Methods: We searched MEDLINE using the terms ‘prostate cancer’, ‘PET’, ‘PET/CT’ and ‘PET/MR’). The current review was limited to 18F-NaF PET/CT, choline-based PET/CT, fluciclovine PET/CT and PSMA-targeted PET/CT, as these modalities have been the most widely adopted.
Results: NaF PET/CT has shown efficacy in detecting bone metastases with high sensitivity, but relatively low specificity. Currently, choline PET/CT has been the most extensively studied modality. Although having superior specificity, choline PET/CT suffers from low sensitivity, especially at low PSA levels. Nevertheless, choline PET/CT was found to significantly improve upon conventional imaging modalities (CIM) in the detection of metastatic lesions at biochemical recurrence (BCR). Newer methods using fluciclovine and PSMA-targeted radiotracers have preliminarily demonstrated great promise in primary and recurrent staging of prostate cancer. However, their superior efficacy awaits confirmation in larger series.
Conclusions: PET/CT has emerged as a promising staging modality for both primary and recurrent prostate cancer. Newer tracers have increased detection accuracies for small, incipient metastatic foci. The clinical implications of these occult PET/ CT detected disease foci require organized evaluation. Efforts should be aimed at defining their natural history as well as responsiveness and impact of metastasis-directed therapy.
INTRODUCTION: Prostate cancer (PCa) is the most common non-cutaneous malignancy in men and the second leading cause of cancer-related death in the United States, with 180,890 cases leading to 26,120 mortalities per year1. Despite major advances, current diagnostic modalities fall short of accuracy standards required for effective management of the disease. Specifically, improved strategies are needed for localizing disease foci within the prostate on primary diagnosis, identifying metastatic sites at primary diagnosis, localizing recurrent disease foci upon BCR after primary treatment and measuring disease response as it relates to the inherent biology.
Traditionally, trans-rectal ultrasound-guided biopsy was used for disease localization within the prostate2,3. Multiparametric MRI (mpMRI), however, has recently evolved into the imaging modality of choice for the identification of PCa in patients with high index of suspicion but negative histologic examinations4,5. Despite its improved sensitivity for clinically significant lesions6,7. mpMRI’s accuracy is far from perfect8,9.
In patients diagnosed with intermediate- to high-risk PCa and those with BCR, current guidelines recommend disease staging using CIM including CT or MRI of the abdomen and pelvis as well as whole-body bone scintigraphy2,3. Unfortunately, these methods frequently understage metastatic disease. As anatomical imaging techniques such as CT or MRI depend solely on morphological features for identifying metastatic disease, lesions smaller than the 8–10 mm threshold are frequently missed10,11. On the other hand, malignant lytic bone lesions may have little uptake on bone scan, whereas areas of benign degenerative changes can be mistaken for osteoblastic osseous metastases12.
The unmet need for accurate and precise localization and staging for primary and recurrent PCa has ushered in various alternative imaging methods. The most promising and thoroughly investigated thus far has been the PET/CT or PET/MRI. Using these combinations, high-resolution 3D anatomical depictions are complemented by functional imaging13. Herein, we provide an overview of the evidence for various methods of PET scan in the abovementioned clinical scenarios.
EVIDENCE ACQUISITION: MEDLINE search of the English literature was conducted from its inception to January 2017 using the following terms: ‘prostate cancer’, ‘PET’, ‘PET/CT’ and ‘PET/MR’). The current review was limited to 18F-NaF PET/CT, choline-based PET/CT, fluciclovine PET/CT and PSMAtargeted PET/CT, as these modalities have been the most widely adopted. Reference list of the pertinent articles were reviewed to augment the source material. The full texts of selected studies focusing on the relevant topic to this manuscript were then reviewed and synthesized by the first and senior authors. Other co-authors added or removed articles and consensus was reached regarding the overall structure of the manuscript. An initial draft was then written and circulated to all co-authors for critical review. After several iterations, consensus regarding the content of the manuscript was reached and submitted herein.
18F-NaF PET/CT: 18F-NaF is a positron emitter that binds to osteoblastic sites of new bone formation14. Therefore, positive findings with 18F-NaF PET/CT could be due to both benign and malignant processes involving the skeleton15. Compared to conventional 99mTc-MDP scintigraphy, 18F-NaF PET/CT has less plasma protein binding, higher and faster bone uptake, improved spatial resolution and increased target-tobackground ratio16-18. Semiquantitative measurements of standardized uptake value (SUV) can be effectively used to distinguish malignant from benign lesions19. In addition, it is able to detect both lytic and blastic osseous lesions, as lytic lesions usually present with a rim of osteoblastic activity on their periphery20 (Table 1).
