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A Systematic Review of the Variability in Performing and Reporting Intraprostatic Prostate-specific Membrane Antigen Positron Emission Tomography in Primary Staging Studies
Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, AustraliaYoung Urology Research Organisation (YURO), Melbourne, VIC, Australia
School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, AustraliaUniversity of Melbourne, Royal Melbourne Hospital Clinical School, Melbourne, VIC, Australia
University of Melbourne, Royal Melbourne Hospital Clinical School, Melbourne, VIC, AustraliaEJ Whitten Foundation Prostate Cancer Research Centre at Epworth, Melbourne, VIC, Australia
Prostate cancer (PCa) remains one of the leading causes of cancer-related deaths in men worldwide. Men at risk are typically offered multiparametric magnetic resonance imaging and, if suspicious, a targeted biopsy. However, false-negative rates of magnetic resonance imaging are consistently 18%; therefore, there is growing interest in improving the diagnostic performance of imaging through novel technologies. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for PCa staging and, more recently, for intraprostatic tumour localisation. However, significant variability has been observed in how PSMA PET is performed and reported.
Objective
In this review, we aim to evaluate how pervasive this variability is in trials investigating the performance of PSMA PET in primary PCa workup.
Evidence acquisition
Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed an optimal search in five different databases. After removing duplicates, 65 studies were included in our review.
Evidence synthesis
Studies dated back as early as 2016, with numerous different source countries. There was variation in the reference standard for PSMA PET, with some using biopsy specimens or surgical specimens, and in some cases, a combination of the two. Similar inconsistencies were noted when studies selected histological definitions of clinically significant PCa, while some omitted their definition altogether. The most significant variations in performing PSMA PET were the radiotracer type, dose, acquisition time after injection, and the PET camera being utilised. Substantial variation in the reporting of PSMA PET was noted, with no consistency in defining what constitutes a positive intraprostatic lesion. Across 65 studies, four different definitions were used.
Conclusions
This systematic review has highlighted considerable variation in obtaining and performing a PSMA PET study in the context of primary PCa diagnosis. Given the discrepancy in how PSMA PET was performed and reported, it questions the homogony of studies from centre to centre. Standardisation of PSMA PET is required for this to become a consistently useful and reproducible modality in the diagnosis of PCa.
Patient summary
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for staging and localisation of prostate cancer (PCa); however, there is significant variability in performing and reporting PSMA PET. Standardisation of PSMA PET is required for results to be consistently useful and reproducible for the diagnosis of PCa.
]. Men with a clinical suspicion of PCa due to an elevated serum prostate-specific antigen level or an abnormal finding on digital rectal examination are currently offered multiparametric magnetic resonance imaging (mpMRI) of the prostate for stratification. Depending on the result, mpMRI may be followed by a systematic and/or targeted biopsy [
]. The negative predictive value and sensitivity of mpMRI for clinically significant PCa are around 90%, though significant interobserver variability can exist between centres [
Negative predictive value of multiparametric magnetic resonance imaging in the detection of clinically significant prostate cancer in the prostate imaging reporting and data system era: a systematic review and meta-analysis.
]. False negatives result in a considerable proportion of patients having delayed diagnosis and treatment, while the low positive predictive value makes this diagnostic algorithm reliant on biopsy [
Positive predictive value of Prostate Imaging Reporting and Data System version 2 for the detection of clinically significant prostate cancer: a systematic review and meta-analysis.
]. As a result, there is value in further improving the diagnostic performance of imaging for intraprostatic disease detection and localisation.
One avenue for improvement is the addition of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) to the diagnostic investigation. PSMA PET is being utilised to assess metastatic spread after biochemical recurrence with reasonable accuracy [
Gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer—updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis.
]. The proPSMA study demonstrated superior accuracy of PSMA PET to conventional imaging when staging men with a biopsy-proven PCa with high-risk features [
Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.
