Current use of PSMA–PET in prostate
`cancer management
`
`Tobias Maurer1, Matthias Eiber2, Markus Schwaiger2 and Jürgen E. Gschwend1
`Abstract | Currently, the findings of imaging procedures used for detection or staging of prostate
`cancer depend on morphology of lymph nodes or bone metabolism and do not always meet
`diagnostic needs. Prostate-specific membrane antigen (PSMA), a transmembrane protein that
`has considerable overexpression on most prostate cancer cells, has gained increasing interest as
`a target molecule for imaging. To date, several small compounds for labelling PSMA have been
`developed and are currently being investigated as imaging probes for PET with the 68Ga-labelled
`PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC being the most widely studied agent.
`68Ga-PSMA–PET imaging in combination with multiparametric MRI (mpMRI) might provide
`additional molecular information on cancer localization within the prostate. In patients with
`primary prostate cancer of intermediate-risk to high-risk, PSMA-based imaging has been
`reported to improve detection of metastatic disease compared with CT or mpMRI, rendering
`additional cross-sectional imaging or bone scintigraphy unnecessary. Furthermore, in patients
`with biochemically recurrent prostate cancer, use of 68Ga-PSMA–PET imaging has been shown
`to increase detection of metastatic sites, even at low serum PSA values, compared with
`conventional imaging or PET examination with different tracers. Thus, although current
`knowledge is still limited and derived mostly from retrospective series, PSMA-based imaging
`holds great promise to improve prostate cancer management.
`
`With an estimated incidence of 1,111,700 cases per
`year and an estimated mortality of 307,000 men per year,
`prostate cancer is one of the most prevalent cancers
`worldwide1. In western countries prostate cancer is the
`most common cancer in men, with roughly 758,700 new
`cases diagnosed per year, and it is the third most com-
`mon cause of cancer-associated mortality in men1. Thus,
`accurate diagnosis and staging of prostate cancer is of
`upmost importance.
`According to current guidelines, diagnosis of prostate
`cancer is most commonly made by sonography-guided
`needle biopsy2,3. In men in whom prostate cancer is sus-
`pected but histological findings are negative, MRI has
`evolved as the standard imaging procedure3,4. Suspicious
`lesions on MRI facilitate histological confirmation of
`prostate cancer by aiding targeted sampling in subse-
`quent biopsies5,6. However, a certain portion of pros-
`tate cancer lesions might still be missed using MRI7–10.
`In these patients, additional molecular information
`obtained by PET imaging with prostate-cancer-specific
`tracers is desirable.
`After diagnosis, patients with histologically con-
`firmed prostate cancer are stratified to distinct risk
`groups according to their digital-rectal examination
`
`results, the level of serum PSA and histological findings
`following analysis of the biopsy sample3,11. In patients
`with intermediate-risk to high-risk prostate cancer, CT
`or MRI of the lower abdomen accompanied by bone
`scintigraphy are currently recommended in guidelines
`from the European Association of Urology3 and the
`National Comprehensive Cancer Network11. In patients
`with recurrent and/or metastatic prostate cancer, bone
`scintigraphy, CT and MRI are recommended for detect-
`ing tumours or evaluating treatment responses3,11. Newer
`imaging modalities that have been investigated for use in
`prostate cancer diagnosis and staging include PET with
`choline-based tracers or fluorodeoxyglucose12,13; how-
`ever, despite these advances in imaging, these procedures
`still have considerable limitations and are not always able
`to meet diagnostic needs as they do not always reliably
`identify local recurrence, lymph node involvement or
`visceral metastases3,13–19.
`The use of PET probes targeting prostate-specific
`membrane antigen (PSMA, also known as glutamate
`carboxypeptidase 2) for imaging prostate cancer has
`gained increasing interest and shows great promise
`for improving the management of patients with pros-
`tate cancer20. This Review will provide an overview of
`
`1Department of Urology,
`Technische Universität
`München.