Table 1 NaF PET/CT
PRIMARY STAGING: Most early studies indicated excellent sensitivity and specificity in detecting osseous lesions (Fig. 1)21-23. In a more recent study, however, Poulsen et al. pointed out the low specificity of 18F-NaF PET/CT (54%) when compared to MRI findings. This was attributed to false positive readings of benign degenerative or inflammatory lesions frequently found in the elderly population suspected for metastatic PCa 24. On the other hand, its high sensitivity was confirmed by other series, proving superior to even choline-based PET/CT25.
The clinical significance of the high sensitivity coupled with low specificity associated with 18F-NaF PET/CT has yet to be established. While some authors recommend its use as the tracer of choice to detect skeletal metastases25, others have reported that the discovery of additional metastatic foci by 18F-NaF PET/CT did not significantly alter management24. Furthermore, verification of 18FNaF PET/CT-positive lesions may be cumbersome. Examination of the data from the National Oncologic PET Registry found that while 18F-NaF PET/CT was the preferred imaging modality in approximately half the patients, management strategies were changed in only 12.2–15.8%26.
Fig. 1 A 67-year-old male with metastatic prostate cancer. Axial 18F-NaF PET (a), CT (b) and fused PET/CT images (c) demonstrate a focus of abnormally increased radiotracer activity (SUVmax 34.7) corresponding to a sclerotic metastasis in the vertebral body of T7 (arrows). Whole-body MIP image (d) demonstrates additional metastases in the cervical spine, thoracic spine, lumbar spine, pelvis, scapulae, left proximal humerus and left proximal femur
RECURRENT STAGING: Few studies investigated the efficacy of 18F-NaF PET/CT for recurrent disease staging. In 37 patients with BCR with median PSA of 3.2 ng/mL, Jadvar et al.27 reported sensitivity and specificity of 42.9% and 82.6%, respectively. The discrepantly low sensitivity and high specificity in recurrent PCa as compared to primary staging needs further investigation.
STRATEGIES FOR IMPROVEMENT: Beyond the simple qualitative assessment, semi-quantitative SUV measurement on 18F-NaF PET/CT-positive foci can be used to distinguish malignant from benign disease. For example, in castrate-resistant prostate cancer (CRPC) patients, SUVmax > 45–50 indicated malignant disease14,19. When traced through the treatment course, SUV increases of ≥50.4% correlated with poorer oncologic outcomes28.
18F- and 11C CHOLINE: Choline based PET/CT has been the most extensively studied for the detection of PCa in various settings (Table 2). Choline is the precursor for phosphatidylcholine, a major component of the cellular membrane. Accumulation of choline is observed in PCa as it is increasingly incorporated into the proliferating tumour cell membranes29. Choline analogs radiolabelled with 11C and 18F have been used with similar efficacies30. Both have shown clear superiority over 18FFDG30. While the 18F-choline tracer has a much longer half-life (T1/2 = 109.8 min; compared to T1/2 = 20.4 min for 11C), making its use possible in PET centers without an on-site cyclotron, it is also excreted in the urine within minutes of injection, making assessment of the prostatic bed difficult31.
Table 2 Choline PET/CT
LOCAL DETECTION: The shortcomings of choline-based PET/CT radiotracers for the local detection and staging of PCa has been well documented. Although showing reliable sensitivity for localizing PCa nodules >5 mm, 11C-choline PET/CT had a dismal 4% sensitivity for smaller lesions32. Moreover, areas of diffuse high uptake often corresponded to benign prostatic tissue. Semiquantitative analysis using SUVmax was not useful in distinguishing malignant from benign lesions33,34. In comparison studies with mpMRI, the accuracy of tumour detection, as well as the ability to detect extraprostatic extension, were found to be inferior 35,36.
PRIMARY STAGING: The sensitivity of choline PET/CT for detecting nodal metastases on primary staging was equally poor 37-39. High false-negative rates were attributed to the limited spatial resolution of PET/CT scanners (~4–5 mm) and the lack of metabolic uptake by certain nodal metastases. In subsequent large surgical series using histologic reference standards, reported sensitivity and specificity ranged between 45–56% and 94–96%, respectively40,41. However, improved sensitivity was demonstrated in patients with high D’Amico risk PCa as well as for larger LNM > 5 mm40,42.