]. Regarding intraprostatic tumour localisation, the concentration of radiotracer uptake (ie, maximum standardised uptake value [SUVmax]) within the primary lesion is associated with adverse pathology and oncological outcomes [
Findings in 1,123 men with preoperative (68)Ga-prostate-specific membrane antigen positron emission tomography/computerized tomography and multiparametric magnetic resonance imaging compared to totally embedded radical prostatectomy histopathology: implications for the diagnosis and management of prostate cancer.
]. The PRIMARY trial was a prospective, multicentre trial that assessed the additive value of PSMA PET to mpMRI prior to prostate biopsy in men with suspected PCa [
The additive diagnostic value of prostate-specific membrane antigen positron emission tomography computed tomography to multiparametric magnetic resonance imaging triage in the diagnosis of prostate cancer (PRIMARY): a prospective multicentre study.
]. In this setting, using both modalities instead of mpMRI alone conferred significant increases in sensitivity and negative predictive value for detecting clinically significant PCa in the initial diagnosis setting.
Significant variability has been observed in how PSMA PET is performed and reported, with moderate inter-rater agreement [
]. The prospective PRIMARY trial and previous retrospective studies have demonstrated the value of PSMA PET for intraprostatic disease evaluation, although the definition of suspicious PET findings in the prostate is still evolving [
]. Without harmonisation, reproducibility and applicability between centres are difficult. This systematic review aims to evaluate the variability of PSMA PET acquisition, interpretation, and reporting among trials investigating intraprostatic imaging.
2. Evidence acquisition
2.1 Search strategy
The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [
]. A literature search was performed in March 2022 using Medline (Ovid), Embase (Ovid), Cochrane Database of Systematic Reviews (Ovid), PubMed, Google Scholar, and Web of science. Two authors (N.P. and G.P.) discussed the search terms in detail. We searched for a combination of subject headings, MeSH terms, and synonyms for PCa, biopsy, and PSMA PET, with the complete strategy provided in the Supplementary material.
2.2 Eligibility criteria
The population, intervention, comparator, outcome (PICO) approach was used to inform the eligibility criteria. The population included studies that examined patients for primary PCa who were otherwise treatment naive, that is, not on active surveillance, or who had not received definitive treatment. The intervention was the patient having PSMA PET as part of the primary PCa diagnosis. Most trials that we included used mpMRI of the prostate as the comparator group. Although the comparator component is an essential aspect of the PICO, we did not exclude studies that did not use a comparator group. The endpoint of the review is to ascertain the variability of how PSMA PET is performed and reported, and not how well it compares with its other primary diagnostic counterparts. We included trials that reported the association between intraprostatic imaging and pathological grade from biopsy or radical prostatectomy specimens (outcome). Articles reporting on fewer than five patients, articles not written in English, book chapters, editorials, reviews, letters, and conference proceedings were excluded.
2.3 Screening and study selection
Two authors (N.P. and G.P.) independently screened the titles and abstracts, and conflicts were resolved by arbitration with a third reviewer. After this stage, the remaining articles were reviewed in their entirety (full text). All articles retrieved in the search for each database were then transferred to Endnote X9. No automation tools were used.
2.4 Quality assessment
The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess the risk of bias in four domains: patient selection, index test, reference standard, and reference test timing (Table 1).
After consultation with a nuclear medicine physician (J.B.) and a radiologist (M.P.), there was a consensus on what information to collect. Extraction from a sample of five studies was done in parallel by two researchers (N.P. and G.P.) with >100% agreement achieved; the remaining extraction was performed by one researcher (G.P.). The following information was obtained.
2.5.1 Study characteristics
Study characteristics included information such as title, first author, year of publication, journal, country, prospective or retrospective, number and mean age of the patients, PET acquired before or after biopsy, and outcome (grade from biopsy or surgical specimen).
2.5.2 Image creation and reporting
Image creation and reporting included data on radiotracer, isotope source, tracer dose, quality control, uptake time, PET camera details, mean days from PET to biopsy, number and experience of reporters, and definition of a positive scan.
3. Evidence synthesis
The search resulted in 4882 articles, with 3257 articles remaining after duplicates excluded. Following the application of inclusion criteria, 289 articles were considered in full, with 65 remaining after further consideration (Fig. 1).
