Diagnostic Accuracy of Molecular Imaging Techniques for Detecting Prostate Cancer: A Systematic Review

Molecular imaging modalities show valuable non-invasive techniques capable of precisely and selectively addressing molecular markers associated with prostate cancer (PCa). This systematic review provides an overview of imaging markers utilized in positron emission tomography (PET) methods, specifically focusing on the pathways and mediators involved in PCa. This systematic review aims to evaluate and analyse existing literature on the diagnostic accuracy of molecular imaging techniques for detecting PCa. The PubMed, EBSCO, ScienceDirect, and Web of Science databases were searched, identifying 32 studies that reported molecular imaging modalities for detecting PCa. Numerous imaging modalities and radiotracers were used to detect PCa, including 68Ga-prostate-specific membrane antigen (PSMA) PET/computed tomography (CT), 68Ga-PSMA-11 PET/magnetic resonance imaging (MRI), 18F-PSMA-1007 PET/CT, 18F-DCFPyL PET/MRI, 18F-choline PET/MRI, and 18F-fluoroethylcholine PET/MRI. Across 11 studies, radiolabelled 68Ga-PSMA PET/CT imaging had a pooled sensitivity of 80 (95% confidence interval [CI]: 35–93), specificity of 90 (95% CI: 71–98), and accuracy of 86 (95% CI: 64–96). The PSMA-ligand 68Ga-PET/CT showed good diagnostic performance and appears promising for detecting and staging PCa.


Introduction
Prostate cancer (PCa) is a common form of cancer affecting men worldwide [1].Early PCa detection is crucial for effective treatment and improved patient outcomes.In recent years, molecular imaging techniques have emerged as promising tools for detecting PCa, its recurrence, and its metastasis [2].These techniques offer the potential for increased accuracy and timely detection, allowing for more targeted and personalised treatments.Conventional imaging methods such as computed tomography (CT) and magnetic resonance imaging (MRI) currently have limited sensitivity for detecting early-stage or low-grade PCa [3].Consequently, molecular imaging techniques targeting specific PCa biomarkers, such as the prostate-specific membrane antigen (PSMA) and androgen receptor (AR), have recently gained significant attention [4][5][6][7][8].These techniques offer a distinct advantage by enabling a thorough and precise delineation, along with quantification, of biological processes at the cellular level in vivo.
Recent developments in imaging tracers and exceptionally targeted probes have elevated molecular imaging into a field of considerable interest [9,10].There are several types of molecular imaging techniques, including conventional planar (2D) scintigraphy, single-photon emission computed tomography (SPECT), positron emission tomography (PET), and hybrid modalities.The SPECT and PET imaging techniques use gamma cameras and different isotopes (positrons) for imaging, respectively [11,12].These radionuclides can be coupled with suitable ligands possessing available binding sites [13].Various molecular imaging modalities, such as PET and MRI, and radiotracers have historically been used to examine patients with known PCa [14].Combining techniques in multimodality probes allows the limitations of using only one type of modality to be overcome, providing increased diagnostic accuracy in detecting PCa lesions than single modalities such as CT, MRI, and bone scintigraphy [8].These imaging techniques have emerged as accurate and precise tools for PCa staging and restaging [15][16][17][18].
There are several promising molecular imaging techniques for detecting PCa.One is PSMA PET/CT.PSMA is a protein that is overexpressed on the surface of PCa cells.PSMA PET/CT uses a radioactive tracer that binds to PSMA, allowing clinicians to visualise the cancer cells in the body [19,20]. 68Ga-PSMA PET/CT is now widely used at initial PCa staging in patients with high metastatic risk or biochemical recurrence [5,21].Active clinical trials are currently evaluating many PSMA-targeting agents, including 18 F-PSMA-1007, 68 Ga-PSMA-617, 68 Ga-PSMA-I&T, and 18 F-rhPSMA-7.3[22,23].Another promising molecular imaging technique is fluorodeoxyglucose (FDG) PET/CT.FDG PET/CT can detect PCa by visualising the areas of the body where the cancer cells are taking up more glucose than normal cells [24].However, FDG PET/CT is not as specific for PCa as PSMA PET/CT.Other promising molecular imaging techniques use PET radiotracers, such as 18 F-choline, 11 C-choline, and fluciclovine, to image patients with known PCa [15,25,26].
The diagnostic accuracy of molecular imaging in prostate cancer is influenced by many factors, such as the imaging modality, radiotracer selection, and technical parameters such as resolution and signal-to-noise ratio [7].Patient-specific factors, tumour characteristics, and operator expertise also significantly impact outcomes.Additionally, technological advancements and comprehensive clinical context integration are crucial for precise and reliable diagnostics [27].
The diagnostic accuracy of molecular imaging techniques for detecting PCa is constantly evolving.As these techniques continue to develop, they will likely become the standard of care for diagnosing and staging PCa.Therefore, this study aims to systematically review the diagnostic accuracy of molecular imaging techniques for detecting PCa, focusing on their role and ability to accurately assess PCa.