`2Department of Nuclear
`Medicine, Technische
`Universität München,
`Klinikum rechts der Isar,
`Ismaninger Strasse 22,
`81671 Munich, Germany.
`
`Correspondence to T.M.
`tobias.maurer@tum.de
`
`doi:10.1038/nrurol.2016.26
`Published online 23 Feb 2016
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`© 2016
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`Key points
`
`• Prostate-specific membrane antigen (PSMA) is a promising and specific target for
`prostate cancer imaging
`• PSMA–PET imaging can add molecular information to multiparametric MRI and,
`therefore, delineate suspicious lesions for targeted biopsies, especially in patients
`whose biopsy samples are tumour-negative
`• PSMA–PET imaging shows increased specificity and sensitivity compared with
`current standard imaging (CT, MRI and bone scintigraphy) in patients with primary
`intermediate-risk or high-risk prostate cancer
`• PSMA–PET imaging improves detection of metastatic lesions even at low serum PSA
`values in biochemically recurrent prostate cancer
`• Enhanced detection of prostate cancer lesions might enable improved
`patient-tailored therapy planning and, therefore, lead to improved therapy outcomes
`
`current knowledge regarding PSMA targeting and ima-
`ging with PSMA ligands, and will highlight the possi-
`ble clinical application of PSMA-based imaging to the
` management of patients with prostate cancer.
`
`PSMA as a target in prostate cancer
`PSMA is a type II transmembrane protein (FIG. 1), which
`has a 19-amino-acid intracellular portion, a 24-amino-
`acid transmembrane portion and a 707- amino- acid
`extracellular portion21. The PSMA gene (also known as
`FOLH1) is located on the short arm of chromosome 11
`in a region that is not commonly deleted in patients with
`prostate cancer22. PSMA expression and localization in
`the normal human prostate is associated with the cyto-
`plasm and apical side of the epithelium surrounding
`prostatic ducts but not basal epithelium, neuro endocrine
`or stromal cells23. Cytoplasmic PSMA is truncated at the
`N-terminus and is called PSMʹ, it has no folate-hydrolase
`activity or capacity to hydrolyse N-acetylaspartylglutamic
`acid24,25, and its function is not known. Dysplastic and/or
`neoplastic transformation of prostate tissue results in
`the transfer of PSMA from the apical membrane to the
`luminal surface of the ducts26,27. The transition to
`androgen- independent prostate cancer eventually leads
`to further PSMA expression28,29 The PSMA:PSMʹ ratio
`increases as prostate tumour cells increase in Gleason
`grade26. Interestingly, PSMA expression has also been
`reported in the tumour neo vasculature of some solid
`tumours (including colon, breast and renal cancer and
`subtypes of bladder cancer) and in newly formed blood
`vessels30–35. PSMA is also expressed on astrocytes of the
`central nervous system and it is known as glutamate
` carboxypeptidase 2 in these cells36,37.
`Consequently, this nonprostatic PSMA expression
`has led to anecdotal reports of high uptake of PSMA
`inhibitors in a variety of lesions that are incidentally
`present in patients that have undergone PSMA–PET for
`staging or restaging of prostate cancer38–43. PSMA is only
`enzymatically active in its homodimeric form44, and is
`made up of two monomers with intracellular, transmem-
`brane and extracellular domains45. After a ligand (such as
`a small- molecule antagonist or a specific antibody) binds
`to PSMA, internalization occurs and it is either retained
`in lysosomal compartments, or released into the cyto-
`plasm44,46. PSMA is an ideal target for molecular imaging
`
`of prostate cancer owing to its biological characteristics,
`including: consider able (100-fold to 1,000-fold) over-
`expression on the cell membrane of nearly all prostatic
`cancer cells compared with normal nontarget expression
`(on normal prostate epithelial cells, in the small intes-
`tine, renal tubular cells and the salivary glands)35,47–50,
`increased expression in advanced-stage and castration-
`resistant prostate cancers — several studies exist show-
`ing that PSMA expression levels increase according to
`the stage and grade of the tumour35,47,51 — potentially
`enabling PSMA imaging to be used for prognosis, a large
`extracellular domain enabling targeting using anti bodies
`and a cytoplasmic domain containing an internaliza-
`tion motif that results in internal ization and endosomal
`recycling, which increases the deposition of conjugated
`radiometals into the cell with subsequent improvement
`of both imaging and thera peutic efficacy52,53. This lat-
`ter feature makes PSMA an attractive target, especially
`for developing small- molecule radiopharmaceuticals
`(PSMA inhibitors) that are typically cleared quickly
`from the bloodstream and have low background activ-
`ity54. However, the degree of internalization has not been
`fully investigated for all available PSMA inhibitors.