Fig. 1PRISMA flow diagram. NA = not available; PET = positron emission tomography; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analyses; PSMA = prostate-specific membrane antigen.
The earliest study included was from 2016, and the year with the most studies (37%) was 2021. Australia and Germany were the most common source countries. Most studies (77%) involved patients who had PSMA PET after a biopsy. Imaging was correlated with biopsy specimens, surgical specimens, and a combination of the two in 11 (17%), ten (15.4%), and 16 (25%), studies, respectively. In 28(25%) studies, the source of tissue used was not mentioned. Different definitions of clinically significant PCa were used: grade group ≥2 (77%), grade group ≥3 (7.7%), grade group ≥4 (7.7%), grade group 3, and/or a cancer core length ≥6 mm (3.1%). The histological definition of cancer was not clear in three (5%) studies [
Improving diagnosis of primary prostate cancer with combined (68)Ga-prostate-specific membrane antigen-HBED-CC simultaneous PET and multiparametric MRI and clinical parameters.
]. When comparing PSMA PET with histology, 23 (35.3%) studies acknowledged whether or not reporters were blinded to histology. In the trials that mentioned blinding reporters, 18 (27.7%) were blinded, while the others acknowledged they were not. Summary details of each study are listed in Table 2.
Table 2Study Characteristics, image acquisition, and image interpretation
Prostate specific membrane antigen positron emission tomography may improve the diagnostic accuracy of multiparametric magnetic resonance imaging in localized prostate cancer.
Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients with primary prostate cancer based on slice by slice comparison with histopathology.
(68)Ga-PSMA positron emission tomography/computerized tomography for primary diagnosis of prostate cancer in men with contraindications to or negative multiparametric magnetic resonance imaging: a prospective observational study.
Improving diagnosis of primary prostate cancer with combined (68)Ga-prostate-specific membrane antigen-HBED-CC simultaneous PET and multiparametric MRI and clinical parameters.
[(68)Ga-]PSMA-11 PET/CT and multiparametric MRI for gross tumor volume delineation in a slice by slice analysis with whole mount histopathology as a reference standard—implications for focal radiotherapy planning in primary prostate cancer.
Diagnostic accuracy of 68 Ga-prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) and multiparametric (mp)MRI to detect intermediate-grade intra-prostatic prostate cancer using whole-mount pathology: impact of the addition of 68 Ga-PSMA PET to mpMRI.
Diagnostic performance of Gallium-68 prostate-specific membrane antigen positron emission tomography-computed tomography in intermediate and high risk prostate cancer.
Improved specificity with 68Ga PSMA PET/CT to detect clinically significant lesions “invisible” on multiparametric MRI of the prostate: a single institution comparative analysis with radical prostatectomy histology.
68Ga-PSMA PET/CT better characterises localised prostate cancer after MRI and transperineal prostate biopsy: is 68Ga-PSMA PET/CT guided biopsy the future?.
(68)Ga-PSMA PET/CT combined with PET/ultrasound-guided prostate biopsy can diagnose clinically significant prostate cancer in men with previous negative biopsy results.
Detection and localisation of primary prostate cancer using 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology.
Detection of intraprostatic tumor localisation with 18-fluorine prostate-specific membrane antigen (PSMA) PET/CT compared to radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial.
Diagnostic ability of Ga-68 PSMA PET to detect dominant and non-dominant tumors, upgrading and adverse pathology in patients with PIRADS 4–5 index lesions undergoing radical prostatectomy.
Head-to-head comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in staging prostate cancer using histopathology and immunohistochemical analysis as a reference standard.
Intraindividual comparison between 68 Ga-PSMA-PET/CT and mpMRI for intraprostatic tumor delineation in patients with primary prostate cancer: a retrospective analysis in 101 patients.
Uncovering the invisible-prevalence, characteristics, and radiomics feature-based detection of visually undetectable intraprostatic tumor lesions in (68)GaPSMA-11 PET images of patients with primary prostate cancer.
