68Ga-Prostate-specific membrane antigen (PSMA) positron emission tomography (pet) in prostate cancer: a systematic review and meta-analysis

Cristina S. Matushita Ana M. Marques da Silva Phelipi N. Schuck Matteo Bardisserotto Diego B. Piant Jonatas L. Pereira Juliano J. Cerci George B. Coura Filho Fabio P. Esteves Barbara J. Amorim Gustavo V. Gomes Ana Emília T. Brito Wanderley M. Bernardo Eduardo Mundstock Stefano Fanti Bruna Macedo Diego H. Roman Cinthia Scatolin Tem-Pass Bruno Hochhegger About the authors

ABSTRACT

Introduction:

Prostate cancer (PC) is the second most commonly diagnosed cancer in males. 68Ga-PSMA PET/CT, a non-invasive diagnostic tool to evaluate PC with prostate-specific membrane antigen (PSMA) expression, has emerged as a more accurate alternative to assess disease staging. We aimed to identify predictors of positive 68Ga-PSMA PET and the accuracy of this technique.

Materials and methods:

Diagnostic accuracy cross-sectional study with prospective and retrospective approaches. We performed a comprehensive literature search on PubMed, Cochrane Library, and Embase database in search of studies including PC patients submitted to radical prostatectomy or radiotherapy with curative intent and presented biochemical recurrence following ASTRO 1996 criteria. A total of 35 studies involving 3910 patients submitted to 68-Ga-PSMA PET were included and independently assessed by two authors: 8 studies on diagnosis, four on staging, and 23 studies on restaging purposes. The significance level was α=0.05.

Results:

pooled sensitivity and specificity were 0.90 (0.86-0.93) and 0.90 (0.82-0.96), respectively, for diagnostic purposes; as for staging, pooled sensitivity and specificity were 0.93 (0.86-0.98) and 0.96 (0.92-0.99), respectively. In the restaging scenario, pooled sensitivity and specificity were 0.76 (0.74-0.78) and 0.45 (0.27-0.58), respectively, considering the identification of prostate cancer in each described situation. We also obtained specificity and sensitivity results for PSA subdivisions.

Conclusion:

68Ga-PSMA PET provides higher sensitivity and specificity than traditional imaging for prostate cancer.

Keywords:
Prostate cancer; familial [Supplementary Concept]; Glu-NH-CO-NH-Lys-(Ahx)-((68)Ga(HBED-CC)) [Supplementary Concept]; (225)Ac-PSMA-617 [Supplementary Concept]

INTRODUCTION

Prostate cancer is the second most commonly diagnosed cancer in males worldwide and, in the United States, the most commonly diagnosed invasive cancer in males. Prostate cancer is also the fifth leading cancer-related cause of death worldwide (11. Steele CB, Li J, Huang B, Weir HK. Prostate cancer survival in the United States by race and stage (2001-2009): Findings from the CONCORD-2 study. Cancer. 2017; 123(Suppl 24):5160-77.). The increase in life expectancy will lead to an increase in disease incidence, which is becoming an epidemic in terms of male public health. In the United States, prostate cancer is also the second most common type of cancer and the second leading cause of cancer death (second only to lung cancer). In 2017, the incidence and deaths from this disease were 161.360 cases and 26.730 cases, respectively (22. [No authors]. National Cancer Institute Surveillance, Epidemiology, and ERP. Cancer Stat Facts: Prostate Cancer. NIH. [Internet]. Availlable at <https://seer.cancer.gov/statfacts/html/prost.html>.
https://seer.cancer.gov/statfacts/html/p...
).

As the presence and location of the primary or recurrent tumors are critical for planning patient management, a vast range of imaging modalities are being assessed as tools for the evaluation of patients with prostate cancer in primary and secondary staging (11. Steele CB, Li J, Huang B, Weir HK. Prostate cancer survival in the United States by race and stage (2001-2009): Findings from the CONCORD-2 study. Cancer. 2017; 123(Suppl 24):5160-77., 22. [No authors]. National Cancer Institute Surveillance, Epidemiology, and ERP. Cancer Stat Facts: Prostate Cancer. NIH. [Internet]. Availlable at <https://seer.cancer.gov/statfacts/html/prost.html>.
https://seer.cancer.gov/statfacts/html/p...
).

While the introduction of PSA-screening has led to earlier diagnosis of prostate cancer, a subset of patients developed high-risk of metastatic disease (33. Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, et al. Sensitivity, Specificity, and Predictors of Positive 68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016; 70:926-37.). A more accurate alternative for assessing disease staging is crucial for treatment decisions. However, all current conventional imaging modalities show limitations, and optimizing these imaging modalities is an intense and rapidly developing field of research. In the last decades, we have seen the development and improvement of functional imaging. Among those, combined positron emission tomography (PET)/computed tomography (CT) is one of the most promising techniques (44. Umbehr MH, Müntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur Urol. 2013; 64:106-17.).

68Ga-PSMA PET-CT is a non-invasive diagnostic tool to evaluate prostate cancer with increased prostate-specific membrane antigen (PSMA) expression. PSMA is a protein expressed on dysplastic prostate cells, with levels of expression of 100-1000 times that of healthy cells, which increase even further with higher stages and grades of prostate cancer (55. Herrmann K, Bluemel C, Weineisen M, Schottelius M, Wester HJ, Czernin J, et al. Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy. J Nucl Med. 2015; 56:855-61., 66. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014; 41:11-20.).

68Ga is a positron emitter obtained from a 68Ge/68Ga generator system with 68min of half-life. PSMA demonstrated to have high affinity and specific internalization into prostate cancer cells (77. Eder M, Schäfer M, Bauder-Wüst U, Hull WE, Wängler C, Mier W, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012; 23:688-97.). 68Ga-PSMA-11 was first synthesized and evaluated by the Heidelberg group in Germany, and its accumulation is proportional to the expression level of PSMA (88. Afshar-Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA, et al. Reply to Reske et al.: PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 2013; 40:971-2.). Other PSMA ligands, such as 68Ga-PSMA-617 and 68Ga-PSMA-I&T, showed similar distribution and image properties to 68Ga-PSMA-11 (66. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014; 41:11-20., 88. Afshar-Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA, et al. Reply to Reske et al.: PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 2013; 40:971-2.), the reason why all three are known as 68Ga-PSMA.