Many investigators have compared the efficacy of choline PET/CT against other imaging modalities for primary LNM staging. Although choline PET/CT has consistently been demonstrated to have higher accuracy for LNM detection than CT scan42,43, its superiority over diffusion-weighted imaging MRI is less clear. Several studies showed low sensitivity for LNM detection in both imaging modalities43,44, while Pinaquy et al.36 showed a clear advantage for choline PET/CT. Through post hoc analysis, Vag et al.45 calibrated the ADC and SUV thresholds to optimize the detection of LNM, and found both modalities to outperform CIM.
The ability of the choline PET/CT to detect PCa bone metastases has been compared to that of 99mTc-MDP bone scintigraphy, MRI and 18F-NaF PET/CT. Choline PET/CT has repeatedly shown superior accuracy than bone scan due to its higher image resolution and ability to detect bone marrow metastases25,42,46,47. Compared to 18F-NaF PET/CT, some studies indicated that choline PET had lower sensitivity but higher specificity24,25. However, a summary of the literature revealed similar accuracies48.
RECURRENT STAGING: Upon BCR, choline PET/CT was only able to detect 54–73% of local relapsing lesions, clearly underperforming mpMRI49–52. A recent meta-analysis of 29 studies with well-defined reference standards showed pooled sensitivity of merely 61%53. Where choline based PET/CT has demonstrated diagnostic value is in the detection of nodal metastases after primary therapy failure. Although perlesion accuracies were similar as when used for primary staging54–58, choline PET/CT’s detection rates far exceeded those of FDG-PET 30, 56 and mpMRI51. More importantly, choline PET/CT findings at BCR have been effectively used to direct site-specific therapy. During salvage radiation, choline PET/CT-guided target volume expansion and dose escalation led to improved disease free survival 59–61. Alternatively, targeted helical tomotherapy can be performed with simultaneous integrated boosts or pulsed-dose-rate brachytherapy to achieve biochemical response62, 63.
While still experimental, retrospective data suggest salvage pelvic lymph node dissection (sPLND) should be considered in patients with limited nodal recurrence, good performance status and long life expectancy 64, 65. Rigatti et al. 65 first demonstrated the feasibility of sitespecific sPLND guided by choline PET/CT, achieving biochemical response (PSA < 0.2 ng/mL) with or without adjuvant hormonal therapy. At a median follow up of 81.1 mo, 38% remained free of clinical recurrence (CR)66. With prudent selection, sPLND can delay implementation of systemic therapy and the ensuing onset of castration resistance. Furthermore, Rischke et al. 67 showed improved cancer control with adjuvant radiotherapy after sPLND, with an impressive 70.7% 5-year BCR-free survival.
The value of recurrent staging by choline PET/CT is augmented by its improved recognition of skeletal metastases (Fig. 2). Upon BCR after RP, choline PET/CT detected occult bone lesions in 14.6% of patients with negative bone scans, and was shown to be equipotent as mpMRI51, 68. An added advantage of the choline PET/ CT is its ability to distinguish the more dangerous osteolytic lesions69. Corrective treatment regimens can then be implemented in a timely manner to prevent skeletal events.
Several meta-analyses have been performed to summarize the diagnostic accuracy of choline PET/CT. For initial staging, per lesion sensitivity was reported to be as low as 49.2% 70. For patients with BCR, sensitivity and specificity were 85% and 88%, respectively71. Variable detection rates for both initial staging (11–100%) and recurrent staging (21–82%) were attributed to the heterogeneity in the study population, study size, and radiology equipment and operator skill72.
Fig. 2 A 68-year-old male with prostate adenocarcinoma status post radical prostatectomy and biochemical relapse (PSA = 4.4 ng/mL). Axial fused PET/CT (a), CT (b) and PET (c) images demonstrate focal increased 11C-choline in the left acetabulum (SUVmax 6.1), compatible with bone metastasis (arrows). The patient was then treated with radiation therapy and androgen deprivation therapy. Follow-up axial fused PET/CT (d), CT (e) and PET (d) images demonstrate interval resolution of the previously seen focus of increased 11C-choline in the left acetabulum. After treatment, the PSA decreased to <0.1 ng/mL
STRATEGIES FOR IMPROVEMENT: To identify the population in whom choline PET/CT performs best, several studies analysed subgroups stratified by PSA, PSA kinetics and tumour stage. Most indicated a positive correlation between choline PET/CT accuracy with increasing PSA, with the optimal threshold to maximize metastatic detection while minimizing negative tests between 1 and 2 ng/ mL 49, 73–75. At levels above 2 ng/mL, the majority of the reported sensitivities were above 80% 49, 73, 74.