Inclusion and Exclusion Criteria
All original human studies involving patients with PCa that used PET/MRI, PET/CT, MRI, or CT scans were included in this review.Reviews and clinical cases studies were excluded from this review.

Study Selection
The study selection and data extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for conducting and reporting systematic reviews (Supplementary Materials) [28].This systematic review focused on studies that investigated the accuracy of PCa detection using molecular imaging techniques, including all studies that investigated the use of PET scintigraphy for PCa diagnosis, prognosis, and therapy response assessment at different clinical stages.
The initial search focused on screening the titles, abstracts, and full-text articles of potentially eligible studies for inclusion.This search was limited to articles published in English in peer-reviewed journals.An additional search was conducted to include all studies on the diagnostic accuracy of molecular imaging techniques for detecting PCa.Finally, two independent reviewers screened the titles and abstracts, and full-text articles of potentially eligible studies were assessed for inclusion.The study selection procedure is shown in a flow chart in Figure 1.
Finally, two independent reviewers screened the titles and abstracts, and full-text articles of potentially eligible studies were assessed for inclusion.The study selection procedure is shown in a flow chart in Figure 1.

Results
The search identified 32 studies that reported molecular imaging modalities for detecting and staging PCa and its recurrence.Several imaging modalities and radiotracers were used to detect PCa, including 68 Ga-PSMA PET/CT, 68 Ga-PSMA-11 PET/MRI, 18

Results
The search identified 32 studies that reported molecular imaging modalities for detecting and staging PCa and its recurrence.Several imaging modalities and radiotracers were used to detect PCa, including 68 Ga-PSMA PET/CT, 68 Ga-PSMA-11 PET/MRI, 18 F-PSMA-1007 PET/CT, 18 F-DCFPyL PET/MRI, 18 F-choline PET/MRI, and 18 F-fluoroethylcholine (FEC) PET/MRI.Eleven studies evaluated PCa staging and accuracy with 68 Ga-PSMA PET/CT and compared it to other modalities and radiotracers.Seven studies evaluated and compared PCa localisation with 68 Ga-PSMA-11 PET/MRI.Six studies evaluated the accuracy of 18 F-PSMA-1007 PET/CT and compared it to other modalities.Two studies evaluated 18 F-2-(3-{1-carboxy-5-[(6-[ 18 F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)pentanedioic acid (DCFPyL) PET/MRI.One study evaluated 18 F-choline PET/MRI, and another evaluated 18 F-FEC PET/MRI.One study evaluated 11 C-choline PET/MRI, and another evaluated 11 C-acetate PET/MRI.Finally, two studies evaluated 18 F-fluciclovine PET/CT.The details of these molecular imaging techniques, including their accuracy, sensitivity, specificity, positive prediction value (PPV), and negative predictive value (NPV), are summarised in Table 1. 68Ga-PSMA PET/CT emerged as a prominent molecular imaging technique in the evaluated studies, with eleven investigations dedicated to assessing its efficacy in PCa staging and accuracy.The studies collectively demonstrated a consistent and notable performance of 68 Ga-PSMA PET/CT in detecting nodal metastasis and recurrent lesions and staging primary PCa.The detection rates ranged from 64% to 96%, exhibiting its robust ability to identify primary lesions, particularly in patients with high-risk disease.Comparative analyses with other imaging modalities (MRI, CT) and radiotracers revealed that 68 Ga-PSMA PET/CT consistently outperformed the alternatives, affirming its superiority in providing accurate and reliable information for PCa staging.Cytawa et al. demonstrated that 68 Ga-PSMA PET/CT has a low sensitivity (35%) and high specificity (98%) for the detection of metastatic lymph nodes in patients with PCa [29].
Furthermore, the examination of PCa localization through 68 Ga-PSMA-11 PET/MRI in seven studies further emphasized the versatility of this technique, showing its capability to precisely localize PCa lesions.The accuracy of this hybrid imaging modality was particularly highlighted in the assessment of PCa localization, with reported rates ranging from 74% to 99%, providing precise and comprehensive information for PCa localization.
Finally, the efficacy of 18 F-PSMA-1007 PET/CT was investigated in six studies, each involving a comparative analysis with alternative imaging modalities for PCa assessment.The results consistently described the robust diagnostic accuracy of 18 F-PSMA-1007 PET/CT in detecting metastasis in recurrent and staging PCa, with reported accuracy rates ranging from 81% to 99%.Ingvar et al. reported that 18 F-PSMA-1007 PET/CT has a low sensitivity (26%) and high specificity (96%) for the detection of lymph node metastases in PCa patients [30].Table 2 compares the accuracy, sensitivity, and specificity of the radiolabelled 68 Ga-PSMA PET/CT, 68 Ga-PSMA-11 PET/MRI, and 18 F-PSMA-1007 PET/C techniques for PCa detection.