Combined utility of 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography and multiparametric magnetic resonance imaging in predicting prostate biopsy pathology.
(68)Ga-PSMA PET/CT targeted biopsy for the diagnosis of clinically significant prostate cancer compared with transrectal ultrasound guided biopsy: a prospective randomized single-centre study.
The additive diagnostic value of prostate-specific membrane antigen positron emission tomography computed tomography to multiparametric magnetic resonance imaging triage in the diagnosis of prostate cancer (PRIMARY): a prospective multicentre study.
Assessing the accuracy of 68Ga-PSMA PET/CT compared with MRI in the initial diagnosis of prostate malignancy: a cohort analysis of 114 consecutive patients.
Biphasic GA 68-labeled prostate specific membrane antigen-11 positron emission tomography/computed tomography scans in the differential diagnosis and risk stratification of initial primary prostate cancer.
Detection of prostate cancer with 18F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible?.
The DeTeCT trial. World J Urol.2021; 39: 2439-2446
Bodar Y, Koene B, Meijer D, et al., editors. Determining the diagnostic value of PSMA-PET/CT imaging in patients with persistent high prostate specific antigen levels and negative prostate biopsies. Urol Oncol 2022;40:58.e1–7.
Establishment and prospective validation of an SUV(max) cutoff value to discriminate clinically significant prostate cancer from benign prostate diseases in patients with suspected prostate cancer by (68)Ga-PSMA PET/CT: a real-world study.
Findings in 1,123 men with preoperative (68)Ga-prostate-specific membrane antigen positron emission tomography/computerized tomography and multiparametric magnetic resonance imaging compared to totally embedded radical prostatectomy histopathology: implications for the diagnosis and management of prostate cancer.
Machine learning-based prediction of invisible intraprostatic prostate cancer lesions on 68 Ga-PSMA-11 PET/CT in patients with primary prostate cancer.
Prospective analysis of clinically significant prostate cancer detection with [18F] DCFPyL PET/MRI compared to multiparametric MRI: a comparison with the histopathology in the radical prostatectomy specimen, the ProStaPET study.
Most radiotracers used in the studies were labelled with gallium-68 (84.6%) with the balance labelled with fluorine-18 (6.5%). The most common gallium-68–labelled tracer was [68Ga]Ga PSMA-11 (77%), followed by [68Ga]Ga-PSMA 617 (3.7%). For the studies that used radiotracers labelled with fluorine-18 (15.9%), [18F]F-DCFBC was the most common (11%). Different tracers had variable administered dose ranges. The dose in studies with gallium-68–labelled radiotracers was reported as the mean in 34 (62%) studies and as the median in 11 (20%) studies. A mean dose of >150 MBq was stated in 19 (34.5%) studies and four (7.2%) had a median dose of >150 MBq, with the range of reported means being between 85 and 315 MBq. The minimum and maximum doses were reported in 34 (52%) studies, 15 (44%) stated a lower bound of <100 MBq, while the upper bound was ≥200 MBq in 17 (50%) studies. For studies using fluorine-18 (15.4%)-labelled radiotracers, five (50%) reported a mean dose (range: 244–329 MBq), 80% of which were >290 MBq. Four (40%) studies with fluorine-18–labelled radiotracers reported a median dose, two (50%) of which were >290 MBq. The highest and lowest doses received were quantified in eight (80%) studies, four (50%) had a lower bound of <245 MBq, and four (50%) had an upper bound of >320 MBq. Seven (10.8%) studies measured a dose as the mean MBq relative to bodyweight, all of which used gallium-68–labelled radiotracers, with an average of 2 MBq/kg. A total of 22 (33.8%) trials did not acknowledge the quality control practices employed when handling/producing the radiotracer.