However, to be useful in guiding sRT within the therapeutic window, choline PET/CT also needs to demonstrate efficacy at low PSA ranges after RP failure 76. To that end, Mamede et al. 77 found it capable of identifying local and distant recurrences in merely 21% of patients with PSA < 0.5 ng/mL. To improve detection rates in this range, Castellucci et al. 78 found PSAdt to be a significant predictor of positive PET/CT findings, with increasing PCa detection in patients with PSAdt < 6 months 78, 79. Overall, choline PET/CT is likely to be useful when PSA > 2 ng/mL and/or PSAdt < 6 months.
Unlike with PSA, the influence of androgen deprivation therapy (ADT) on the accuracy of choline PET/CT is not as clear. Several studies have shown ADT to differentially affect choline PET tracer uptake by androgen sensitive and resistant PCa cells80–82. Two small studies demonstrated attenuated choline PET signals after the initiation of ADT in hormone naive patients 83, 84. Additionally, interruption of ADT led to the reappearance of PET avid lesions85. Similar attenuation in image signaling was observed upon biochemical response to newer ADT agents such as abiraterone 86 and enzalutamide 87. Conversely, the attenuation is less obvious after ADT treatment in patients with BCR, presumably due to the increased composition of androgen-resistant PCa49, 75, 78, 88. Nevertheless, the effect of ADT on CRPC cannot be properly assessed without paired imaging studies while on and off ADT after biochemical progression89.
IMPACT ON CLINICAL DECISION MAKING: Choline PET/CT appears to have prognostic value, with positive 11C-choline PET/CT findings predicting shorter cancer-specific survival in BCR patients on ADT 90. Different groups have also shown significant rates (46.7–48%) of therapeutic strategy alterations based on choline PET/CT findings 91, 92. However, whether these altered strategies led to improved outcomes is unknown. Despite its low sensitivity, choline PET/CT is a good option for PCa staging, most helpful when used to detect recurrent cancer after primary treatment failure. Choline PET/CT has been quickly adopted into clinical practice throughout the world. However, caution must be exercised in interpreting the data until prospective evaluation determines whether the enhanced disease detection can be translated into improved patient outcomes.
18F-FACBC (FLUCICLOVINE): 18F-FACBC (1-amino-3-fluorine 18F-fluorocyclobutane-1- carboxylic acid/fluciclovine) is a synthetic amino-acid analog that has been used as a tracer for PCa, taking advantage of the carcinoma’s increased energy demand and substrate transport (Table 3). In particular, fluciclovine transport is thought to be facilitated by the system ASC transporter ASCT2 and system L transporter LAT1 93. This agent’s favourable biodistribution, as well as slow renal excretion, make it an ideal PET tracer for metastatic lesion detection 94. Additionally, its long half-life as a fluorinated radiotracer enables use without an onsite cyclotron 95. On the other hand, a major disadvantage of the 18F-fluciclovine PET tracer is its non-specific uptake by benign inflammatory prostatic tissue 96.
Table 3 Fluciclovine PET/CT
LOCAL DETECTION: Due to the non-specific uptake, 18F-fluciclovine PET/CT performed poorly in primary PCa localization 97, 98. Sensitivity and specificity were inferior to those of mpMRI. However, the highest PPV was achieved when MRI was used in conjunction with 18F-fluciclovine PET/CT. As such, although not qualifying as an independent modality for primary tumour localization, 18F-fluciclovine PET/CT may act as a useful adjunct.
PRIMARY STAGING: On primary staging, 18F-fluciclovine PET/CT had high concordance with CIM, but failed to detect nodal lesions <5 mm 99. Additional industry sponsored Phase 3b trials are ongoing in the United States and Europe to assess its efficacy for primary staging of PCa.
RECURRENT STAGING: In contrast, 18F-fluciclovine PET/CT has proven valuable for the detection of recurrent PCa after treatment failure (Fig. 3). In a cohort suspected for PCa recurrence with negative bone scintigraphy, Schuster et al. 100 demonstrated sensitivity and specificity of 90.2% and 40%, respectively, for recurrence within the prostatic fossa and 55% and 96.7%, respectively, for nodal and distant recurrences. Detection rates far exceeded those with PSMA-targeted 111In-capromab pendetide (ProstaScint, Jazz Pharmaceuticals, USA) SPECT as well as contrastenhanced CT 100, 101. Another prospective trial demonstrated comparable accuracy with 11C-choline PET/ CT. However, on subgroup analyses, fluciclovine PET/CT was found to have higher sensitivity across almost all PSA ranges102. Additionally, it was shown to have more favourable bio-distribution and higher lesion conspicuity. In a recent meta-analysis summarizing findings from six studies consisting of 251 patients, AUC was found to be 0.93 103.