`Since the 1980s, efforts have been made to target spe-
`cific regions of the intracellular or extracellular domain
`of PSMA with monoclonal antibodies labelled with dif-
`ferent isotopes for nuclear medicine imaging55 (FIG. 1).
`To date, only one radiolabelled anti-PSMA antibody
`(ProstaScint®, Jazz Pharmaceuticals, USA) targeting an
`intracellular epitope (7E11) of PSMA has been approved
`by the FDA56. J591, a monoclonal antibody targeting the
`extracellular domain of PSMA, localizes to viable tumour
`cells and has shown effective image contrast in clinical
`trials57. However, in general, the effectiveness of anti-
`bodies as diagnostic radiopharmaceuticals is limited by
`a long circulating half-life resulting in a high unspeci fic
`background activity and poor tumour penetrability. The
`combination of antibodies with long-lived PET radio-
`isotopes (such as 89Zr) or using only single-chain frag-
`ments (such as antibody fragments D7-Fc and D7-CH3)
`could be potential solutions to these limitations58–60.
`
`PSMA ligands
`The identification of the active substrate recognition
`site of PSMA with its structural and functional homol-
`ogy to glutamate carboxypeptidase 2 (also known as
`N-acetylated-α-linked acidic dipeptidase I) promoted
`the development of small molecules as PSMA lig-
`ands or inhibitors61,62. The recognition site contains
`two zinc ions and is composed of two pockets, the
`glutamate- sensing pocket (the S1ʹ pocket) and the
`non- pharmacophore pocket (the S1 pocket). Most
`of the inhibitors have a zinc-binding component and
`glutamate or glutamate isostere, which resides in the
`S1ʹ pocket63. PSMA inhibitors fall into three families:
`phosphorous- based (including phosphonate, phosphate,
`and phosphoramidate), thiol-based and urea-based.
`Urea-based inhibitors have a high affinity for PSMA,
`specificity for PSMA and fast and efficient internal-
`ization in LNCaP cells54; therefore, current research into
`small- molecule PSMA inhibitors is mainly focused on
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`these pharmaceutically engineered agents. The struc-
`tural and functional variety of PSMA ligands and their
` development is reviewed elsewhere64.
`Several research groups have reported the use
`of small-molecule inhibitors of PSMA labelled with
`123I  (REFS  65–67),99mTc (REFS  68,69),18F  (REFS  70,71),
`111In  (REFS 50,72) and 68Ga (REFS 20,54,73–76).