3.3 Image acquisition
Image acquisition time after tracer injection varied considerably. Most trials (83.1%) mentioned their image acquisition time in minutes after radiotracer administration (48 gallium-68 [89%] and eight fluorine-18 [15%]), either as a mean (95%) or as a median (4%). The mean acquisition time of gallium-68 was shorter than that of fluorine-18. In the gallium-68 papers, 60.1% had a mean acquisition time of >60 min (range: 30–158 min). For fluorine-18 papers, 40% had a mean acquisition time of ≥120 min (range: 90–123 min). The manufacturers of the PET scanners also varied, the most common ones being Siemens (44.6%), GE Healthcare (24.6%), and Phillips (16.9%), with the manufacturer not mentioned in 15.4% studies. In one (1.5%) study, both a Siemens and a GE Healthcare PET camera were used.
3.4 Definition of PSMA PET–positive imaging
Four methods were used to define what constituted a positive scan, with 18 (27.7%) studies not mentioning about stating the definition. A target-to-background ratio was the most common method (43.1%). However, the specific background tissue (ie, liver or gluteus maximus) was not always detailed amongst this group of studies. Only eight (12.3%) studies defined a positive lesion using a target-to-background ratio with a specific tissue mentioned: liver (3.1%), surrounding prostate tissue (7.7%), or the contralateral prostate hemisphere (1.5%). A general SUVmax cut-off was used in eight (12.3%) papers (all using gallium-68 tracers), with the cut-off being ≥2.5 in six (9.2%) and <2.5 in three (4.6%) studies. A relative SUVmax criterion (percentage of the hottest lesion in unit area) was used in three papers (4.6%). Other studies (4.6%) defined positivity in a nonquantitative manner and referred to avidity of a lesion in the prostate when correlating to a histopathology specimen.
3.5 PSMA PET readers
The number of clinicians reporting the PET scan varied between three (4.6%), two (3.1%), one (1.5%), and not stated (52.3%). Readers most (55.4%) often included nuclear medicine physicians as part of the assessors (50% had only nuclear medicine readers, with radiologists used in 33.8% papers; 18.2% used only radiologists). In 18 (27.7%) studies, both nuclear medicine physicians and radiologists were employed to interpret the study, of which two (11.1%) studies stated that the radiologists were dual trained. Reader experience was mentioned in 30 (46.2%) papers, with 24 (80%) describing the number of years’ experience the physicians had and six (20%) the number of cases per year. In studies with nuclear medicine physician readers, the range of experience was 4–15 yr and the range of cases per year was 200–500, and in studies with radiologist readers, the range of experience was 4–25 yr (with cases read per year not mentioned).
3.6 Discussion
We have demonstrated a wide disparity in how intraprostatic PSMA PET imaging is performed and reported in the literature, which in turn affects the generalisability of any conclusions. Attempts at homologation include, in 2017, the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging creating a joint procedure guideline for PCa imaging [
]. The guideline aimed to provide a “standard for the recommendation, performance, interpretation and reporting” of PSMA PET. The guidelines covered image acquisition and reporting [
]. More recently, a worldwide panel of experts designed a consensus to better harmonise PSMA PET acquisition and interpretation to improve reproducibility and utility of this novel imaging modality [
]. Although these guidelines were intended for prostate staging, these provide a sensible guide for performing and reporting PSMA PET in primary diagnosis and localisation of PCa.
3.6.1 Radiotracer types
Prospective trials have demonstrated the benefit of radiopharmaceuticals that target PSMA [
A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/CT with (18)F-DCFPyL in prostate cancer patients (OSPREY).
]. Currently, two have been approved by the US Food and Drug administration: [68Ga]Ga-PSMA 11 and [18F]F-DCFPyL. Although there are practical differences in producing radiopharmaceuticals and physical characteristics of the isotopes, there is no evidence to date that one has superiority over the other in diagnostic performance [
Head-to-head comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in staging prostate cancer using histopathology and immunohistochemical analysis as a reference standard.
]. Although there are no diagnostics benefit, gallium-68 appeared more prevalently in our review than fluorine-18. The disproportionate split is likely due to logistic considerations. For example, a generator provides a reliable daily source of gallium-68 in a nuclear medicine department, while obtaining fluorine-18–labelled radiotracers from a cyclotron, and external radiopharmacy can have occasional production or delivery issues.