Fig. 3 A 65-year-old male with prostate cancer status post radical prostatectomy with biochemical relapse (PSA 1.6 ng/mL). Axial fused PET/CT (a), CT (b) and PET (c) images of the pelvis demonstrate mild 18F- fluciclovine activity (SUVmax 1.9) localizing to a 0.7 cm nodal metastasis in the right internal iliac region (arrows)
IMPACT ON CLINICAL DECISION MAKING: In clinical practice, findings on 18F-fluciclovine PET/CT influenced radiotherapy planning in over 40% of the patients104. As pertaining to choline PET/CT, whether these reflex changes in management are actually impacting disease outcomes is less clear. Nevertheless, the US FDA approved 18F-fluciclovine PET tracer to be used for the detection of recurrent PCa after BCR. As an alternative to choline PET/CT, 18F-fluciclovine PET/CT is best used for the identification of borderline nodal metastases ranging from 5 to 15 mm in diameter. Anecdotal evidence also suggests higher sensitivity at lower PSA thresholds and for lytic or mixed skeletal lesions found in metastatic PCa.
68Ga- and 18F-LABELLED PSMA INHIBITORS: Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein normally found in the cytoplasm or on the apical side of the prostatic epithelium 105. During neoplastic transformation, PSMA is transferred to the luminal side of the epithelium, resulting in 100–1000-fold higher expression on the cell surface106. PSMA expression had been linked to increased cancer aggressiveness as well as progression to androgen independence 107.
PSMA’s large extracellular domain enables conspicuous targeting for radiolabelled molecules. Antibody binding activates PSMA’s cytoplasmic internalization motif, leading to internalization of the antigen–antibody complex, further improving imaging sensitivity 105. Multiple efforts have been made to target both intra- and extracellular domains of PSMA using radiolabelled antibodies and small molecular ligands. To date, only the radiolabelled anti-PSMA antibody targeting intracellular epitope (7E11) (ProstaScint®, Jazz Pharmaceuticals, USA) has been approved by the FDA 105.
The molecular structure of the active substrate binding site on PSMA has been extensively studied108. Urea-based small molecules were found to have high affinity and specificity for PSMA as well as efficient internalization in LNCaP cells 109. Moreover, these agents have the advantage of rapid clearance from non-target tissue, making them ideal tracers for PCa detection 105.
68Ga-PSMA-HBED-CC: Eder et al. first described using the 68Ga-labelled ligand inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (68GaPSMA-HBED-CC or 68Ga-PSMA-11) for PSMAtargeted PET imaging109. Since then, 68Ga-PSMA-11 has shown promise as a valuable diagnostic PET tracer due to the ease of its radiolabelling, favourable biodistribution, specificity for PCa cells and rapid non-target clearance 105 (Table 4).
Table 4 68Ga-PSMA-HBEDCC
LOCAL DETECTION: Previous discussion has alluded to the imperfect local detection of PCa by mpMRI. Despite its established value in the detection of PCa after inconclusive biopsy findings110, mpMRI is often incapable of distinguishing malignant lesions from BPH nodules111. Furthermore, image quality is hindered by the inflammatory and hemorrhagic changes after prostate biopsies, precluding its use until 3–4 months after biopsies112.
As a result, strategies to improve the efficacy of local PCa detection have been sought. One such method is combined PET/MRI, in which the anatomical details on MRI is complemented by the metabolic activity shown on PET 113. Despite its theoretical advantages, such a strategy has largely failed to produce meaningful clinical benefit, until it incorporated 68Ga-PSMA-11 as PET tracer. Eiber et al. found sensitivity and specificity improving from 48% and 82%, respectively, for mpMRI alone, to 76% and 97%, respectively, for combined 68Ga-PSMA-11 PET/MRI 114. On separate analyses, both mpMRI and 68Ga-PSMA-11 PET complemented each other by detecting lesions not found on the other modality.
