The role of prostate-specific membrane antigen PET/computed tomography
The role of prostate-specific membrane antigen PET/computed tomography in primary staging of prostate cancer
Current Opinion in Urology
Samantha Koschel, Declan G. Murphy, Michael S. Hofman, and Lih-Ming Wong
Purpose of review: Functional imaging with PET combined with computed tomography (CT) is of emerging interest in prostate cancer (PCa). Development of prostate-specific membrane antigen (PSMA) radiolabelled ligands has thrust PET/CT into the limelight as an alternative to conventional imaging techniques, and the evidence base to support its utility in primary staging of newly diagnosed PCa is rapidly growing. This review focuses on the most recent and important publications evaluating PSMA PET/CT in primary staging of PCa.
Recent Findings: Three recent meta-analyses have reported 68Ga-PSMA PET/CT to demonstrate superior sensitivity and specificity for pelvic lymph node detection than conventional imaging. A recent systematic review also suggests 68Ga-PSMA PET/CT to be superior to bone scan for identifying bone metastases. However, the majority of studies are of a retrospective nature, and few provide histopathological correlation of PSMA PET/CT findings. Data from prospective studies are awaited to determine accuracy and management impact of PSMA PET/CT in primary staging.
Summary: PSMA PET/CT is rapidly altering the landscape of primary staging in PCa. It appears to be superior to conventional imaging for detecting regional and distant metastasis, though caution should be applied given the lack of prospective studies assessing how significant findings should be integrated into patient management. PSMA PET/CT could potentially become the gold standard for primary staging of high-risk PCa if future prospective data can prove its validity in this space.
Prostate cancer (PCa) is one of the most frequently diagnosed cancers in men, with an estimated 1.3 million new cases predicted globally in 2018 . Early detection of PCa with prostate-specific antigen (PSA) screening, has contributed to an increased incidence but improved survival. Many men have low-grade indolent disease, but in the 20–25% of men who present with high-risk PCa, accurate staging of regional and distant metastatic disease is crucial .
Conventional imaging modalities remain standard-of-care for primary staging but are significantly limited by poor sensitivity for detecting metastatic disease, particularly at low-PSA levels. Cross-sectional imaging with computed tomography (CT) and multiparametric MRI (mpMRI) has poor sensitivity to detect pelvic lymph node involvement (39 and 42%, respectively) . Bone scintigraphy demonstrates only moderate sensitivity of 59% and has poor diagnostic specificity of 85% to detect bone metastases, with benign lesions such as fractures and Paget's disease frequently misidentified .
Road from conventional imaging to prostate-specific membrane antigen PET/computed tomography
Disease burden in PSA recurrence post radical treatment (biochemical recurrence, BCR) is often not confined to the pelvis, thus salvage pelvic radiotherapy can have disappointing results sometimes with considerable morbidity . Suboptimal staging with conventional imaging in this setting led to exploration of molecular imaging with PET as an alternative. Fluorine and choline labelled PET (18F-FDG, 11C-choline, 18F-choline) have been extensively studied, but detection rates remained suboptimal . 18F-FDG PET/CT has traditionally been considered of limited value in primary staging, but may improve staging and prognostic stratification in patients with high-grade PCa . 11C and 18F labelled choline PET/CT has limited sensitivity of 49% for primary staging of nodal disease , however, has improved accuracy in BCR patients with pooled sensitivity of 86% .
The development of targeted molecular imaging with prostate-specific membrane antigen (PSMA) has since revolutionized PET in PCa. PSMA is a type II membrane glycoprotein that is overexpressed in more than 90% of PCa epithelial cells [10,11], is reflective of disease aggression and serves as a marker to predict disease progression [12,13].
PSMA small molecules labelled with 68-gallium (68Ga) or 18-fluoride (18F) are rapidly taken up by PCa cells, and rapidly cleared to result in high tumour-to-background contrast . 68Ga labelled PSMA (68Ga-PSMA-11) remains the most widely used and reported tracer, particularly in the setting of primary staging; however, 18F labelled PSMA agents (18F-DCFPyL, 18F-PSMA-1007) appear to be comparable alternatives, but published experience is limited [6,15].
PSMA PET/CT has rapidly emerged since 2013 with much of the published literature retrospective, and without histopathological correlation to ensure what we see on PSMA PET/CT is indeed metastatic PCa. Despite this, PSMA PET/CT is frequently used outside of clinical trials where readily available, impacting on patient management because the temptation to treat disease we see on such a promising imaging modality is so high. As Vapiwala et al., eloquently described, ‘applying information from new imaging modalities without having first learned their value from systematic analyses of data collected in a standardised approach, risks putting the cart before the horse’.