`The inhibitor Glu-NH-CO-NH-Lys(Ahx)-
`HBED-CC (68Ga-PSMA-HBED-CC), which was initi-
`ally described by Eder et al.54 in 2012, is the most widely
`used agent for PET imaging. On binding to prostate
`cancer cells, internalization occurs and high accumula-
`tion of 68Ga-PSMA-HBED-CC, even in small metasta-
`ses, is observed. This agent is also rapidly cleared from
`nontarget tissue. Physiologically, this radiotracer shows
`enhanced accumulation in salivary glands, the liver, the
`spleen, the small bowel and the urinary tract77. However,
`hardly any uptake is observed in retro peritoneal fatty
`tissue, benign lymphatic tissue and bone, which are
`locations where prostate cancer is likely to metasta-
`size35,41,77.68Ga-PSMA-HBED-CC has become a valu-
`able diagnostic agent in monitoring of both recurrent
`prostate cancer and responses to therapy. N,Nʹ- bis[2–
`hydroxy- 5- (carboxyethyl)- benzyl]ethylenediamine-
`N,Nʹ-diacetic acid (HBED-CC) can easily be labelled
`with 68Ga at room temperature as it is an efficient 68Ga
`chelator with fast complexing kinetics and good stabil-
`ity78. Eder and colleagues54 described its synthesis using
`HBED-CC, which is an analogue of hydroxy benzyl
`ethylenediamine (HBED). HBED is an attractive che-
`lator for 68Ga as they form a thermodynamically stable
`complex74. In an initial preclinical in vivo study, PSMA-
`positive LNCaP tumour xenografts were visible at 1 h
`after injection and tumour:muscle and tumour:blood
`uptake ratios were favourable54. Reports on the clini-
`cal value of 68Ga-PSMA-HBED-CC in PET imaging of
`recurrent and primary prostate cancer showed that it has
`high detection rates compared with data from literature
`and in direct comparison with 18F-choline20,67–69,75–79.
`In 2015, a different 68Ga-labelled PSMA ligand for
`PET imaging, EuK-Subkff-68Ga-DOTAGA (68Ga-PSMA
`Imaging & Therapy (I&T)) was introduced, which can
`also be labelled with 177Lu or 111In (REFS 50,76,79–81).
`Thus, it can serve as a theranostic agent for both imag-
`ing (68Ga) and radioguided surgery (111In) or PSMA-
`targeted endoradiotherapy (177Lu). Another theranostic
`agent, referred to as PSMA-DKFZ-617, was described
`initially by Benešová and colleagues82, with the first stud-
`ies using a 68Ga-labbelled compound and reporting low
`radiation exposure and very high contrast when used for
`detection of prostate cancer lesions82,83. Currently, this
`agent is being investigated for use in PSMA-targeted
`endoradiotherapy84,85.
`The development of 18F-labelled PSMA compounds
`offers potential advances with regard to increasing the
`number of examinations possible, owing to a higher
`available amount of the radioisotope 18F produced by
`a cyclotron compared with 68Ga eluted from a gener-
`ator86. An excellent image quality is also likely, which
`will result from optimized tracer doses leading to high
`imaging statistics and the decay properties of 18F itself
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`e
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`d
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`c
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`b
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`a
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`J591 antibodies
`
`Active centre
`PSMA-inhibitors
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`Extracellular
`
`Intracellular
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`
`
`Cell membraneCell membrane
`
`7E11 antibodies
`
`Figure 1 | The structure of prostate-specific membrane
`Nature Reviews | Urology
`antigen (PSMA), its binding sites for PSMA ligands
`and the most frequently used antibodies. a | The short
`intracellular domain containing a binding site that can be
`targeted with 7E11 antibodies. b | The hydrophobic
`transmembrane region. The extracellular part of PSMA
`consists of section c | that contains two domains of
`unknown function and proline-rich and glycine-rich regions
`as linkers, d | that is the large catalytic domain, which
`contains a binding site for J591 antibodies as well as the
`active substrate recognition site that is being targeting by
`PSMA inhibitors and e | the final domain of unknown
`function to which a helical dimerization domain is localized.
`
`(as it requires a much shorter distance to decelerate the
`positron in human tissue in comparison with 68Ga owing
`to its low positron emission energy, resulting in higher
`image resolution)86. Labelling PSMA with 18F could also
`be achieved by fluorinating the HBED compound. Malik
`and colleagues87 showed this approach to be successful
`when they applied this agent to PSMA-positive LNCaP
`cells; however, further preclinical and clinical studies on
`the effectiveness of this agent are currently lacking.
`Besides fluorination of known compounds,
`new, specifically 18F-labelled compounds have been
`reported. A first generation 18F-labelled PSMA ligand,
`18F-DCFBC, was described by Mease and colleagues88.