Discussion
Several studies have evaluated the diagnostic accuracy of molecular imaging techniques for PCa detection with different radiotracers [15][16][17]26,.Various PET/CT and PET/MRI radiotracers have been investigated for diagnosing and staging metastatic PCa.The compared radiotracers include 18 F or 11 C-choline, 11 C-acetate, 18 F-fluorocyclobutane-1-carboxylic acid ( 18 F-FACBC or 18 F-fluciclovine), and those targeting PSMA.Most are radiolabelled with either Gallium-68 or Fluorine-18.18 F-FDG is of limited use in PCa staging due to the relatively low glycolytic activity of most PCa tumours [56].

Diagnostic Performance of 68 Ga-PSMA PET/CT
PSMA is an excellent target for radionuclide PCa imaging due to its high expression in PCa cells.Recent studies have consistently demonstrated the superior diagnostic accuracy of 68 Ga-PSMA PET/CT in various aspects of PCa detection and characterization compared to multiparametric MRI (mpMRI) and other imaging modalities.Sonni et al. 2022 found that 68 Ga-PSMA-11 PET/CT outperformed mpMRI in detecting primary PCa, especially in high-risk cases, with detection rates of 85% and 83%, respectively [31].Donato et al., 2020, reported higher sensitivity for PSMA-PET/CT (95%) compared to MRI (86%), without compromising specificity [32].Glemser et al. 2020.demonstrated the superiority of 68 Ga-PSMA-11 PET-CT and PET-MRI over MRI alone, with higher accuracy for detecting PCa relapse lesions (64% for PET-CT, 67% for PET-MRI, and 43% for MRI) [16].Hofman et al. 2020 found that 68 Ga-PSMA PET/CT provided superior accuracy and sensitivity for N-staging compared to combined CT and bone scan findings [5]. 68Ga-PSMA PET/CT showed higher accuracy for detecting nodal metastasis in biochemically recurring and high-risk primary PCa.Hijazi et al., 2015, found that 68 Ga-PSMA PET/CT had 94% sensitivity and 99% specificity [33].Cytawa et al. 2020 reported a high accuracy of 93% and specificity of 98% for 68 Ga-PSMA I&T PET/CT in staging primary PCa.However, they reported a low sensitivity of 35% due to the high appearance of micrometastases [29].Liu et al., 2020, compared the diagnostic accuracy of 68 Ga-PSMA PET/CT and standard plus PET/CT-Ultrasound fusion targeted prostate biopsy for diagnosing clinically significant PCa. 68Ga-PSMA PET/CT had an accuracy of 83%, a sensitivity of 93%, and a specificity of 75% [34]. 68Ga-PSMA PET/CT was superior in terms of detecting metastasis in recurrent PCa compared to diffusion-weighted MRI, with a diagnostic accuracy of 89%, a sensitivity of 80%, and a specificity of 98% [35].Moreover, 68 Ga-PSMA PET/CT significantly impacted the initial staging and management plans for high-risk PCa patients, outperforming CT, MRI, and bone scans in terms of diagnostic accuracy [36].Chandra et al., 2020, highlighted the high diagnostic accuracy of prebiopsy 68 Ga-PSMA PET/CT in differentiating benign and malignant prostate lesions (sensitivity: 74%, specificity: 92%, overall accuracy: 86%) [37].Finally, the combination of 68 Ga-PSMA PET/CT and mpMRI demonstrated a higher diagnostic accuracy than either modality alone for detecting clinically significant PCa, with a sensitivity of 89%, specificity of 96%, and overall accuracy of 96% [17].
These findings collectively support the increasing role of 68 Ga-PSMA PET/CT as a powerful tool in the diagnosis and management of PCa.Although there are some limitations for primary lesions and T and N-staging, 68 Ga-PSMA PET/CT is the superior method for distant metastases compared to conventional methods.