In the setting of BCR where the evidence for PSMA PET/CT is the most established, the majority of studies are retrospective [17▪▪]. However, PSMA PET/CT is clearly superior to conventional imaging in BCR, reflected in the recent EAU 2019 guidelines which now recommend PSMA PET/CT for restaging when PSA reaches 0.2 ng/ml postradical treatment .
The article aims to summarize the evidence published in the last 18 months analysing PSMA PET/CT in primary staging of pelvic nodal and distant disease in high-risk PCa.
Evidence for prostate-specific membrane antigen PET/computed tomography in primary staging: the meta-analyses
In the last 18 months, three meta-analyses have examined the existing evidence for 68Ga-PSMA PET/CT in primary staging of pelvic nodal disease [17▪▪,19▪▪,20▪▪], and one systematic review has assessed 68Ga-PSMA PET/CT in detection of bone metastases .
Perera et al. have updated their 2016 meta-analysis to now include 13 studies on 68Ga-PSMA PET/CT for primary staging [17▪▪]. Of note, five studies encompassing 244 patients provided histopathological correlation with pelvic lymph node dissection (PLND) at time of radical prostatectomy for predictive ability of 68Ga-PSMA PET/CT to identify pelvic nodal disease. Pooled sensitivity was 75 and 77% on per-lesion and per-patient analyses, respectively, and specificity 97–99% [17▪▪]. The pooled estimate of intraprostatic positivity in the 13 studies was 90%, but detection of extrapelvic nodal, visceral and bony disease was very low [17▪▪].
Kim et al. analysed six studies with 298 patients where PSMA PET/CT had been performed prior to radical prostatectomy and PLND in intermediate to high-risk PCa. Pooled sensitivity for detection of nodal disease was slightly lower than Kim et al., at 71%, and specificity similar at 95% [19▪▪].
Hope et al.[20▪▪] analysed 266 patients from five studies, where 68Ga-PSMA PET/CT was performed for primary staging prior to radical prostatectomy and PLND in intermediate to high-risk PCa. Reported pooled sensitivity was 74%, specificity 96%, positive predictive value 93%, negative predictive value 85% and accuracy 86% when compared with nodal histopathology [20▪▪] which is consistent with other published figures.
When comparing five meta-analyses that have assessed the ability of 68Ga-PSMA PET/CT to predict pelvic nodal disease with PLND histopathology as reference, confidence intervals of sensitivity are wide due to low patient numbers, as seen in Table 1.
Evidence examining PSMA PET/CT for detection of bony metastases in primary staging is limited. Zacho et al. published a systematic review demonstrating 68Ga-PSMA PET/CT outperforms technetium 99m-methyl diphosphonate (99mTc-MDP) bone scintigraphy in four studies. In the one study with subgroup analysis of 37 primary staging patients that reported sensitivity (100% 68Ga-PSMA PET/CT vs. 71% 99mTc-MDP bone scintigraphy when equivocal studies treated as positive) and specificity (91 vs. 65%), a best value comparator using imaging and follow-up clinical data were used as the reference standard . It is important to remember that established imaging modalities including CT, bone scintigraphy and MRI do not have prospective data or histopathological validation to warrant their use in identification of bone metastases, because it is accepted that retrospective analyses in this context can be powerful and negate the need for unnecessary bone biopsies that are often subject to sampling error.
In multiple review articles published in the last 18 months, the overwhelming consensus is that PSMA PET/CT has shown promising evidence of superior sensitivity in primary staging but further prospective data are necessary [6,25–27]. Esen et al. concluded their recent review with the bold statement that 68Ga-PSMA PET/CT can now be used as the sole imaging modality for primary staging of pelvic lymph nodes and bone in high-risk PCa.
Evidence for prostate-specific membrane antigen PET/computed tomography in primary staging: the new studies
Table 2 summarizes the 11 new studies published in the last 18 months that assess PSMA PET/CT in varying contexts across primary staging of PCa.
Assessment of pelvic nodal disease
A prospective study of 122 patients with 68Ga-PSMA PET/mpMRI by Grubmuller et al.[29▪], demonstrated slightly lower sensitivity for pelvic nodal disease at 68.8% than the discussed meta-analyses, but introduced the novel modality of hybrid PSMA PET/mpMRI in the context of primary staging. Although providing prospective evidence with histopathological correlation, they only analysed the combined hybrid PET/MRI compared with the radical prostatectomy specimen, without separately reporting on the accuracy of 68Ga-PSMA PET and of mpMRI in this cohort which would be of value.