To date, the use of 68Ga-PSMA has been well reported, and initial staging revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers (77. Eder M, Schäfer M, Bauder-Wüst U, Hull WE, Wängler C, Mier W, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012; 23:688-97.). Not only diagnosis but also among the management changes observed in the studies, the proportion of inter and intra-modality was relatively similar, indicating that 68Ga-PSMA-PET may help better plan the optimal dose, site, and volume of radiation in the case of salvage radiotherapy. We systematically reviewed the literature outlining the use of 68Ga-PSMA PET imaging in prostate cancer. Our primary objective was to perform a literature review to determine 68Ga-PSMA PET accuracy in prostate cancer, and our secondary objective was to identify predictors of positive 68Ga-PSMA PET.

MATERIALS AND METHODS

Bibliographic search

A systematic review was performed under the Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines (99. Afshar-Oromieh A, Hetzheim H, Kratochwil C, Benesova M, Eder M, Neels OC, et al. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. J Nucl Med. 2015; 56:1697-705., 1010. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700.).

We performed a comprehensive literature search of PubMed, Cochrane Library, Embase, Web of Science, Scielo, Scopus and Lilacs database, without date restriction up to 05/04/2019, using the following MeSH vocabulary key words and free text words: ((Prostate Neoplasms OR Prostate Neoplasm OR Prostatic Neoplasm OR Prostate Cancer OR Prostate Cancers OR Prostatic Cancer OR Prostatic Cancers) AND (Positron Emission Tomography OR PET) AND (PROSTATIC SPECIFIC MEMBRANE ANTIGEN OR PSMA OR GALLIUM OR GA)).

Inclusion and exclusion criteria

Patients: patients diagnosed with prostate cancer and patients initially submitted to radical prostatectomy (RP) or radiotherapy with curative intent who showed biochemical recurrence defined as a prostate-specific antigen (PSA) elevation of ≥0.2ng/mL in patients with primary prostatectomy or as a PSA above the nadir after primary radiation therapy (according to the ASTRO 1996 criteria (1111. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane 2011. [Internet]. Available at. <https://training.cochrane.org/cochrane-handbook-systematic-reviews-interventions#how-to-access>
https://training.cochrane.org/cochrane-h...
)).

Index test: 68Ga-PSMA-11 PET

Target condition: Diagnostic, staging, local recurrence, lymph nodal spread, distant metastasis.

Study design: Diagnostic accuracy cross-sectional study with prospective and retrospective approaches.

Exclusion criteria: case reports, animal, and phantom studies were excluded.

No language or sample-size restrictions were used.

Reference standard

A composite standard including changing in PSA values, clinical follow-up, and histopathological findings.

Outcome measures

The outcome measures included identification of predictors of 68Ga-PSMA-PET positivity, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy.

Study selection

The titles and abstracts retrieved from bibliographic searches were independently screened by two authors (MCS and PDB). The full texts of all relevant articles were obtained and independently assessed for inclusion by the same authors aforementioned. Studies that did not fulfill the inclusion criteria were excluded.

Quality assessment

The studies were independently assessed by two authors (MCS and PDB) using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS 2) checklist tool (1212. Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006; 65:965-74.). The QUADAS-2 tool assesses four domains: risk of bias in patient selection, index test, reference standard, and the timing of reference standard. Each paper was scored independently by two evaluators (MCS and PDB), and discrepancies were discussed and resolved in common agreement.

Data extraction

The following information was extracted from each study: sample size, age of the patients, indication for PET (diagnosis, primary staging or recurrent disease staging), PSA level, previous therapies, initial cancer stage, 68Ga-PSMA-11 PET characteristics, rates of positive PET, and pathology correlation data (when available). When pathology correlation data were available, numbers of true positives, false positives, true negatives and false negatives were collected as appropriated. The 68Ga-PSMA-PET for diagnosis, primary staging, and recurrent cancer staging purposes data were displayed separately, when available.

The extracted data were collected in Excel 2007 (Microsoft Corporation, Redmond, CA, USA), and analysis was performed using Meta-Disc 1,4 (1313. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011; 155:529-36.). The detection rates were pooled using the generic inverse variance approach in the random-effects model (1414. Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol. 2006; 6:31.). Heterogeneity in the meta-analysis of detection rates was assessed using the X2 statistic in the I2 statistic (1010. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700.). The I2 statistic indicates the percentage of the overall variability that can be attributed to between-study (or inter-study) variability, as opposed to within-study (or intra-study) variability. An I2 more significant than 50% is considered to indicate substantial heterogeneity (1010. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700.).

We explored the variability in diagnostic accuracy across studies by plotting the estimates of the observed sensitivities and specificities in forest plots and receiver-operating characteristic (ROC) space. Whenever data for computing true-positive, false-negative, true-negative, and false-positive rates were available, we performed meta-analyses using the bivariate model to produce summary sensitivities and specificities (1313. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011; 155:529-36.). We remade the calculations, excluding one article at a time, to verify if one of the studies was the main responsible for the heterogeneity in the meta-analyses. If substantial heterogeneity in the prevalence among the studies was observed, we estimated PPVs and NPVs by considering their relationship in the sensitivity, specificity and prevalence, and generating different scenarios with different prevalence. The significance level was set at α=0.05.

In patients undergoing a scan for disease recurrence, we correlated the data (sensitivity and specificity) to PSA level, in subgroups divided as follow: PSA level <0.5ng/mL, PSA level between 0.5ng/mL and 1ng/mL, PSA level between 1ng/mL and 2ng/mL and PSA level higher than 2ng/mL.

RESULTS

Identification of Studies

Figure-1 summarizes the process of identification and selection of studies. The electronic search was complemented by manually checking the reference lists in review papers and all included studies. Overall, we included 87 studies comprising of a total of 9046 patients (range: 6-635 patients per study): 17 studies on diagnostic (1515. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88.

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17. Zamboglou C, Drendel V, Jilg CA, Rischke HC, Beck TI, Schultze-Seemann W, et al. 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. Theranostics. 2017; 7:228-237.

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21. Zamboglou C, Schiller F, Fechter T, Wieser G, Jilg CA, Chirindel A, et al. (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison. Theranostics. 2016; 6:1619-28.

22. Sahlmann CO, Meller B, Bouter C, Ritter CO, Ströbel P, Lotz J, et al. Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma. Eur J Nucl Med Mol Imaging. 2016; 43:898-905.