`PSMA-positive PC-3 PIP xenografts were clearly vis-
`ible as early as 20–30 min after injection with only
`faint uptake observed in the PSMA-negative PC-3
`FLU xenografts. In a clinical study, researchers investi-
`gated 18F-DCFBC in five patients who had radio logi-
`cal evidence of metastatic disease, and imaging with
`18F-DCFBC identified more suspicious lesions than bone
`scintigraphy or CT, but whether any of these lesions
`were false positives was not investigated89. In another
`preliminary study in 13 patients with primary prostate
`cancer, 18F-DCFBC–PET was able to reliably detect clini-
`cally significant high-grade and large-volume tumours
`(Gleason scores 8 and 9) with relatively low uptake in
`benign prostatic lesions71. The disadvantage of using this
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`Slice number: 6/20
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`c
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`Signal intensity
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`f
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`a
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`d
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`b
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`e
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`Figure 2 | 68Ga-PSMA–PET–MRI of a 50-year-old patient who had a rising serum PSA value (16 ng/ml at imaging)
`Nature Reviews | Urology
`and two tumour-negative previous biopsy samples. a | T2-weighted image showing a hypointense mass in the anterior
`fibromuscular stroma with pronounced arterial enhancement. b | Typical pronounced arterial contrast enhancement
`compared with the surrounding tissue. c | Intensity curve of the dynamic contrast enhanced sequence shows a typical fast
`washin followed by washout in the late phase. d | Diffusion-weighted imaging demonstrates markedly restricted diffusion.
`e | PET image and f | fused PET–MRI showing intense prostate-specific membrane antigen (PSMA) expression in the
`corresponding region. Targeted PET–MRI fusion biopsy revealed prostate cancer with Gleason score 7 in this region.
`
`agent lies in the considerable activity of this agent in the
`bloodstream, which could potentially interfere with the
`detection of lymph-node metastases89.
`In 2011, a second generation 18F-labelled PSMA ligand
`18F-DCFPyL was introduced, with favourable results for
`tissue binding in vitro and in vivo. High tumour uptake
`ratios between PSMA-positive PC3 PIP and PSMA-
`negative PC3 FLU xenografts were also observed70. In the
`first clinical investigation in nine patients, 18F-DCFPyL
`showed very high levels of uptake in sites of putative
`metastatic disease, as well as in primary tumours90. Very
`low blood pool activity was observed and the conspicu-
`ousness of lesions was notably higher with 18F-DCFPyL
`than with the first-generation radiotracer 18F-DCFBC
`making it a promising agent. Data from a first prelim-
`inary study comparing 68Ga-PSMA-HBED-CC with
`18F-DCFPyL showed that 18F-DCFPyL had a better
`tumour:background accumulation ratio, and additional
`lesions plausible for metastases were detected in three of
`the 14 patients when 18F-DCFPyL was used86.
`
`Local detection
`MRI has emerged as the imaging technique of choice for
`detection of prostate cancer after inconclusive or nega-
`tive biopsy findings, as well as for local staging regard-
`ing capsule penetration or seminal vesicle involvement3.
`T2-weighted MRI sequences enable anatomical resolu-
`tion of the zonal anatomy of the prostate and the delin-
`eation of suspicious areas. The addition of functional
`MRI sequences — namely dynamic-contrast-enhanced
`
`(DCE) and diffusion-weighted imaging (DWI), and to a
`lesser extent MRI spectroscopy (termed mulitparamen-
`tric MRI (mpMRI)) — often enables a more accurate
`investigation of the prostate than MRI alone91–94. Prostate
`cancer lesions often appear hypointense in T2-weighted
`sequences, but they typically show fast influx and wash-
`out of contrast material on DCE. In DWI, a reduced dif-
`fusion capacity of water molecules (reduced apparent
`diffusion coefficient (ADC)) owing to densely packed
`tumour cells as well as shifted choline and citrate metab-
`olism on MRI spectroscopy have been observed27,95–98.
`Furthermore, mpMRI can be used to detect aggres-
`sive prostate cancer lesions with greater sensitivity and
` specificity than MRI alone99–101.