PRIMARY STAGING: To stage newly diagnosed PCa using 68Ga-PSMA-11 PET/ CT, some of the tracer’s characteristics must be considered. First, up to 10% of PCa do not overexpress PSMA115. In patients with PSMA-negative primary tumours, staging with PSMA PET/CT is not recommended. Secondly, PSMA expression in a primary tumor and LNM have been shown to be higher than in bone metastases116. Despite these findings, PSMA still outperformed CIM in the detection of skeletal lesions117 (Fig. 4). Moreover, 68GaPSMA-11 PET/CT is capable of detecting rare visceral lesions, such as brain metastases, which can easily be missed by the standard staging protocol118.
Early on, a modest 33% sensitivity was reported for staging patients with high-risk PCa119. On the other hand, PET-positive lesions were highly specific for malignancy. The size of the LNM was found to be a critical determinant of PET positivity. Subsequently, higher sensitivities ranging from 66% to 88% were reported in larger series incorporating robust histologic reference standards115, 120. Furthermore, a significant proportion of the false-negative findings was associated with PSMA-negative primary tumours. In spite of these caveats, 68Ga-PSMA-11 PET/CT was consistently found to outperform MRI and CT.
Fig. 4 A 78-year-old male with biochemical recurrent prostate cancer (PSA 1.18 ng/mL) after radical prostatectomy 4 years ago (pT4 pN0 (0/20) R1 Gleason-score 9, initial PSA 13 ng/mL) followed by adjuvant ADT 68Ga-PSMA-11 PET/CT (d–f) shows three highly suspicious lesions with high tracer uptake in the manubrium sterni, a thoracic vertebra and in the left hip. All lesions do not demonstrate a morphological finding in the corresponding CT (a–c).
RECURRENT STAGING: In the largest study of patients with recurrent disease, Afshar-Oromieh et al. found sensitivity and specificity of 76.6% and 100%, respectively, in 319 patients with median PSA of 4.6 ng/mL 121. Excellent sensitivity was maintained in a cohort with mean PSA under 2 ng/mL 112. In a recent meta-analysis, the detection rate was 76% for patients with BCR, and 42% and 58% in those with PSA ranging from 0–0.2 to 0.2–1 ng/mL, respectively122.
Three studies compared the efficacy of lesion detection by 68Ga-PSMA-11 and 18F-choline PET/CT in patients with BCR 123–125. While generally performing better than 18F-choline PET/CT, the true advantage of 68Ga-PSMA-11 PET/CT lied in the detection of metastases in patients with PSA under 2 ng/mL. In patients with PSA ranging from 0.5 to 2 ng/mL, detection rates using 68Ga-PSMA-11 PET/CT and 18F-choline PET/CT were 69% and 31%, respectively (Fig. 5). For PSA < 0.5 ng/mL, the respective detection rates were 50% vs. 12.5%. Overall, the evidence available strongly supports the use of 68Ga-PSMA-11 PET/CT for recurrence staging.
Fig. 5 A 61-year-old male with biochemical persistent prostate cancer after radical prostatectomy 7 months ago (pT3a pN0 (0/25) R0 Gleason-score 8, initial PSA 10.3 ng/mL) and incomplete PSA response (PSA-value 0.8 ng/mL). 68Ga-PSMA-11 PET/MR (b) demonstrates high tracer uptake in a morphologically unsuspicious pararectal lymph node indicating a lymph node metastasis (a). Subsequent secondary lymphadenectomy (PSMA-radio-guided surgery) validated a solitary lymph node metastasis.
STRATEGIES FOR IMPROVEMENT: As seen with choline PET/CT, detection rates correlated with increasing PSA levels. However, even with PSA below 0.5 ng/mL, detection rates exceeded 50%126. With salvage radiotherapy known to maximally benefit patients with low PSA127, 68Ga-PSMA-11 PET/CT’s ability for early detection of metastatic lesions may be especially useful in directing salvage therapy. However, current guidelines on salvage radiotherapy have been restricted to CIM findings heretofore128. It is unknown whether curative therapy should be changed based on metastatic findings on PSMA PET/CT.
Detection rates were also found to be increased with the use of ADT 121, 126. In fact, previous animal studies demonstrated that quantitative measurement of PSMA expression with PET scan can be used as a surrogate marker to monitor androgen receptor signaling 129. Used in this way, PSMA PET/CT has the potential to act as a noninvasive marker for response to ADT, and can guide treatment planning for patients whose cancer is not responsive to androgen blockade.