23. Rahbar K, Weckesser M, Huss S, Semjonow A, Breyholz HJ, Schrader AJ, et al. Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer. J Nucl Med. 2016; 57:563-7.

24. Hijazi S, Meller B, Leitsmann C, Strauss A, Meller J, Ritter CO, et al. Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography. Prostate. 2015; 75:1934-40.

25. Kabasakal L, Demirci E, Ocak M, Akyel R, Nematyazar J, Aygun A, et al. Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging. Nucl Med Commun. 2015; 36:582-7.

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27. Sanli Y, Kuyumcu S, Sanli O, Buyukkaya F, İribaş A, Alcin G, et al. Relationships between serum PSA levels, Gleason scores and results of 68Ga-PSMAPET/CT in patients with recurrent prostate cancer. Ann Nucl Med. 2017; 31:709-17.

28. Budäus L, Leyh-Bannurah SR, Salomon G, Michl U, Heinzer H, Huland H, et al. Initial Experience of (68)Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. Eur Urol. 2016; 69:393-6.

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30. Lopci E, Saita A, Lazzeri M, Lughezzani G, Colombo P, Buffi NM, et al. 68Ga-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. J Urol. 2018; 200:95-103.
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33. Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D, et al. 68Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging. 2017; 44:941-9.

34. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic Efficacy of (68)Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol. 2016; 195:1436-43. [Internet]. Available at. < https://www.sciencedirect.com/science/article/abs/pii/S0022534715053975?via%3Dihub>
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39. Herlemann A, Wenter V, Kretschmer A, Thierfelder KM, Bartenstein P, Faber C, et al. 68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol. 2016; 70:553-7.

40. Giesel FL, Sterzing F, Schlemmer HP, Holland-Letz T, Mier W, Rius M, et al. Intra-individual comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:1400-6.

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42. Vinsensia M, Chyoke PL, Hadaschik B, Holland-Letz T, Moltz J, Kopka K, et al. 68Ga-PSMA PET/CT and Volumetric Morphology of PET-Positive Lymph Nodes Stratified by Tumor Differentiation of Prostate Cancer. J Nucl Med. 2017; 58:1949-55.

43. Afshar-Oromieh A, Sattler LP, Mier W, Hadaschik BA, Debus J, Holland-Letz T, et al. The Clinical Impact of Additional Late PET/CT Imaging with 68Ga-PSMA-11 (HBED-CC) in the Diagnosis of Prostate Cancer. J Nucl Med. 2017; 58:750-5.

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45. Dyrberg E, Hendel HW, Huynh THV, Klausen TW, Løgager VB, Madsen C, et al. 68Ga-PSMA-PET/CT in comparison with 18F-fluoride-PET/CT and whole-body MRI for the detection of bone metastases in patients with prostate cancer: a prospective diagnostic accuracy study. Eur Radiol. 2019; 29:1221-30.

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47. Grubmüller B, Baltzer P, D'Andrea D, Korn S, Haug AR, Hacker M, et al. 68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making. Eur J Nucl Med Mol Imaging. 2018;45:235-42.

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50. Lengana T, Lawal IO, Boshomane TG, Popoola GO, Mokoala KMG, Moshokoa E, et al. 68Ga-PSMA PET/CT Replacing Bone Scan in the Initial Staging of Skeletal Metastasis in Prostate Cancer: A Fait Accompli? Clin Genitourin Cancer. 2018; 16:392-401.

51. Soldatov A, von Klot CAJ, Walacides D, Derlin T, Bengel FM, Ross TL, et al. Patterns of Progression After 68Ga-PSMA-Ligand PET/CT-Guided Radiation Therapy for Recurrent Prostate Cancer. Int J Radiat Oncol Biol Phys. 2019; 103:95-104.

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53. Uprimny C, Kroiss AS, Fritz J, Decristoforo C, Kendler D, von Guggenberg E, et al. Early PET imaging with [68]Ga-PSMA-11 increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence. Eur J Nucl Med Mol Imaging. 2017; 44:1647-55.

54. Uprimny C, Svirydenka A, Fritz J, Kroiss AS, Nilica B, Decristoforo C, et al. Comparison of [68Ga]Ga-PSMA-11 PET/CT with [18F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy. Eur J Nucl Med Mol Imaging. 2018; 45:1873-83.

55. Uslu-Beşli L, Sağer S, Akgün E, Asa S, Şahin OE, Demirdağ Ç, et al. Comparison of Ga-68 PSMA positron emission tomography/computerized tomography with Tc-99m MDP bone scan in prostate cancer patients. Turk J Med Sci. 2019; 49:301-10.

56. von Klot CJ, Merseburger AS, Böker A, Schmuck S, Ross TL, Bengel FM, et al. 68Ga-PSMA PET/CT Imaging Predicting Intraprostatic Tumor Extent, Extracapsular Extension and Seminal Vesicle Invasion Prior to Radical Prostatectomy in Patients with Prostate Cancer. Nucl Med Mol Imaging. 2017; 51:314-22.
-5757. Wong HS, Leung J, Bartholomeusz D, Sutherland P, Le H, Nottage M, et al. Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer. J Med Imaging Radiat Oncol. 2018; 62:816-22.), and 45 studies on restaging (55. Herrmann K, Bluemel C, Weineisen M, Schottelius M, Wester HJ, Czernin J, et al. Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy. J Nucl Med. 2015; 56:855-61., 2323. Rahbar K, Weckesser M, Huss S, Semjonow A, Breyholz HJ, Schrader AJ, et al. Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer. J Nucl Med. 2016; 57:563-7., 5757. Wong HS, Leung J, Bartholomeusz D, Sutherland P, Le H, Nottage M, et al. Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer. J Med Imaging Radiat Oncol. 2018; 62:816-22.

58. Roach PJ, Francis R, Emmett L, Hsiao E, Kneebone A, Hruby G, et al. The Impact of 68Ga-PSMA PET/CT on Management Intent in Prostate Cancer: Results of an Australian Prospective Multicenter Study. J Nucl Med. 2018; 59:82-8.

59. Bluemel C, Krebs M, Polat B, Linke F, Eiber M, Samnick S, et al. 68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT. Clin Nucl Med. 2016; 41:515-21.

