¹⁸F-DCFPyL PET/CT in primary staging of prostate cancer

Primary staging of prostate cancer remains challenging, while correct staging is mandatory for optimal therapy selection and to determine prognosis. Generally prostate cancer spreads to lymph nodes and/or bone before other tissues are affected and therefore screening for metastases at primary staging is primarily focussed at detection of bone and lymph node metastases. According to recent European Association of Urology (EAU) prostate cancer guidelines metastatic screening is recommended for intermediate and high risk prostate cancer, including at least cross-sectional abdominopelvic imaging and ^99mTc-phosphonate bone scan (Mottet et al. 2017).

Different cross-sectional imaging options are available for screening for lymph node metastases, of which abdominopelvic Computed Tomography (CT) and T1-T2-weighted Magnetic Resonance Imaging (MRI) are most commonly used. Assessment of nodal invasion is done by using of the short axis lymph node diameter and morphology. However there is a significant overlap in size of metastatic and non-metastatic lymph nodes and the best cut-off value remains a matter of debate. As a result the sensitivity of CT and MRI is around 40% with specificities around 80% (Hovels et al. 2008; Harisinghani et al. 2003). ¹¹C-choline or ¹⁸F-fluorocholine Positron Emission Tomography/Computed Tomography (Choline PET/CT) provides functional characterisation in addition to morphological characterisation and could therefore overcome the limitations of CT and MRI. Reported sensitivities and specificities for ¹¹C-choline or ¹⁸F-fluorocholine PET/CT are around 50 and 95%, respectively (Evangelista et al. 2013; Mapelli and Picchio 2015).

Due to limited diagnostic accuracy of abovementioned imaging modalities extended Pelvic Lymph Node Dissection (ePLND) is still considered the most accurate procedure for staging of lymph node metastases (Fossati et al. 2017). According to the EAU guidelines ePLND is recommended when risk on lymph node metastasis, as calculated by established prediction models, exceeds 5% (Mottet et al. 2017). Although considered most accurate, also ePLND has suboptimal diagnostic characteristics. Several studies have reported a considerable percentage of positive nodes outside the dissected area, even when no metastases are found in ePLND specimens (Jeschke et al. 2005; Brenot-Rossi et al. 2005; Heidenreich et al. 2002). Furthermore, this invasive procedure is accompanied by significant morbidity while presence of any therapeutic effect is still doubtful (Fossati et al. 2017).

PET/CT with radiopharmaceuticals that target the Prostate Specific Membrane Antigen (PSMA) is increasingly used for imaging of prostate cancer. PSMA is a transmembrane protein that has 100 to 1000 fold higher expression at membranes of prostate cancer cells as compared to normal prostate cells and expression is higher in dedifferentiated tumours (Sokoloff et al. 2000). Initially PSMA PET/CT replaced Choline PET/CT for detection and localisation of lesions responsible for a biochemical recurrence after previous therapies with curative intent. Given the reported higher accuracy, including both better sensitivity and specificity of PSMA targeted radiopharmaceuticals in comparison to Choline PET/CT (Afshar-Oromieh et al. 2014; Bluemel et al. 2016), PET/CT with PSMA targeted radiopharmaceuticals may also play a role in primary staging of prostate cancer.

At present ⁶⁸Ga-HEDB-CC (⁶⁸Ga-PSMA) is the most extensively studied PSMA targeting radiopharmaceutical in literature and also most widely used in clinical practice. However, the role of ¹⁸F-labelled PSMA targeted radiopharmaceuticals is evolving as a result of theoretically favourable imaging characteristics and the possibility to produce relatively large amounts of those tracers in cyclotron facilities (Sanchez-Crespo 2013). Clinical data on PSMA targeted PET/CT for primary staging is relatively scarce, especially for ¹⁸F-labelled PSMA targeting radiopharmaceuticals. Therefore, in this study data is presented of a retrospective cohort of patients that received PET/CT with ¹⁸F-DCFPyL, a promising ¹⁸F-labelled PSMA targeting radiopharmaceutical (Szabo et al. 2015), for staging of primary prostate cancer.