Diagnostic Performance of 68 Ga-PSMA-11 PET/MRI
In a series of studies, researchers explored the diagnostic potential of combining PET/MRI techniques with PSMA tracers for PCa imaging.Jena et al. 2018 andTaneja et al. 2018 revealed that combining 68 Ga-PSMA-HBED-CC uptake patterns with simultaneously acquired mpMRI parameters using PET/MRI improved primary PCa diagnosis compared to using each technique alone [38,39].Al-Bayati et al. 2018 and Doan et al. 2023 found that integrated 68 Ga-PSMA-11 PET/MRI exhibited higher diagnostic accuracy than mpMRI alone, particularly in PCa tumours [40,42].Afshar-Oromieh et al., 2014, demonstrated that 68 Ga-PSMA PET/MRI outperformed PET/CT, detecting recurrent PCa more easily and accurately with lower radiation exposure.PET/CT was reported to have a sensitivity of 76% and specificity of 89%, while PET/MRI was reported to have a sensitivity of 87% and specificity of 89% [41].Muehlematter et al. 2019 compared mpMRI and 68 Ga-PSMA-11 PET/MRI for extracapsular extension (ECE) and seminal vesicle invasion (SVI), revealing higher specificity for 68 Ga-PSMA-11 PET/MRI [43].Finally, Eiber et al., 2016, found that simultaneous 68 Ga-PSMA HBED-CC PET/MRI improved the diagnostic accuracy for localizing primary PCa compared to mpMRI or PET alone, with reported accuracy, sensitivity, and specificity of 88%, 76%, and 97%, respectively [44].These studies collectively underscore the enhanced diagnostic capabilities of combining PSMA-targeted PET imaging with MRI for various aspects of PCa assessment.In summary, there are some limitations of PET/MRI in detecting small LNs metastases, and a limited number of studies exist to compare the performance of PET/MRI against PET/CT.
This review focused on collecting data on the diagnostic performance of various imaging modalities in patients with PCa.The current study's data show the good diagnostic performance of PET/CT or PET/MRI with different radiopharmaceuticals, which have high accuracy in detecting metastases and provide valuable insights for diagnosing, staging, and managing PCa.Molecular imaging techniques can add clinical benefits compared to conventional imaging for detecting PCa lymph node metastasis and recurrence after radical prostatectomy [2].The limitation of this review is the limited number of studies on the diagnostic performance of all PET/MRI tracers in PCa, which reduces the statistical power of the analysis.
The diagnostic accuracy of molecular imaging techniques for detecting PCa has been a subject of research in recent years.Therefore, more research is needed to confirm these findings and to determine the optimal use of these techniques in clinical practice.

Conclusions
Molecular imaging techniques offer several advantages over traditional imaging techniques for PCa detection, including increased accuracy, personalised treatment, timely detection, and comprehensive assessment.PSMA-ligand PET/CT is superior to conventional methods for detecting distant metastases, mainly due to its greater accuracy. 68Ga-PSMA PET/CT offers an approach with moderate sensitivity and high specificity for detecting metastatic LNs and staging PCa.Furthermore, PET/MRI with different radiopharmaceuticals has shown promising accuracy and effectiveness for PCa diagnosis and management.Further research is needed to explore the diagnostic accuracy of these techniques in different patient populations and disease stages.

A
systematic search was performed in several databases including PubMed, EBSCO, ScienceDirect, and Web of Science for relevant articles published between 2010 and 2023.The search strategy used a combination of medical subject headings [Mesh] and keywords related to molecular imaging techniques and PCa.Several keywords (alone or in combination) were searched to find relevant articles: molecular imaging [*], prostate cancer [*], detecting [*], and accuracy [*].

Figure 1 .
Figure 1.PRISM flow chart illustrates the process of identifying eligible studies for inclusion.

Figure 1 .
Figure 1.PRISM flow chart illustrates the process of identifying eligible studies for inclusion.

Table 1 .
Summary of the studies that reported molecular imaging techniques for the detection of prostate cancer.