60. Schmuck S, Nordlohne S, von Klot CA, Henkenberens C, Sohns JM, Christiansen H, et al. Comparison of standard and delayed imaging to improve the detection rate of [68Ga]PSMA I&T PET/CT in patients with biochemical recurrence or prostate-specific antigen persistence after primary therapy for prostate cancer. Eur J Nucl Med Mol Imaging. 2017; 44:960-8.

61. Uprimny C, Kroiss AS, Decristoforo C, Fritz J, Warwitz B, Scarpa L, et al. Early dynamic imaging in 68Ga- PSMA-11 PET/CT allows discrimination of urinary bladder activity and prostate cancer lesions. Eur J Nucl Med Mol Imaging. 2017; 44:765-75.

62. Berliner C, Tienken M, Frenzel T, Kobayashi Y, Helberg A, Kirchner U, et al. Detection rate of PET/CT in patients with biochemical relapse of prostate cancer using [68Ga]PSMA I&T and comparison with published data of [68Ga]PSMA HBED-CC. Eur J Nucl Med Mol Imaging. 2017; 44:670-7.

63. Einspieler I, Rauscher I, Düwel C, Krönke M, Rischpler C, Habl G, et al. Detection Efficacy of Hybrid 68Ga-PSMA Ligand PET/CT in Prostate Cancer Patients with Biochemical Recurrence After Primary Radiation Therapy Defined by Phoenix Criteria. J Nucl Med. 2017; 58:1081-7.

64. Kabasakal L, Demirci E, Nematyazar J, Akyel R, Razavi B, Ocak M, et al. The role of PSMA PET/CT imaging in restaging of prostate cancer patients with low prostate-specific antigen levels. Nucl Med Commun. 2017; 38:149-55.

65. Schwenck J, Rempp H, Reischl G, Kruck S, Stenzl A, Nikolaou K, et al. Comparison of 68Ga-labelled PSMA-11 and 11C-choline in the detection of prostate cancer metastases by PET/CT. Eur J Nucl Med Mol Imaging. 2017; 44:92-101.

66. Hruby G, Eade T, Kneebone A, Emmett L, Guo L, Ho B,et al. Delineating biochemical failure with 68Ga-PSMA-PET following definitive external beam radiation treatment for prostate cancer. Radiother Oncol. 2017; 122:99-102.

67. Dietlein F, Kobe C, Neubauer S, Schmidt M, Stockter S, Fischer T, et al. PSA-Stratified Performance of 18F- and 68Ga-PSMA PET in Patients with Biochemical Recurrence of Prostate Cancer. J Nucl Med. 2017; 58:947-52.

68. Meredith G, Wong D, Yaxley J, Coughlin G, Thompson L, Kua B, et al. The use of 68 Ga-PSMA PET CT in men with biochemical recurrence after definitive treatment of acinar prostate cancer. BJU Int. 2016; 118 Suppl 3:49-55.

69. Pfister D, Porres D, Heidenreich A, Heidegger I, Knuechel R, Steib F, et al. Detection of recurrent prostate cancer lesions before salvage lymphadenectomy is more accurate with (68)Ga-PSMA-HBED-CC than with (18)F-Fluoroethylcholine PET/CT. Eur J Nucl Med Mol Imaging. 2016;43:1410-7.

70. Sachpekidis C, Eder M, Kopka K, Mier W, Hadaschik BA, Haberkorn U, et al. (68)Ga-PSMA-11 dynamic PET/CT imaging in biochemical relapse of prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:1288-99.

71. Henkenberens C, von Klot CA, Ross TL, Bengel FM, Wester HJ, Merseburger AS, et al. (68)Ga-PSMA ligand PET/CT-based radiotherapy in locally recurrent and recurrent oligometastatic prostate cancer: Early efficacy after primary therapy. Strahlenther Onkol. 2016; 192:431-9.

72. van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B, et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int. 2016; 117:732-9.

73. Verburg FA, Pfister D, Heidenreich A, Vogg A, Drude NI, Vöö S, et al. Extent of disease in recurrent prostate cancer determined by [(68)Ga]PSMA-HBED-CC PET/CT in relation to PSA levels, PSA doubling time and Gleason score. Eur J Nucl Med Mol Imaging. 2016; 43:397-403.

74. Ceci F, Uprimny C, Nilica B, Geraldo L, Kendler D, Kroiss A, et al. (68)Ga-PSMA PET/CT for restaging recurrent prostate cancer: which factors are associated with PET/CT detection rate? Eur J Nucl Med Mol Imaging. 2015; 42:1284-94.

75. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. 2015;56:668-74.

76. Schmidt-Hegemann NS, Eze C, Li M, Rogowski P, Schaefer C, Stief C, et al. Impact of 68Ga-PSMA PET/CT on the Radiotherapeutic Approach to Prostate Cancer in Comparison to CT: A Retrospective Analysis. J Nucl Med. 2019; 60:963-70.

77. Afaq A, Alahmed S, Chen SH, Lengana T, Haroon A, Payne H, et al. Impact of 68Ga-Prostate-Specific Membrane Antigen PET/CT on Prostate Cancer Management. J Nucl Med. 2018; 59:89-92.

78. Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M, et al. The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015; 42:197-209.

79. Akdemir EN, Tuncel M, Akyol F, Bilen CY, Baydar DE, Karabulut E, et al. 68Ga-labelled PSMA ligand HBED-CC PET/CT imaging in patients with recurrent prostate cancer. World J Urol. 2019; 37:813-21.

80. Barbaud M, Frindel M, Ferrer L, Le Thiec M, Rusu D, Rauscher A, et al. 68Ga-PSMA-11 PET-CT study in prostate cancer patients with biochemical recurrence and non-contributive 18F-Choline PET-CT: Impact on therapeutic decision-making and biomarker changes. Prostate. 2019; 79:454-61.

81. Bashir U, Tree A, Mayer E, Levine D, Parker C, Dearnaley D, et al. Impact of Ga-68-PSMA PET/CT on management in prostate cancer patients with very early biochemical recurrence after radical prostatectomy. Eur J Nucl Med Mol Imaging. 2019; 46:901-7.

82. Calais J, Fendler WP, Eiber M, Gartmann J, Chu FI, Nickols NG, et al. Impact of 68Ga-PSMA-11 PET/CT on the Management of Prostate Cancer Patients with Biochemical Recurrence. J Nucl Med. 2018; 59:434-41.