3.7 Recommendations for radiotracer application and administered activity
Most guidelines recommend that tracer activity should be reported in MBq, whether in a total dose (MBq per patient represented as a mean or range) or on a weight-based dose (MBq/kg) [
]. Although the optimal injected activity is still debated for MBq/kg, published data suggest an approximate dose of 1.8–2.2 MBq/kg and 4 MBq/kg for [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL, respectively [
]. For the studies in our review that used gallium-68 derivatives, the average dose was within an appropriate range. The very few studies that measured their dose in MBq/kg were also within an appropriate range, and all these studies used gallium-68. The average upper range of gallium-68 was also within the recommended range (111–259); however, in ten studies, the lower range was below the recommended range. Similarly, in four studies, the lower range for [18F]F-DCFPyL was below the recommended lower range of 296–370 MBq. This could lead to suboptimal scan quality/resolution, though it can be compensated by longer acquisition times. A recent retrospective study by Rauscher et al [
] aimed to define the lowest clinically useful dose for [68Ga]Ga-PSMA-11. They described a proportional relationship between lower injected doses and correct identification of PCa lesions.
3.7.1 Uptake time
Lesion-to-background contrast, quantitative reads, and detection rates vary depending on image acquisition time because tumour PSMA uptake does not reach a plateau [
]. Therefore, reporting on the time and keeping within recommendations are essential for reproducibility and accuracy across centres. When accounting for image acquisition time after injection, a 60-min interval time is recommended, with a range of 50–100 min for [68Ga]Ga-PSMA-11 [
]. Contrastingly, a prospective study that evaluated the optimal image acquisition time for [18F]F-DCFPyL found that 100% of lesions discovered at 60 min were present at 120 min [
]. Furthermore, 38% of lesions found at 120 min were not present at 60 min. This raises the possible conclusion of a recommended image acquisition time of 120 min to optimise the detection rate of intraprostatic cancer lesions. A large proportion of trials omitted their acquisition time, which if too short, could underestimate the presence of clinically significant PCa. In contrast, the detection rate may be far overestimated if the image acquisition time is well above the recommended range. Owing to PSMA tracer kinetics, the radiotracer background activity decreases per unit time, while the tracer accumulation in the prostate cells increases [
]. Therefore, numerous studies reported that delayed image acquisition times up to 180 min for [68Ga]Ga-PSMA-11 improves prostate tumour detection. However, uptake times of >100 min have practicality issues and are therefore unlikely to be reproducible in other centres [
PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions.
]. Of the trials that mentioned the image acquisition time, [68Ga]Ga-PSMA-11 trials followed the mean acquisition time recommendations in 31/47 studies. However, four of eight [18F]F-DCFPyL studies had their average acquisition time below Wondergem et al’s [
] recommendations, which potentially implies an increased false-negative rate.
3.7.2 Reader experience
A retrospective study displayed a proportional relationship with PSMA PET/computed tomography user experience (in biochemical recurrence and primary diagnosis) and overall interobserver agreement [
]. However, a panel of worldwide experts reached a consensus that reporters’ experience need not be reported; they concede that the reporters should comment on the quality and reproducibility of the scan, which depends on experience [
]. This poses a problem as there was little consistency amongst the trials with regard to user experience, how the experience was measured, qualifications of reporters, and whether user’s experience was reported at all. This inconsistency could have an impact on the reproducibility of results across centres.