`The introduction of whole-body hybrid PET–MRI
`scanners with simultaneous acquisition and exact ana-
`tomical coregistration of PET imaging and mpMRI
`has enabled functional and molecular information to
`be combined102,103. PSMA ligands, as prostate-cancer-
`specific PET tracers, might help to visualize and delin-
`eate cancerous lesions more accurately within the
`prostate than choline derivatives, which are currently
`the most widely used PET tracers14,104,105 (FIG. 2). The
`high lesion:background ratio of the 68Ga-PSMA–PET
`signal of suspicious lesions, as well as the information
`obtained from mpMRI, enables histological confirma-
`tion of prostate cancer using targeted fusion biopsies,
`especially in patients with previously negative findings
`on biopsy- sample analyses, as has been shown in pre-
`liminary studies106,107. In slight contrast to these findings,
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`a
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`b
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`c
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`Figure 3 | 68Ga-PSMA–PET–CT of a 52-year-old patient with primary prostate cancer (serum PSA value of
`19 ng/ml and Gleason score 7 at biopsy). a | Contrast enhanced CT shows a small lymph node (6 mm) adjacent to the
`Nature Reviews | Urology
`right internal iliac artery. b | PET and c | fused PET–CT images demonstrate intense prostate-specific membrane antigen
`(PSMA) expression in this lymph node. Radical prostatectomy and lymphadenectomy revealed a lymph node metastasis
`in the corresponding template field.
`
`in an initial series of 13 patients Rowe et al.71 reported a
`decreased sensitivity of 18F-DCFBC–PET for the detec-
`tion of prostate cancer lesions compared with mpMRI;
`however, the specificity for detection of high-grade and
`more clinically significant disease was increased71. In
`addition, interpretation of mpMRI might be hindered by
`changes after biopsy sampling such as local haemorrhage
`or inflammation, whereas interpretation of 68Ga-PSMA–
`PET does not seem to be influenced by biopsy104. Thus,
`the combination of 68Ga-PSMA–PET with mpMRI
`might improve rates of prostate cancer detection and at
`the same time avoid the use of unnecessary biopsy pro-
`cedures. However, not all prostate cancers have substan-
`tial PSMA overexpression (~10% of primary prostate
`cancers do not overexpress PSMA)105,108.
`
`Primary staging
`The goal of primary staging is to detect metastatic spread
`to the first landing sites — primarily lymph nodes, bone
`or other, visceral, organs. In low-risk prostate cancer
`metastatic spread is very unlikely; consequently, current
`guidelines suggest staging examinations should only be
`undertaken for intermediate-risk to high-risk prostate
`cancer3,11. For evaluation of spread to lymph nodes and
`visceral organs CT or MRI are used, whereas bone scin-
`tigraphy is recommended for excluding bony metastases,
`although data from an initial study indicated that whole-
`body MRI might be a superior modality for detecting
`metastasis to bone109. Naturally, staging has considerable
`influence on further treatment choices (such as radical
`prostatectomy, radiotherapy or palliative systemic treat-
`ment and the extent of pelvic lymph node dissection
`during surgery or planning of the radiation field, and
`also the consideration of multimodal therapy), exact
`staging assists in making the most appropriate choice.
`Evaluation of lymph nodes using CT or MRI solely
`depends on morphological information, and meta-
`static lymph nodes are mainly detected on the basis of
`increased size. However, almost 80% of metastatic lymph
`nodes in prostate cancer are smaller than the threshold
`size of 8 mm and, therefore, cannot be detected using
`morphological imaging110,111. The use of DWI in MRI
`
`can help to distinguish between metastatic and normal
`lymph nodes112–114. However, a broad overlap in DWI
`measurements between malignant and benign lymph
`nodes has been noted113. In general, the performance
`of CT and MRI for lymph node staging is not signifi-
`cantly different, as demonstrated in a meta-analysis that
`included 24 studies108. In this meta-analysis, the pooled
`sensitivity was 42% and 39% and the pooled specificity
`was 82% and 82%, for CT and MRI, respectively111. The
`authors concluded that both modalities are insufficient
`to reliably identify lymphatic spread, which in turn could
`jeopardize further treatment success.