83. Calais J, Czernin J, Cao M, Kishan AU, Hegde JV, Shaverdian N, et al. 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. J Nucl Med. 2018; 59:230-7.

84. Caroli P, Sandler I, Matteucci F, De Giorgi U, Uccelli L, Celli M, et al. 68Ga-PSMA PET/CT in patients with recurrent prostate cancer after radical treatment: prospective results in 314 patients. Eur J Nucl Med Mol Imaging. 2018; 45:2035-44.

85. Ceci F, Castellucci P, Graziani T, Farolfi A, Fonti C, Lodi F, et al. 68Ga-PSMA-11 PET/CT in recurrent prostate cancer: efficacy in different clinical stages of PSA failure after radical therapy. Eur J Nucl Med Mol Imaging. 2019; 46:31-9.

86. Dewes S, Schiller K, Sauter K, Eiber M, Maurer T, Schwaiger M, et al. Integration of (68)Ga-PSMA-PET imaging in planning of primary definitive radiotherapy in prostate cancer: a retrospective study. Radiat Oncol. 2016;11:73.

87. Dietlein M, Kobe C, Kuhnert G, Stockter S, Fischer T, Schomäcker K, et al. Comparison of [(18)F]DCFPyL and [(68)Ga]Ga-PSMA-HBED-CC for PSMA-PET Imaging in Patients with Relapsed Prostate Cancer. Mol Imaging Biol. 2015; 17:575-84.

88. Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol. 2019; 5:856-63.

89. Fennessy N, Lee J, Shin J, Ho B, Ali SA, Paschkewitz R, et al. Frusemide aids diagnostic interpretation of 68 Ga-PSMA positron emission tomography/CT in men with prostate cancer. J Med Imaging Radiat Oncol. 2017; 61:739-44.

90. Gauthé, M et al. “TEP/TDM et récidive biologique d'adénocarcinome prostatique: apport du 68Ga-PSMA-11 lorsque la 18F-fluorocholine n'est pas contributive” [PET/CT and biochemical recurrence of prostate adenocarcinoma: Added value of 68Ga-PSMA-11 when 18F-fluorocholine is non-contributive]. Progrès en Urologie 2017;27: 474-81. Available at. < https://www.urofrance.org/sites/default/files/fileadmin/documents/data/PU/2017/3247/69449/FR/1128952/main.pdf>
https://www.urofrance.org/sites/default/...

91. Hamed MAG, Basha MAA, Ahmed H, Obaya AA, Afifi AHM, Abdelbary EH. 68Ga-PSMA PET/CT in Patients with Rising Prostatic-Specific Antigen After Definitive Treatment of Prostate Cancer: Detection Efficacy and Diagnostic accuracy. Acad Radiol. 2019; 26:450-60.

92. Hope TA, Aggarwal R, Chee B, Tao D, Greene KL, Cooperberg MR, et al. Impact of 68Ga-PSMA-11 PET on Management in Patients with Biochemically Recurrent Prostate Cancer. J Nucl Med. 2017; 58:1956-61.

93. Jilg CA, Drendel V, Rischke HC, Beck T, Vach W, Schaal K, et al. Diagnostic Accuracy of Ga-68-HBED-CC-PSMA-Ligand-PET/CT before Salvage Lymph Node Dissection for Recurrent Prostate Cancer. Theranostics. 2017; 7:1770-80.

94. Mattiolli AB, Santos A, Vicente A, Queiroz M, Bastos D, Herchenhorn D, et al. Impact of 68GA-PSMA PET / CT on treatment of patients with recurrent / metastatic high risk prostate cancer - a multicenter study. Int Braz J Urol. 2018; 44:892-9.

95. McCarthy M, Francis R, Tang C, Watts J, Campbell A. A Multicenter Prospective Clinical Trial of 68Gallium PSMA HBED-CC PET-CT Restaging in Biochemically Relapsed Prostate Carcinoma: Oligometastatic Rate and Distribution Compared With Standard Imaging. Int J Radiat Oncol Biol Phys. 2019; 104:801-8.

96. Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. 2015; 56:1185-90.

97. Rauscher I, Maurer T, Beer AJ, Graner FP, Haller B, Weirich G, et al. Value of 68Ga-PSMA HBED-CC PET for the Assessment of Lymph Node Metastases in Prostate Cancer Patients with Biochemical Recurrence: Comparison with Histopathology After Salvage Lymphadenectomy. J Nucl Med. 2016; 57:1713-9.

98. Schmidkonz C, Cordes M, Beck M, Goetz TI, Schmidt D, Prante O, et al. SPECT/CT With the PSMA Ligand 99mTc-MIP-1404 for Whole-Body Primary Staging of Patients With Prostate Cancer. Clin Nucl Med. 2018; 43:225-31.

99. Walacides D, Meier A, Knöchelmann AC, Meinecke D, Derlin T, Bengel FM, et al. Comparison of 68 Ga-PSMA ligand PET/CT versus conventional cross-sectional imaging for target volume delineation for metastasis-directed radiotherapy for metachronous lymph node metastases from prostate cancer. Strahlenther Onkol. 2019; 195:420-9.
-100100. Wondergem M, van der Zant FM, Knol RJJ, Lazarenko SV, Pruim J, de Jong IJ. 18F-DCFPyL PET/CT in the Detection of Prostate Cancer at 60 and 120 Minutes: Detection Rate, Image Quality, Activity Kinetics, and Biodistribution. J Nucl Med. 2017; 58:1797-804.).

Figure 1
Summary of the study selection process.

Study design and quality

A total of 52 studies used a retrospective design (66. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014; 41:11-20., 1515. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88., 2121. Zamboglou C, Schiller F, Fechter T, Wieser G, Jilg CA, Chirindel A, et al. (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison. Theranostics. 2016; 6:1619-28.

22. Sahlmann CO, Meller B, Bouter C, Ritter CO, Ströbel P, Lotz J, et al. Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma. Eur J Nucl Med Mol Imaging. 2016; 43:898-905.

23. Rahbar K, Weckesser M, Huss S, Semjonow A, Breyholz HJ, Schrader AJ, et al. Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer. J Nucl Med. 2016; 57:563-7.

24. Hijazi S, Meller B, Leitsmann C, Strauss A, Meller J, Ritter CO, et al. Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography. Prostate. 2015; 75:1934-40.