In order to position ¹⁸F-DCFPyL PET/CT between commonly used diagnostic procedures and prediction models we studied different aspects of ¹⁸F-DCFPyL PET/CT. First we report the detection rates of ¹⁸F-DCFPyL at different anatomical localisations and for different categories of serum PSA-values, Gleason-score, T-stage and risk on having lymph node metastases according to established prediction models. Second, functional characterisation of lymph nodes according to increased ¹⁸F-DCFPyL uptake is compared to morphological features of those lymph nodes on the co-registered contrast enhanced CT in order to indicate additional value of ¹⁸F-DCFPyL PET/CT. Third, it is reported for patients with risk on lymph node metastases > 5% according to prediction models, whether ¹⁸F-DCFPyL positive lymph nodes were present at locations that would be resected during ePLND, as well as presence of positive nodes or other metastases outside this area. Finally, the possible clinical impact, which may be derived from the presented data, of ¹⁸F-DCFPyL PET/CT as a diagnostic procedure in primary staging of prostate cancer is discussed.

There is very limited data on the value of ¹⁸F-DCFPyL PET/CT in primary staging of prostate cancer in present literature. ¹⁸F-DCFPyL PET/CT has been intra-individually compared with ¹⁸F-PSMA-1007 for primary staging in a pilot study in 12 prostate cancer patients (Giesel et al. 2017). Imaging with both tracers resulted in identical clinical findings. No histopathological confirmation of metastases is reported in this study. To our knowledge no other data is present in literature on ¹⁸F-DCFPyL PET in primary staging, therefor this study is the first to present data of a large cohort (> 100 patients) in the setting of primary staging. Also for other ¹⁸F-labbeld PSMA targeting radiopharmaceuticals there is no data present on its role in newly diagnosed prostate cancer. For ⁶⁸Ga labelled PSMA targeting radiopharmaceuticals, a recent systematic review focussing on primary staging of prostate cancer shows a substantial variation in methodology and outcomes amongst studies. However it is concluded that the ability of ⁶⁸Ga-PSMA PET to detect malignant lesions is evident across studies, with most studies demonstrating increased detection rates with respect to conventional imaging modalities (Corfield et al. 2018).

All but two studies included a limited number of up to 30 patients. A study by Maurer et al. included 130 patients with intermediate to high risk prostate cancer staged with ⁶⁸Ga-PSMA PET/CT or PET/MRI and compared PET findings for lymph nodes with morphological findings on CT or MRI with histopathological evaluation as the standard of reference (Maurer et al. 2016). In 119 (91.6%) patients increased uptake in the primary tumour was found. Increased tracer uptake was found in lymph nodes in 28 patients (21.5%). Compared to histopathology ⁶⁸Ga-PSMA-PET detected 27 of 41 patients with histologically proven lymph node metastases while 1 of 89 patients without metastatic disease in lymph node was positive on ⁶⁸Ga-PSMA PET. As a result sensitivity and specificity of ⁶⁸Ga-PSMA PET for lymph node metastases was 66 and 99%, respectively. The other large cohort study by Uprimny et al. included 90 patients, which received ⁶⁸Ga-PSMA PET/CT for primary staging (Uprimny et al. 2017). Eighty-two patients (91.1%) demonstrated pathologic tracer accumulation in the primary tumour, 24 patients (26.7%) lymph nodes with pathologic tracer accumulation consistent with metastases were detected and 11 patients (12.2%) revealed lesions suspicious for bone metastases. The relatively high detection rate of the primary tumour in studies with ⁶⁸Ga-PSMA is in line with the results of the present study. However, in the present study metastases in lymph nodes and bone marrow were detected more frequently compared to the studies using ⁶⁸Ga-PSMA. This can possibly be explained by the relatively higher PSA at time of PET/CT in the present cohort (median PSA 25.0 ng/ml) in contrast to the studies using ⁶⁸Ga-PSMA (median PSA respectively 9.7 and 11.5 ng/ml). The ⁶⁸Ga-PSMA studies did not present detection rates for different PSA categories and therefore a fair comparison cannot be made.

According to morphological imaging (contrast enhanced CT), the presented data show that ¹⁸F-DCFPyL PET/CT is superior to morphological criteria found on the co-registered contrast enhanced CT alone, which is in agreement with findings with ⁶⁸Ga-PSMA PET/CT (Corfield et al. 2018). Locoregional lymph node and distant lymph node metastases were detected with ¹⁸F-DCFPyL PET/CT in 33 and 13 patients, respectively, without lymph nodes > 6 mm in these areas on CT. According to ePLND, 57/133 of the patients (43.2%) with risk on lymph node metastases exceeding 5%, had evidence of metastasised disease outside the ePLND area. Twenty of those patients had lymph node metastases only. Patients with metastases outside the ePLND area will not benefit from ePLND and can be excluded for this procedure by ¹⁸F-DCFPyL PET/CT. Twenty-one patients (15.9%) had evidence of lymph node metastases in the ePLND area only. It could be speculated that those patients might benefit from ePLND. Another 54 patients (40.9%) showed no evidence of metastases at all, given the generally moderate sensitivity found in studies with ⁶⁸Ga-PSMA (Maurer et al. 2016; Budaus et al. 2016; van Leeuwen et al. 2017; Rahbar et al. 2016), this category of patients may also benefit from ePLND. Although, the sensitivity of ¹⁸F-DCFPyL in this patient category remains unknown, which emphasizes the need of histopathological confirmed studies with ¹⁸F-DCFPyL PET/CT.