`With the introduction of PET imaging and its com-
`bination with CT or MRI hopes were raised for an
`increased detection rate, especially of small meta static
`lymph nodes, owing to the addition of metabolic infor-
`mation to morpho logical cross- sectional imaging. Several
`different PET tracers, including 18F-fluordeoxyglucose,
`11C-choline, 18F-choline, 18F-fluorocholine and
`11C-acetate, have been studied in patients with pros-
`tate cancer15,115–118. To date, the most evidence exists for
`choline- based tracers. However, after the first enthusi-
`astic reports119,120, a systematic review and meta- analysis
`conducted in 2013 revealed a only moderate pooled
`sensitivity of 49.2%, at the same time demonstrating a
`high specificity of 95%, for the detection of metastatic
`lymph nodes in prostate cancer16. Data from other studies
`showed sensitivities ranging from 33 to 45%, but con-
`firmed high specificities of over 95% in larger patient
`cohorts121,122. Despite its high specificity, current guide-
`lines do not recommend PET imaging for lymph node
`staging of patients with primary prostate cancer with
`choline-based tracers as detection of metastatic lymph
`nodes is still hampered by the moderate sensitivity of
`this technique3.
`The use of PSMA ligands for PET imaging might par-
`tially overcome this limitation. In a retrospective analysis
`of 130 consecutive patients with primary intermediate-
`risk to high-risk prostate cancer who underwent radi-
`cal prostatectomy with template pelvic lymph node
`dissection, our group observed a sensitivity of 65.9%
`and specificity of 98.9% for lymph node staging with
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`a
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`c
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`b
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`d
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`Figure 4 | 68Ga-PSMA–PET–CT of a 73-year-old patient with recurrent prostate
`Nature Reviews | Urology
`cancer after radical prostatectomy (initial Gleason score 9) and local salvage
`radiotherapy. Upper images are from a staging 68Ga-PSMA-PET–CT examination at a
`serum PSA value of 3.6 ng/ml and the lower images are from a restaging examination
`six months later at a serum PSA value of 1.8 ng/ml. a | Fused PET–CT demonstrates an
`intense uptake in the thoracic spine suspicious for a bone metastasis. b | The
`corresponding CT reveals no morphological correlation. c | Fused PET–CT images,
`6 months later, shows no substantial uptake of 68Ga-PSMA in the lesion after external
`radiotherapy. d | CT shows a new sclerosis indicating post-therapeutic changes.
`PSMA, prostate-specific membrane antigen.
`
`68Ga-PSMA–PET108 (FIG. 3). Of note, the patients with
`tumour-positive lymph nodes that were missed by
`PSMA-PET presented with PSMA-negative primary
`tumours or had micrometastases in single lymph
`nodes. In line with our findings, other groups have also
`reported a high specificity of lymph node detection
`with use of 68Ga-PSMA–PET (REFS 75,120), although,
`small metastatic lymph nodes might still be missed.
`Furthermore, bony and visceral lesions of prostate can-
`cer that might not be detectable using standard imaging
`can be visualized by 68Ga-PSMA–PET (REFS 123–125).
`Thus, especially in patients with high-risk prostate can-
`cer, 68Ga-PSMA–PET in combination with CT or MRI
`could enable a complete staging of the local tumour,
`lymph node involvement, bone metastases and organ
`metastases with increased accuracy within one single
`examination, superseding current standard imaging
`and possibly improving treatment planning125. However,
`published data on primary staging with PSMA ligands is
`still very limited and further research is needed before
`drawing robust conclusions.
`
`Staging of recurrent prostate cancer
`Localization of prostate cancer lesions is a major challenge
`in patients with biochemical recurrence. The differenti-
`ation of localized disease and metastatic spread is of great
`importance for further disease management, especially at
`low serum PSA values. For example, salvage radiotherapy
`in patients whose cancer recurs after radical prostatectomy
`is most effective at serum PSA values <0.5 ng/ml126,127.