25. Kabasakal L, Demirci E, Ocak M, Akyel R, Nematyazar J, Aygun A, et al. Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging. Nucl Med Commun. 2015; 36:582-7.

26. Gupta M, Choudhury PS, Hazarika D, Rawal S. A Comparative Study of 68Gallium-Prostate Specific Membrane Antigen Positron Emission Tomography-Computed Tomography and Magnetic Resonance Imaging for Lymph Node Staging in High Risk Prostate Cancer Patients: An Initial Experience. World J Nucl Med. 2017;16:186-91.

27. Sanli Y, Kuyumcu S, Sanli O, Buyukkaya F, İribaş A, Alcin G, et al. Relationships between serum PSA levels, Gleason scores and results of 68Ga-PSMAPET/CT in patients with recurrent prostate cancer. Ann Nucl Med. 2017; 31:709-17.
-2828. Budäus L, Leyh-Bannurah SR, Salomon G, Michl U, Heinzer H, Huland H, et al. Initial Experience of (68)Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. Eur Urol. 2016; 69:393-6., 3131. Wu SY, Boreta L, Shinohara K, Nguyen H, Gottschalk AR, Hsu IC, et al. Impact of Staging 68Ga-PSMA-11 PET Scans on Radiation Treatment Plansin Patients With Prostate Cancer. Urology. 2019; 125:154-62.

32. Zhang J, Shao S, Wu P, Liu D, Yang B, Han D, et al. Diagnostic performance of 68Ga-PSMA PET/CT in the detection of prostate cancer prior to initial biopsy: comparison with cancer-predicting nomograms. Eur J Nucl Med Mol Imaging. 2019; 46:908-20.

33. Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D, et al. 68Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging. 2017; 44:941-9.
-3434. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic Efficacy of (68)Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol. 2016; 195:1436-43. [Internet]. Available at. < https://www.sciencedirect.com/science/article/abs/pii/S0022534715053975?via%3Dihub>
https://www.sciencedirect.com/science/ar...
, 3737. van Leeuwen PJ, Emmett L, Ho B, Delprado W, Ting F, Nguyen Q, et al. Prospective evaluation of 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer. BJU Int. 2017; 119:209-15.

38. Pyka T, Okamoto S, Dahlbender M, Tauber R, Retz M, Heck M, et al. Comparison of bone scintigraphy and 68Ga-PSMA PET for skeletal staging in prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:2114-21.

39. Herlemann A, Wenter V, Kretschmer A, Thierfelder KM, Bartenstein P, Faber C, et al. 68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol. 2016; 70:553-7.

40. Giesel FL, Sterzing F, Schlemmer HP, Holland-Letz T, Mier W, Rius M, et al. Intra-individual comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:1400-6.
-4141. Bräuer A, Rahbar K, Konnert J, Bögemann M, Stegger L. Diagnostic value of additional 68Ga-PSMA-PET before 223Ra-dichloride therapy in patients with metastatic prostate carcinoma. Nuklearmedizin. 2017; 56:14-22., 4343. Afshar-Oromieh A, Sattler LP, Mier W, Hadaschik BA, Debus J, Holland-Letz T, et al. The Clinical Impact of Additional Late PET/CT Imaging with 68Ga-PSMA-11 (HBED-CC) in the Diagnosis of Prostate Cancer. J Nucl Med. 2017; 58:750-5., 4545. Dyrberg E, Hendel HW, Huynh THV, Klausen TW, Løgager VB, Madsen C, et al. 68Ga-PSMA-PET/CT in comparison with 18F-fluoride-PET/CT and whole-body MRI for the detection of bone metastases in patients with prostate cancer: a prospective diagnostic accuracy study. Eur Radiol. 2019; 29:1221-30., 4646. Ergül N, Yilmaz Güneş B, Yücetaş U, Toktaş MG, Çermik TF. 68Ga-PSMA-11 PET/CT in Newly Diagnosed Prostate Adenocarcinoma. Clin Nucl Med. 2018; 43:e422-7., 4848. Hruby G, Eade T, Emmett L, Ho B, Hsiao E, Schembri G, et al. 68 Ga-PSMA-PET/CT staging prior to definitive radiation treatment for prostate cancer. Asia Pac J Clin Oncol. 2018; 14:343-6., 5151. Soldatov A, von Klot CAJ, Walacides D, Derlin T, Bengel FM, Ross TL, et al. Patterns of Progression After 68Ga-PSMA-Ligand PET/CT-Guided Radiation Therapy for Recurrent Prostate Cancer. Int J Radiat Oncol Biol Phys. 2019; 103:95-104.

52. Thomas L, Kantz S, Hung A, Monaco D, Gaertner FC, Essler M, et al. 68Ga-PSMA-PET/CT imaging of localized primary prostate cancer patients for intensity modulated radiation therapy treatment planning with integrated boost. Eur J Nucl Med Mol Imaging. 2018; 45:1170-8.

53. Uprimny C, Kroiss AS, Fritz J, Decristoforo C, Kendler D, von Guggenberg E, et al. Early PET imaging with [68]Ga-PSMA-11 increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence. Eur J Nucl Med Mol Imaging. 2017; 44:1647-55.

54. Uprimny C, Svirydenka A, Fritz J, Kroiss AS, Nilica B, Decristoforo C, et al. Comparison of [68Ga]Ga-PSMA-11 PET/CT with [18F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy. Eur J Nucl Med Mol Imaging. 2018; 45:1873-83.

55. Uslu-Beşli L, Sağer S, Akgün E, Asa S, Şahin OE, Demirdağ Ç, et al. Comparison of Ga-68 PSMA positron emission tomography/computerized tomography with Tc-99m MDP bone scan in prostate cancer patients. Turk J Med Sci. 2019; 49:301-10.
-5656. von Klot CJ, Merseburger AS, Böker A, Schmuck S, Ross TL, Bengel FM, et al. 68Ga-PSMA PET/CT Imaging Predicting Intraprostatic Tumor Extent, Extracapsular Extension and Seminal Vesicle Invasion Prior to Radical Prostatectomy in Patients with Prostate Cancer. Nucl Med Mol Imaging. 2017; 51:314-22., 5858. Roach PJ, Francis R, Emmett L, Hsiao E, Kneebone A, Hruby G, et al. The Impact of 68Ga-PSMA PET/CT on Management Intent in Prostate Cancer: Results of an Australian Prospective Multicenter Study. J Nucl Med. 2018; 59:82-8.