Yaxley et al. reported a negative predictive value of 80.8% for 68Ga-PSMA PET/CT in pelvic nodal disease in 208 patients who underwent PLND. In 172 LN metastases, the reported per-node sensitivity was poor at 24.4% which is much lower than the 71–75% in the previously discussed meta-analyses [17▪▪,19▪▪]. In the 21 patients with metastatic disease on PLND, per-patient sensitivity of 68Ga-PSMA PET/CT was slightly better at 38.2% . Yaxley et al. concluded that the resolution of 68Ga-PSMA PET/CT remains insufficient to differentiate all discrete positive nodes seen at histopathology, particularly those less than 5 mm in diameter where sensitivity drops to 14.6%.
Two small retrospective studies have reported 68Ga-PSMA PET/CT to be superior to conventional imaging for detection of pelvic nodal disease [31,32]. However, similar to other studies, PLND was not performed to provide histopathological reference, and conventional imaging was not uniform.
Assessment of bone metastasis
The prospective study of 113 patients by Lengana et al. provides higher level evidence for the superiority of 68Ga-PSMA PET/CT compared with 99mTc-MDP bone scintigraphy in detection of skeletal metastasis. They reported both sensitivity and specificity to be superior (96.2 and 99.1% for 68Ga-PSMA PET/CT compared with 73.1 and 84.1% for 99mTc-MDP bone scintigraphy, respectively) with all positive 68Ga-PSMA uptake presumed to be pathologic on the basis of follow-up imaging, and histopathological confirmation only performed where necessary .
Assessment of management impact
Several new studies have assessed the impact of 68Ga-PSMA PET/CT on staging and management of PCa. Roach et al.[34▪] reported management intent was impacted by 68Ga-PSMA PET/CT in 21% of their prospective cohort of 108 patients, with disease upstaged in 16%. Another prospective study of 173 patients reported change in stage post-68Ga-PSMA PET/CT when compared with conventional imaging in 28.6%, with 17.9% upstaged and 10.7% downstaged . Two retrospective cohorts comprising 187 patients collectively also reported 68Ga-PSMA PET/CT to significantly change stage when compared with conventional imaging [36,37].
Downstaging of disease by PSMA PET/CT can have a significant impact on management as demonstrated by Fig. 1 and can also highlight the diagnostic inaccuracy of conventional imaging when a negative PSMA PET/CT proves the CT and/or bone scintigraphy to be a false positive.
Detection rates of avid metastatic disease on upfront primary staging 68Ga-PSMA PET/CT significantly varies across studies. The recently published cohort of 1253 patients by Yaxley et al.[38▪▪] is the largest single study to date to do this with 12.1% demonstrating avid metastatic disease in a population with more than 98% intermediate to high-risk PCa. In those presenting with PSA more than 20 ng/ml, 43% had metastatic disease on staging 68Ga-PSMA PET/CT. Increasing PSA, increasing ISUP grade group at biopsy, and increased T stage at mpMRI were all statistically significant prognostic factors for metastasis on 68Ga-PSMA PET/CT. Pelvic nodal disease was seen in 8.5%, and importantly 48% of these were considered nodes outside of an extended PLND template field, thus representing the dilemma faced by urologists when considering whether disease is surgically resectable. Skeletal metastasis was detected in 4.7% of this cohort [38▪▪]. Smaller retrospective studies reported much higher rates of upfront metastatic disease on 68Ga-PSMA PET/CT, with Kuten et al., reporting 25.5% in a cohort of 137 patients, and Hruby et al., reporting 51.2% in 78 patients.
Uncertainty surrounds how to integrate significant findings from PSMA PET/CT into patient management, given the lack of prospective data. For example, Fig. 2 demonstrates 18F-DCFPyL uptake on PSMA PET/CT in two mesorectal nodes that would not have been defined as pathologic on CT according to standard criteria. Prospective data on including PSMA-avid nodes outside the standard radiotherapy template has not been assessed, highlighting the need for caution in treating all disease we see on PSMA PET/CT.
Prospective studies on the horizon for prostate-specific membrance antigen-PET in primary staging
ProPSMA, the Australian prospective multicentre randomized control trial of 300 patients with newly diagnosed high-risk PCa that compares 68Ga-PSMA PET/CT to conventional imaging with CT and whole-body bone scintigraphy, will be of considerable interest when published in 2020 [40▪]. It will provide robust data to establish whether 68Ga-PSMA PET/CT should replace conventional imaging in primary staging, and will provide reliable information as to the accuracy and feasibility of using incremental diagnostic information provided by 68Ga-PSMA PET/CT in this context.