Another strategy to further enhance metastatic detection is by using gamma emitting 111In-PSMA tracer for intraoperative guidance in patients with positive 68Ga-PSMA-11 PET/CT lesions130. Maurer et al. found this strategy to not only facilitate complete surgical resection of predetermined metastatic lesions but also helped to detect lesions missed on the preoperative 68Ga-PSMA-11 PET/CT. As the initial reports consisted of only 31 patients, further studies with larger sample sizes are awaited to prove generalizability.
IMPACT ON CLINICAL DECISION MAKING: As a novel PET agent, few studies have evaluated the impact of 68Ga-PSMA-11 PET/CT findings on clinical practice. Sterzing et al. assessed radiotherapy planning in a mixed group of 57 patients with primary and recurrent PCa, and found staging to be changed in 51% of the patients based on 68Ga-PSMA-11 PET/CT findings. The change in staging also led to adjustments in the radiotherapy regimen131.
FLUORINATED PSMA-TARGETED RADIOTRACERS: Besides 68Ga-PSMA-11, other radiolabelled, urea-based small molecules targeting PSMA have also been described 132, 133. Of these, 18F-labelled PSMA inhibitors have shown great promise and may offer several advantages over 68Ga-PSMA-11 (Table 5). With its longer half-life (~ 109 min vs. 68 min for 68Ga), 18F can be produced en mass at a central site and distributed to satellite locations via preexisting distribution infrastructures (e.g. PETNET in the United States) 134 (other PET tracers available via PETNET include 18F-NaF, 18F Choline, and 18F-FACBC). Compared to 68Ga, 18F emitted positrons have lower energy, require shorter deceleration distances in human tissue, and creates sharper PET images as a result. In addition, 18F tracer doses can be maximized to enhance imaging statistics. Together, these properties lead to improved lesion conspicuity and may aid in the identification of subcentimeter LNM135.
Thus far, three different 18F-labelled radiotracers, N- [N-[(S)-1,3-dicarboxypropl]-4-[18F]fluorobenzyl-L-cysteine ( 18F-DCFBC), 2-(3-136-Ureido)-Pentanedioic Acid (18FDCFPyL) and 18F-PSMA-1007 have shown efficacy in detecting PCa. Of these, 18F-DCFPyL is the secondgeneration agent that is the furthest along in clinical development.
Table 5 18F-PSMA
18F-DCFBC
LOCAL DETECTION: Rowe et al.137 compared primary cancer localization within the prostate using 18F-DCFBC PET/CT vs. mpMRI. Imaging findings were then correlated with 12-core biopsy results. Although having inferior per segment sensitivity for PCa detection, 18F-DCFBC PET/CT reliably detected clinically significant tumours with Gleason scores ≥8 and volumes ≥1 mL 137.
PRIMARY STAGING: Feasibility and biodistribution of 18F-DCFBC was first described by Cho et al. Subsequently, in a small proof-of-concept study, the same authors demonstrated 18F-DCFBC PET/CT having superior detection rates than CIM in both hormone naive and resistant patients 138.
18F-DCFPyL
PRIMARY STAGING: By comparison, a stronger case has been made for the use of the second generation tracer, 18F-DCFPyL 136. Compared to its predecessor 18F-DCFBC, 18F-DCFPyL has higher uptake by target tissues as well as lower blood pool activity. In the clinical setting, primary staging using 18F-DCFPyL PET/CT has also been demonstrated to be superior over CIM133, 139. Additionally, Rowe et al. 140 found 18F-DCFPyL PET/CT capable of detecting a large number of bone lesions missed on both 99mTC-MDP bone scan as well as 18F-NaF PET/CT.
RECURRENT STAGING: For recurrent staging, the performance of the 18F-DCFPyL PET/CT has been tested against the high standards set by 68Ga-PSMA-11 PET/CT 135. In a small cohort of 14 patients, 18F-DCFPyL PET/CT demonstrated higher tumor-to-background PET ratio, enabling detection of metastatic lesions in three of the patients. 18F-DCFPyL is currently being studied in a multicentre phase II/III study with the intention to be registered by the FDA (NCT 02981368). An example of recurrent staging by 18FDCFPyL PET/CT is shown in Fig. 6.
Fig. 6 A 66-year-old male biochemically recurrent prostate cancer (PSA 1.5 ng/mL) 2 years after undergoing a radical prostatectomy (Gleason 4 + 4 = 8, pT2N0R0). The patient was imaged with PSMA-targeted 18F-DCFPyL PET/CT. Fused PET/CT (a, b) and maximal intensity projection (c) demonstrate a positive pelvic lymph node (a) as well as a soft-tissue lesion lateral to the obturator internus muscle (b)
ADDITIONAL TRACERS: Additional 18F-labelled PET tracers are currently under investigation. Of these, 18F-PSMA-17 has already shown efficacy in humans 141. 18F-labeled triazolylphenyl ureas and 18F-10a are just two of the myriad 18F-labelled PSMAtargeted compounds in preclinical development today 142, 143. As mentioned above, an 89Zr-labelled PSMA-targeted tracer is also under development.