59. Bluemel C, Krebs M, Polat B, Linke F, Eiber M, Samnick S, et al. 68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT. Clin Nucl Med. 2016; 41:515-21.

60. Schmuck S, Nordlohne S, von Klot CA, Henkenberens C, Sohns JM, Christiansen H, et al. Comparison of standard and delayed imaging to improve the detection rate of [68Ga]PSMA I&T PET/CT in patients with biochemical recurrence or prostate-specific antigen persistence after primary therapy for prostate cancer. Eur J Nucl Med Mol Imaging. 2017; 44:960-8.

61. Uprimny C, Kroiss AS, Decristoforo C, Fritz J, Warwitz B, Scarpa L, et al. Early dynamic imaging in 68Ga- PSMA-11 PET/CT allows discrimination of urinary bladder activity and prostate cancer lesions. Eur J Nucl Med Mol Imaging. 2017; 44:765-75.

62. Berliner C, Tienken M, Frenzel T, Kobayashi Y, Helberg A, Kirchner U, et al. Detection rate of PET/CT in patients with biochemical relapse of prostate cancer using [68Ga]PSMA I&T and comparison with published data of [68Ga]PSMA HBED-CC. Eur J Nucl Med Mol Imaging. 2017; 44:670-7.

63. Einspieler I, Rauscher I, Düwel C, Krönke M, Rischpler C, Habl G, et al. Detection Efficacy of Hybrid 68Ga-PSMA Ligand PET/CT in Prostate Cancer Patients with Biochemical Recurrence After Primary Radiation Therapy Defined by Phoenix Criteria. J Nucl Med. 2017; 58:1081-7.
-6464. Kabasakal L, Demirci E, Nematyazar J, Akyel R, Razavi B, Ocak M, et al. The role of PSMA PET/CT imaging in restaging of prostate cancer patients with low prostate-specific antigen levels. Nucl Med Commun. 2017; 38:149-55., 6767. Dietlein F, Kobe C, Neubauer S, Schmidt M, Stockter S, Fischer T, et al. PSA-Stratified Performance of 18F- and 68Ga-PSMA PET in Patients with Biochemical Recurrence of Prostate Cancer. J Nucl Med. 2017; 58:947-52., 7272. van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B, et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int. 2016; 117:732-9.

73. Verburg FA, Pfister D, Heidenreich A, Vogg A, Drude NI, Vöö S, et al. Extent of disease in recurrent prostate cancer determined by [(68)Ga]PSMA-HBED-CC PET/CT in relation to PSA levels, PSA doubling time and Gleason score. Eur J Nucl Med Mol Imaging. 2016; 43:397-403.

74. Ceci F, Uprimny C, Nilica B, Geraldo L, Kendler D, Kroiss A, et al. (68)Ga-PSMA PET/CT for restaging recurrent prostate cancer: which factors are associated with PET/CT detection rate? Eur J Nucl Med Mol Imaging. 2015; 42:1284-94.

75. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. 2015;56:668-74.

76. Schmidt-Hegemann NS, Eze C, Li M, Rogowski P, Schaefer C, Stief C, et al. Impact of 68Ga-PSMA PET/CT on the Radiotherapeutic Approach to Prostate Cancer in Comparison to CT: A Retrospective Analysis. J Nucl Med. 2019; 60:963-70.
-7777. Afaq A, Alahmed S, Chen SH, Lengana T, Haroon A, Payne H, et al. Impact of 68Ga-Prostate-Specific Membrane Antigen PET/CT on Prostate Cancer Management. J Nucl Med. 2018; 59:89-92., 7979. Akdemir EN, Tuncel M, Akyol F, Bilen CY, Baydar DE, Karabulut E, et al. 68Ga-labelled PSMA ligand HBED-CC PET/CT imaging in patients with recurrent prostate cancer. World J Urol. 2019; 37:813-21., 8080. Barbaud M, Frindel M, Ferrer L, Le Thiec M, Rusu D, Rauscher A, et al. 68Ga-PSMA-11 PET-CT study in prostate cancer patients with biochemical recurrence and non-contributive 18F-Choline PET-CT: Impact on therapeutic decision-making and biomarker changes. Prostate. 2019; 79:454-61., 8282. Calais J, Fendler WP, Eiber M, Gartmann J, Chu FI, Nickols NG, et al. Impact of 68Ga-PSMA-11 PET/CT on the Management of Prostate Cancer Patients with Biochemical Recurrence. J Nucl Med. 2018; 59:434-41., 8585. Ceci F, Castellucci P, Graziani T, Farolfi A, Fonti C, Lodi F, et al. 68Ga-PSMA-11 PET/CT in recurrent prostate cancer: efficacy in different clinical stages of PSA failure after radical therapy. Eur J Nucl Med Mol Imaging. 2019; 46:31-9., 9292. Hope TA, Aggarwal R, Chee B, Tao D, Greene KL, Cooperberg MR, et al. Impact of 68Ga-PSMA-11 PET on Management in Patients with Biochemically Recurrent Prostate Cancer. J Nucl Med. 2017; 58:1956-61., 9393. Jilg CA, Drendel V, Rischke HC, Beck T, Vach W, Schaal K, et al. Diagnostic Accuracy of Ga-68-HBED-CC-PSMA-Ligand-PET/CT before Salvage Lymph Node Dissection for Recurrent Prostate Cancer. Theranostics. 2017; 7:1770-80., 9696. Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. 2015; 56:1185-90.