In comparison to established prediction models of risk on lymph node metastases, detection of lymph node metastases with ¹⁸F-DCFPyL PET/CT shows great similarities. In comparison to MSKCC nomograms, ¹⁸F-DCFPyL only finds a lower number of patients with lymph node metastases (45.5%) in the category with a risk between 60.0 and 79.9%. While in comparison with the ROACH formula, ¹⁸F-DCFPyL PET/CT detected at least as much patients with lymph node metastases as predicted in all categories. Those prediction models are based on lymph node dissection templates (Roach 3rd et al. 1994). Therefore the similarities found between those prediction models and ¹⁸F-DCFPyL PET/CT detection rates suggest a good sensitivity of ¹⁸F-DCFPyL PET/CT, which may suggest that ¹⁸F-DCFPyL PET/CT can be used to deselect patients for ePLND if no lymph node metastases are found with ¹⁸F-DCFPyL PET/CT, which would be in contrast to the relatively low sensitivity found for ⁶⁸Ga-PSMA PET/CT. Therefore this finding warrants large prospective trials that compare ¹⁸F-DCFPyL findings with histopathological findings after ePLND in order to position ¹⁸F-DCFPyL PET/CT in the staging algorithm for primary prostate cancer.

Since there is a significant overlap in size of metastatic and non-metastatic lymph nodes the best cut-off value remains a matter of debate. In literature it can be found that a short-axis diameter larger than 6 mm on CT images of patients with prostate cancer, results in specificity for the detection of a malignant nodes of 97% (Oyen et al. 1994). If the threshold is changed to a short-axis diameter larger than 5 mm for metastases (in pelvic malignancies), the specificity drops to 78% (McMahon et al. 2010). Therefore in this study a cut-off value of larger than 6 mm was used for determination of malignant nodes on CT.

Although this cohort shows heterogeneity regarding some aspects, it is representative for the clinical practice in hospitals that treat large numbers of patients with prostate cancer. As an example of heterogeneity this cohort includes 38 patients that received other imaging studies for prostate cancer staging prior to ¹⁸F-DCFPyL PET/CT, which may introduce bias in the cohort. Most of those prior studies had equivocal or negative results for metastases, especially for bone metastases. The pre-test likelihood of presence of metastases in these patients is probably lower than in patients without any prior imaging study, which is supported by the fact that bone metastases were found in 18.5% of patients that had prior imaging procedures and in 29.2% of patients without prior imaging. Therefore, it is likely that the detection rates of ¹⁸F-DCFPyL PET/CT in a non-biased cohort will be at least as high as found in the present cohort.

Another limitation of the present study is the lack of histopathological confirmation of the suspected metastases on ¹⁸F-DCFPyL PET/CT, which is a consequence of the retrospective nature of the study and loss to follow-up of patients, which were referred for ¹⁸F-DCFPyL PET/CT by other hospitals. However, other PSMA targeting radiopharmaceuticals, of which those labelled with ⁶⁸Ga are most extensively studied, show generally high specificities and positive predictive values both exceeding 90% (Maurer et al. 2016; Budaus et al. 2016; van Leeuwen et al. 2017; Rahbar et al. 2016; Afshar-Oromieh et al. 2015). Therefore lesions with increased ¹⁸F-DCFPyL, which fit in the pattern of metastatic spread of prostate cancer, should be considered as highly suggestive of prostate cancer.

¹⁸F-DCFPyL PET/CT shows more lymph nodes with pathological characteristics as compared to the co-registered contrast enhanced CT alone. ¹⁸F-DCFPyL PET/CT detects lesions suspicious for metastases outside the ePLND area in 43% of patients, with risk on lymph node metastases exceeding 5%, which therefore may be excluded for ePLND. ¹⁸F-DCFPyL PET/CT detection rates are in line with established prediction models of risk on lymph node metastases. Large prospective trials that compare ¹⁸F-DCFPyL findings with histopathological findings after ePLND are needed in order elucidate sensitivity of ¹⁸F-DCFPyL PET/CT and to position ¹⁸F-DCFPyL PET/CT in the staging algorithm for primary prostate cancer.