A crucial component of proPSMA is the randomization of patients to either the 68Ga-PSMA PET/CT or conventional imaging arm, then crossover to the alternate arm 2 weeks later if no more than three sites of metastatic disease are identified. If N1 or M1 disease is identified, patients undergo repeat imaging at 6 months to determine diagnostic accuracy of 68Ga-PSMA PET/CT and conventional imaging [40▪]. Management intent by referring practitioners is collected at initial enrolment, post first-line and second-line imaging, and at 6 months; with implemented treatment including histopathology also collected. Secondary endpoints will evaluate the difference in rate of equivocal studies and radiation exposure between the two arms, and the reporter agreement of PSMA PET/CT between local site and central review.
The study will also perform an economic analysis comparing conventional imaging with PSMA PET/CT, extending beyond cost of the scans but also patient relevant factors. For example, conventional imaging typically requires two patient visits, for bone scintigraphy and CT. The bone scintigraphy typically requires an injection, wait of 4 h and scanning that can take up to 60 min if SPECT/CT is performed. PSMA PET/CT can be performed in a single patient visit taking less than 90 min, with scanning time of less than 15 min.
Two further prospective trials (NCT02611882, NCT02678351) are also underway. The first will assess 68Ga-PSMA PET/CT in 225 patients across three populations, of which one is primary staging. The second will examine 68Ga-PSMA PET/mpMRI in 200 patients with high-risk PCa planned to undergo surgery. Radical prostatectomy ± PLND performed post-68Ga-PSMA PET/CT in both cohorts will provide further histopathological data to evaluate the accuracy of pelvic nodal detection.
Where to next with prostate-specific membrane antigen?
PSMA PET/CT has demonstrated great potential for detection of intraprostatic lesions with Perera et al.[17▪▪] reporting 90% positivity. The logical progression is to assess the performance of PSMA PET/CT to detect and localize clinically significant PCa compared with the well established mpMRI.
Early studies report PSMA PET/CT to have a similar detection sensitivity for primary disease compared with mpMRI , with one study reporting concordance between PET and MRI of 91% . Figure 3 demonstrates concordance between PSMA PET/CT and mpMRI for a primary prostate lesion. Hybrid PSMA PET/mpMRI is a novel imaging modality that introduces the potential of these two imaging techniques providing a superior sensitivity in detecting PCa than either alone, but at a significant cost with hybrid machines expensive. Grubmuller et al.[29▪] reported hybrid 68Ga-PSMA PET/mpMRI in 122 patients with tumour focus matched to whole-mount radical prostatectomy specimens with promising results. The positivity rate was 97.5%, and PSMA PET/mpMRI correctly identified organ-confined disease with 85% accuracy, extraprostatic extension with 79% accuracy and seminal vesicle invasion with 94% accuracy.
Coregistration of PSMA PET/CT and mpMRI images is a potential way to examine the accuracy of these modalities individually and combined, without the expense of a hybrid machine. Reynolds et al. report a promising prospective pilot study where five patients underwent 68Ga-PSMA PET and mpMRI prior to radical prostatectomy, with PET/CT data successfully coregistered with mpMRI and histology data.
The recently published retrospective study by Kalapara et al. compared 68Ga-PSMA PET/CT with mpMRI for the detection of intraprostatic lesions in 205 patients who underwent radical prostatectomy, of which 133 had clinically significant disease. They report no significant difference between 68Ga-PSMA PET/CT and mpMRI to identify any tumour (94 vs. 95%), clinically significant index tumours (96 vs. 91%) or transition zone tumours (85 vs. 80%), which certainly reflects the promise of 68Ga-PSMA PET/CT in this setting given how accurate we know mpMRI to be.
Further prospective data are clearly needed to assess the accuracy and feasibility of PSMA PET/CT in this context, but this early data are certainly promising.
PSMA PET/CT has and continues to rapidly change primary staging in PCa. 68Ga-PSMA PET/CT appears to be superior to conventional imaging for detecting regional and distant metastasis in the available data, though caution should be applied when using the information clinically given the lack of prospective studies with histopathological validation and assessment of impact on patient management thus far. It is highly likely with the imminent publication of a large prospective randomized control trial (proPSMA), that PSMA PET/CT will potentially become the gold standard for primary staging of high-risk PCa.
We would like to thank A/Prof Thomas Sutherland for his assistance with selecting PSMA PET/CT and mpMRI images to be included with the review articles.
Financial support and sponsorship
M.S.H. is supported by a Clinical Fellowshipf from Peter MacCallum Foundation.
Conflicts of interest
M.S.H. is the principal investigator of the ProPSMA study, funded by Movember and the Prostate Cancer Foundation of Australia (PCFA). M.S.H. receives research support from Endocyte (a Novartis company), Movember Australia, Prostate Cancer Foundation of Australia (PCFA), Prostate Cancer Foundation (PCF), Cancer Australia and the Victorian Cancer Agency (VCA). He has received honoraria and travel support for delivering educational talks for Jannsen, Ipsen and Sanofi Genzyme.
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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