET-based) decisions have yet been sufficiently studied in clinical trials [3,29,32].

18
F-DCFPyL PET/CT appears effective for detecting metastases in patients with BCR, even at PSA values <0.5 ng/ml. The detection efficacy appears at least comparable to published results with 68 Ga-PSMA and 18 F-PSMA-1007.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Ethical approval This retrospective study was approved by the institutional review board of the Amsterdam Medical Centers (VU University) and Noordwest Ziekenhuisgroep; the need for written informed consent was waived (review number 2018.453).
Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.