Other identified targets for PET tracers include gastrin-releasing peptide receptor (GRP) and uPAR, both highly expressed in PCa. Various radiolabels have been used to tag ligands of these receptors to specifically detect PCa lesions on primary and recurrent staging 144, 145. Although several of these tracers hold promise, in-human experiences are still lacking.
DISCUSSION ON CLINICAL IMPLICATIONS: Despite the enthusiasm surrounding PET imaging for PCa detection, additional information is needed to couple this exciting novel technology to improved patient outcomes. First, well-designed studies in homogenous populations must be carried out with stringent histologic correlation to establish the true sensitivity and specificity of novel PET modalities. Particularly for primary staging, the clinicopathologic characteristics in patients for whom metastatic workup is mandated needs to be clearly delineated. Only then can meaningful detection rates and accurate information be gathered and compared amongst the different modalities. The specificities reported in the studies reviewed herein need to be viewed in the context of the reference standard. Selective lesion biopsies in the majority of the studies make reported negative predictive value and specificities unreliable.
More importantly, the implications of metastatic findings on primary and recurrent staging need to be explored. First, we must advance our understanding of the biology of these incipient lesions. As pointed out by Murphy et al. 146, any image taken of a cancer is merely a snapshot that does not inform the kinetics of progression. To verify this, serial PET/ CT imaging can be used to delineate the natural history of these lesions. In turn, their transformation can be correlated with overall disease progression and survival. If proven to be true, the paradigm of metastatic disease in PCa may be fundamentally altered. As seen with other genitourinary cancers, conservative treatment strategies can be effectively undertaken in highly selective metastatic cases 147.
Equally important, we must not repeat the mistake of ignoring the consequences of overtreatment, as seen previously with PCa screening. The therapeutic benefit derived from treatment of the metastatic lesion must be measured within the context of overall disease progression 146. To this end, emerging data does suggest control of disease spread with stereotactic body radiotherapy for oligometastatic PCa patients 148. However, such studies often neglect the effects of stage migration made possible with the increasingly sensitive technology.
In addition, the role of primary tumour extirpation in the setting of these incipient metastatic lesions needs to be clearly defined. Cytoreductive prostatectomies have been suggested to provide a survival benefit and its efficacy is currently being tested in ongoing prospective randomized trials 149. In the absence of prospective data assessing the prognostic/predictive capabilities of these newer imaging modalities, aggressive local therapies should not be abandoned due to the detection of indolent metastatic lesions.
Finally, to widely implement these novel technologies, logistic barriers must be overcome. Tracer development requires commercialization, the distribution must be optimized, operational procedures need to be standardized, and consensus must be reached over the interpretation of the results 150, 151. Most importantly, adoption by insurance payment systems must be sought. Though much has yet to be learned, PET/CT and PET/MRI have the potential to offer unprecedented diagnostic prowess leading to significant improvement in the way we manage prostate cancer.
Conflict of Interest MAG has served as a consultant and received research support from Progenics Pharmaceuticals, Inc., the licensee of 18F-DCFPyL.
Authors: Roger Li1, Gregory C. Ravizzini2, Michael A. Gorin3, Tobias Maurer4, Matthias Eiber5, Matthew R. Cooperberg6, Mehrdad Alemozzaffar7, Matthew K. Tollefson8, Scott E. Delacroix9, Brian F. Chapin1
Author Affiliation:
1. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4. Department of Urology, Technical University of Munich, Munich, Germany
5. Department of Nuclear Medicine, Technical University of Munich, Munich, Germany
6. Department of Urology, UCSF, San Francisco, CA, USA
7. Department of Urology, Emory University, Atlanta, GA, USA
8. Department of Urology, Mayo Clinic, Rochester, MN, USA
9. Department of Urology, Louisiana State University, New Orleans, LA, USA
Read More: A Commentary from the Associate Editor of PCAN - J. Kellogg Parsons, MD, MHS
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Received: 5 June 2017 / Accepted: 28 July 2017 / Published online: 11 December 2017 © Macmillan Publishers Limited, part of Springer Nature 2018