`Thus, radiotherapy should be initiated as early as possi-
`ble in these circumstances3. Conventional bone scintig-
`raphy or CT imaging show very limited detection rates
`for metastatic prostate cancer lesions at low serum PSA
`values at the time of biochemi cal recurrence after cura-
`tive treatment128; therefore, in most guidelines, ima ging
`is recommended for patients who are symptomatic or
`whose serum PSA levels are >10 ng/ml3,17. PET imaging
`with choline-based tracers has been found to improve
`staging and enhance detection of recurrent prostate can-
`cer15. However, these tracers still lack the ability to iden-
`tify smaller lesions or prostate cancer without increased
`metabolic activity — especially at low PSA velocity or
`serum PSA values <2 ng/ml18. Thus, PET imaging with
`choline-based tra cers is not usually recommended at early
`stages of recurrence. Considering the fact that biochemi-
`cal relapse is already expected in patients after radical
`prostatectomy with serum PSA levels >0.2 ng/ml, imaging
`techniques with improved sensitivity are highly desired.
`In 2015, reports from two studies, with large patient
`cohorts, investigating 68Ga-PSMA–PET were published
`addressing the issue of staging of recurrent prostate can-
`cer73,129. Afshar-Oromieh and colleagues77 investi gated
`the performance of this tracer in 319 patients with recur-
`rent prostate cancer (226 had received radical prostatec-
`tomy) and a median serum PSA value of 4.6 ng/ml. At
`least one lesion typical of prostate cancer was found in
`~83% of patients. The authors demonstrated detection
`rates of 50% for serum PSA values <0.5 ng/ml and 58%
`for serum PSA values from 0.5–1 ng/ml. In 42 patients,
`histological confirmation of lesions could be obtained.
`Of note, in these patients, all lesions that had a positive
`68Ga-PSMA–PET signal had histologically confirmed
`metastatic prostate cancer (n = 98); however, 29 lymph
`nodes and one local relapse was missed. Tumour
`Gleason score and/or androgen deprivation therapy did
`not significantly influence detection rates.
`Data from our group support these findings. In a
`homogeneous consecutive cohort of 248 patients with
`biochemical recurrence after radical prostatectomy who
`had a mean serum PSA value of 1.99 ng/ml, 89.5% of
`patients had suspicious lesions detected by 68Ga-PSMA–
`PET–CT. For serum PSA values of 0.2–<0.5 ng/ml, 0.5–
`<1 ng/ml, 1–<2 ng/ml and ≥2 ng/ml, detection rates were
`57.9%, 72.7%, 93.0% and 96.8%, respectively129. These
`rates are substantially higher than those reported for
`choline-based PET tracers, which have reported detec-
`tion rates of between 19% and 36% at serum PSA lev-
`els <1.5 ng/ml18,130–132. These enhanced detection rates
`can be mainly attributed to information obtained from
`68Ga-PSMA–PET, as opposed to diagnostic CT, as it
`exclusively showed suspicious findings not evident
`on diagnostic CT in 32.7% of patients and provided
`
`NATURE REVIEWS | UROLOGY
`
` VOLUME 13 | APRIL 2016 | 231
`
`©2016MacmillanPublishersLimited.Allrightsreserved.
`
`R E V I E W S
`
`Petitioner GE Healthcare – Ex. 1036, p. 231
`
`

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`a
`
`b
`
`Figure 5 | Imaging of 65-year-old patient with prostate cancer and diffuse
`Nature Reviews | Urology
`bone metastases. a | Bone scintigraphy demonstrates multiple bone metastases
`predominantly in the pelvis and ribs. b | Corresponding maximum-intensity projection
`of 68Ga-PSMA–PET shows considerably more bone metastases than bone scintigraphy.
`PSMA, prostate-specific membrane antigen.
`
`information about additional inv