3.7.3 Definition of positive imaging
As the application of PSMA PET to primary diagnosis is recent, there is poor consensus on defining a positive lesion. Guidelines such as those of the European Association of Nuclear Medicine (EANM) and joint guidelines with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) were predominantly designed for biochemical recurrence and staging, and not for primary localisation. As a result, four different methods were used across the 65 trials. Although some tissues do not express PSMA, there will be a predicted amount of radiation absorbed per unit of injected activity depending on the organ. These estimated results are the baseline physiological PET uptake for each organ [
] consider a lesion to be suspicious if the uptake is greater than the estimated physiological uptake for that organ or relative to background if no physiological uptake is predicted in that organ. This fundamental principle gives valuable insight into why this definition was the most common one when defining intraprostatic cancer. However, the target-to-background ratio is still subjective to readers as the threshold greater than the background is variable, especially if this is a visual interpretation rather than quantitatively measuring differences in uptake. On the contrary, providing an absolute threshold of SUVmax can also introduce variability as several technical factors influence it, such as uptake time, image reconstruction, and PET camera technology.
The second most common method for defining a positive scan seen in our review was an absolute SUVmax cut-off, though the value of this threshold varied. A recent prospective trial attempted to define the optimal SUVmax cut-off for clinically significant (grade group ≥2) PCa. According to the receiver operating characteristic curve analysis, the absolute SUVmax cut-off of 5.3 achieved sensitivity, specificity, positive predictive value, and negative predictive value of 83%, 81%, 92%, and 65%, respectively [
Establishment and prospective validation of an SUV(max) cutoff value to discriminate clinically significant prostate cancer from benign prostate diseases in patients with suspected prostate cancer by (68)Ga-PSMA PET/CT: a real-world study.
]. However, it is inadvisable to choose a threshold without regard to clinical consequences, that is, whether it is preferable to maximise sensitivity or specificity in this context.
To this end, a more nuanced definition of positive scan has been proposed in a post hoc analysis of the PRIMARY trial [
]. Analogous to the Prostate Imaging Reporting and Data System reporting system for mpMRI, an intraprostatic lesion was given a “PRIMARY score” of between 1 and 5. Primary scores 3–5 (high-risk patterns) translated to a higher likelihood of clinically significant cancer, with 100% of patients with a PRIMARY score of 5 having grade group ≥2 cancer.
4. Conclusions
Prospective trials have established a place for PSMA PET in the primary diagnosis of PCa. However, given the novelty of this modality and the exponential growth of research in this field, considerable variability in the way imaging is performed and reported in the literature was observed in this systematic review. Research into the clinical consequences of this variation and efforts at homogenising reporting are encouraged to facilitate wider generalisability of trial findings.
Author contributions: Gideon Ptasznik had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kelly, Buteau, Papa, Page, Moon, Ong.
Acquisition of data: Ptasznik, Papa.
Analysis and interpretation of data: Moon, Murphy, Buteau, Papa.
Drafting of the manuscript: Ptasznik.
Critical revision of the manuscript for important intellectual content: Papa, Buteau, Moon.
Statistical analysis: Ptasznik, Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Moon, Kelly.
Other: None.
Financial disclosures: Gideon Ptasznik certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Data sharing: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Bray F.
Ferlay J.
Soerjomataram I.
Siegel R.L.
Torre L.A.
Jemal A.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
Negative predictive value of multiparametric magnetic resonance imaging in the detection of clinically significant prostate cancer in the prostate imaging reporting and data system era: a systematic review and meta-analysis.
Positive predictive value of Prostate Imaging Reporting and Data System version 2 for the detection of clinically significant prostate cancer: a systematic review and meta-analysis.
Gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer—updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis.
Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.
Findings in 1,123 men with preoperative (68)Ga-prostate-specific membrane antigen positron emission tomography/computerized tomography and multiparametric magnetic resonance imaging compared to totally embedded radical prostatectomy histopathology: implications for the diagnosis and management of prostate cancer.
The additive diagnostic value of prostate-specific membrane antigen positron emission tomography computed tomography to multiparametric magnetic resonance imaging triage in the diagnosis of prostate cancer (PRIMARY): a prospective multicentre study.
Improving diagnosis of primary prostate cancer with combined (68)Ga-prostate-specific membrane antigen-HBED-CC simultaneous PET and multiparametric MRI and clinical parameters.
A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/CT with (18)F-DCFPyL in prostate cancer patients (OSPREY).
Head-to-head comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in staging prostate cancer using histopathology and immunohistochemical analysis as a reference standard.
PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions.
Establishment and prospective validation of an SUV(max) cutoff value to discriminate clinically significant prostate cancer from benign prostate diseases in patients with suspected prostate cancer by (68)Ga-PSMA PET/CT: a real-world study.
Improved specificity with 68Ga PSMA PET/CT to detect clinically significant lesions “invisible” on multiparametric MRI of the prostate: a single institution comparative analysis with radical prostatectomy histology.
[(68)Ga-]PSMA-11 PET/CT and multiparametric MRI for gross tumor volume delineation in a slice by slice analysis with whole mount histopathology as a reference standard—implications for focal radiotherapy planning in primary prostate cancer.
(68)Ga-PSMA PET/CT combined with PET/ultrasound-guided prostate biopsy can diagnose clinically significant prostate cancer in men with previous negative biopsy results.
(68)Ga-PSMA positron emission tomography/computerized tomography for primary diagnosis of prostate cancer in men with contraindications to or negative multiparametric magnetic resonance imaging: a prospective observational study.
Detection and localisation of primary prostate cancer using 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology.
Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume detection in patients with primary prostate cancer based on slice by slice comparison with histopathology.
Combined utility of 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography and multiparametric magnetic resonance imaging in predicting prostate biopsy pathology.
Detection of intraprostatic tumor localisation with 18-fluorine prostate-specific membrane antigen (PSMA) PET/CT compared to radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial.
Diagnostic ability of Ga-68 PSMA PET to detect dominant and non-dominant tumors, upgrading and adverse pathology in patients with PIRADS 4–5 index lesions undergoing radical prostatectomy.
Diagnostic accuracy of 68 Ga-prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) and multiparametric (mp)MRI to detect intermediate-grade intra-prostatic prostate cancer using whole-mount pathology: impact of the addition of 68 Ga-PSMA PET to mpMRI.
Diagnostic performance of Gallium-68 prostate-specific membrane antigen positron emission tomography-computed tomography in intermediate and high risk prostate cancer.
68Ga-PSMA PET/CT better characterises localised prostate cancer after MRI and transperineal prostate biopsy: is 68Ga-PSMA PET/CT guided biopsy the future?.
Intraindividual comparison between 68 Ga-PSMA-PET/CT and mpMRI for intraprostatic tumor delineation in patients with primary prostate cancer: a retrospective analysis in 101 patients.
Prostate specific membrane antigen positron emission tomography may improve the diagnostic accuracy of multiparametric magnetic resonance imaging in localized prostate cancer.
Uncovering the invisible-prevalence, characteristics, and radiomics feature-based detection of visually undetectable intraprostatic tumor lesions in (68)GaPSMA-11 PET images of patients with primary prostate cancer.
(68)Ga-PSMA PET/CT targeted biopsy for the diagnosis of clinically significant prostate cancer compared with transrectal ultrasound guided biopsy: a prospective randomized single-centre study.
Assessing the accuracy of 68Ga-PSMA PET/CT compared with MRI in the initial diagnosis of prostate malignancy: a cohort analysis of 114 consecutive patients.
Biphasic GA 68-labeled prostate specific membrane antigen-11 positron emission tomography/computed tomography scans in the differential diagnosis and risk stratification of initial primary prostate cancer.
Detection of prostate cancer with 18F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible?.
The DeTeCT trial. World J Urol.2021; 39: 2439-2446
Bodar Y, Koene B, Meijer D, et al., editors. Determining the diagnostic value of PSMA-PET/CT imaging in patients with persistent high prostate specific antigen levels and negative prostate biopsies. Urol Oncol 2022;40:58.e1–7.
Machine learning-based prediction of invisible intraprostatic prostate cancer lesions on 68 Ga-PSMA-11 PET/CT in patients with primary prostate cancer.
Prospective analysis of clinically significant prostate cancer detection with [18F] DCFPyL PET/MRI compared to multiparametric MRI: a comparison with the histopathology in the radical prostatectomy specimen, the ProStaPET study.
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