97. Rauscher I, Maurer T, Beer AJ, Graner FP, Haller B, Weirich G, et al. Value of 68Ga-PSMA HBED-CC PET for the Assessment of Lymph Node Metastases in Prostate Cancer Patients with Biochemical Recurrence: Comparison with Histopathology After Salvage Lymphadenectomy. J Nucl Med. 2016; 57:1713-9.
-9898. Schmidkonz C, Cordes M, Beck M, Goetz TI, Schmidt D, Prante O, et al. SPECT/CT With the PSMA Ligand 99mTc-MIP-1404 for Whole-Body Primary Staging of Patients With Prostate Cancer. Clin Nucl Med. 2018; 43:225-31.), 27 studies used a prospective design (1818. Sachpekidis C, Kopka K, Eder M, Hadaschik BA, Freitag MT, Pan L, et al. 68Ga-PSMA-11 Dynamic PET/CT Imaging in Primary Prostate Cancer. Clin Nucl Med. 2016; 41:e473-9., 1919. Fendler WP, Schmidt DF, Wenter V, Thierfelder KM, Zach C, Stief C, et al. 68Ga-PSMA PET/CT Detects the Location and Extent of Primary Prostate Cancer. J Nucl Med. 2016; 57:1720-5., 2929. Hicks RM, Simko JP, Westphalen AC, Nguyen HG, Greene KL, Zhang L, et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET/MRI Compared with Multiparametric MRI in the Detection of Prostate Cancer. Radiology. 2018; 289:730-7., 3030. Lopci E, Saita A, Lazzeri M, Lughezzani G, Colombo P, Buffi NM, et al. 68Ga-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. J Urol. 2018; 200:95-103., 3535. Fendler WP, Calais J, Allen-Auerbach M, Bluemel C, Eberhardt N, Emmett L, et al. 68Ga-PSMA-11 PET/CT Interobserver Agreement for Prostate Cancer Assessments: An International Multicenter Prospective Study. J Nucl Med. 2017; 58:1617-23..[Internet]. Available at. < http://jnm.snmjournals.org/content/58/10/1617>
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, 3636. Zang S, Shao G, Cui C, Li TN, Huang Y, Yao X, et al. 68Ga-PSMA-11 PET/CT for prostate cancer staging and risk stratification in Chinese patients. Oncotarget. 2017; 8:12247-58. [Internet]. Available at. <http://www.oncotarget.com/abstract/14691>
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, 4444. Demirkol MO, Acar Ö, Uçar B, Ramazanoğlu SR, Sağlıcan Y, Esen T. Prostate-specific membrane antigen-based imaging in prostate cancer: impact on clinical decision making process. Prostate. 2015; 75:748-57., 4747. Grubmüller B, Baltzer P, D'Andrea D, Korn S, Haug AR, Hacker M, et al. 68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making. Eur J Nucl Med Mol Imaging. 2018;45:235-42., 4949. Kuten J, Mabjeesh NJ, Lerman H, Levine C, Barnes S, Even-Sapir E. Ga-PSMA PET/CT Staging of Newly Diagnosed Intermediate- and High-Risk Prostate Cancer. Isr Med Assoc J. 2019; 21:100-4., 5757. Wong HS, Leung J, Bartholomeusz D, Sutherland P, Le H, Nottage M, et al. Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer. J Med Imaging Radiat Oncol. 2018; 62:816-22., 6666. Hruby G, Eade T, Kneebone A, Emmett L, Guo L, Ho B,et al. Delineating biochemical failure with 68Ga-PSMA-PET following definitive external beam radiation treatment for prostate cancer. Radiother Oncol. 2017; 122:99-102., 6868. Meredith G, Wong D, Yaxley J, Coughlin G, Thompson L, Kua B, et al. The use of 68 Ga-PSMA PET CT in men with biochemical recurrence after definitive treatment of acinar prostate cancer. BJU Int. 2016; 118 Suppl 3:49-55., 7070. Sachpekidis C, Eder M, Kopka K, Mier W, Hadaschik BA, Haberkorn U, et al. (68)Ga-PSMA-11 dynamic PET/CT imaging in biochemical relapse of prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:1288-99., 7171. Henkenberens C, von Klot CA, Ross TL, Bengel FM, Wester HJ, Merseburger AS, et al. (68)Ga-PSMA ligand PET/CT-based radiotherapy in locally recurrent and recurrent oligometastatic prostate cancer: Early efficacy after primary therapy. Strahlenther Onkol. 2016; 192:431-9., 7878. Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M, et al. The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015; 42:197-209., 8181. Bashir U, Tree A, Mayer E, Levine D, Parker C, Dearnaley D, et al. Impact of Ga-68-PSMA PET/CT on management in prostate cancer patients with very early biochemical recurrence after radical prostatectomy. Eur J Nucl Med Mol Imaging. 2019; 46:901-7., 8383. Calais J, Czernin J, Cao M, Kishan AU, Hegde JV, Shaverdian N, et al. 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. J Nucl Med. 2018; 59:230-7., 8484. Caroli P, Sandler I, Matteucci F, De Giorgi U, Uccelli L, Celli M, et al. 68Ga-PSMA PET/CT in patients with recurrent prostate cancer after radical treatment: prospective results in 314 patients. Eur J Nucl Med Mol Imaging. 2018; 45:2035-44., 8787. Dietlein M, Kobe C, Kuhnert G, Stockter S, Fischer T, Schomäcker K, et al. Comparison of [(18)F]DCFPyL and [(68)Ga]Ga-PSMA-HBED-CC for PSMA-PET Imaging in Patients with Relapsed Prostate Cancer. Mol Imaging Biol. 2015; 17:575-84.

88. Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol. 2019; 5:856-63.

89. Fennessy N, Lee J, Shin J, Ho B, Ali SA, Paschkewitz R, et al. Frusemide aids diagnostic interpretation of 68 Ga-PSMA positron emission tomography/CT in men with prostate cancer. J Med Imaging Radiat Oncol. 2017; 61:739-44.

90. Gauthé, M et al. “TEP/TDM et récidive biologique d'adénocarcinome prostatique: apport du 68Ga-PSMA-11 lorsque la 18F-fluorocholine n'est pas contributive” [PET/CT and biochemical recurrence of prostate adenocarcinoma: Added value of 68Ga-PSMA-11 when 18F-fluorocholine is non-contributive]. Progrès en Urologie 2017;27: 474-81. Available at. < https://www.urofrance.org/sites/default/files/fileadmin/documents/data/PU/2017/3247/69449/FR/1128952/main.pdf>
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-9191. Hamed MAG, Basha MAA, Ahmed H, Obaya AA, Afifi AHM, Abdelbary EH. 68Ga-PSMA PET/CT in Patients with Rising Prostatic-Specific Antigen After Definitive Treatment of Prostate Cancer: Detection Efficacy and Diagnostic accuracy. Acad Radiol. 2019; 26:450-60., 9494. Mattiolli AB, Santos A, Vicente A, Queiroz M, Bastos D, Herchenhorn D, et al. Impact of 68GA-PSMA PET / CT on treatment of patients with recurrent / metastatic high risk prostate cancer - a multicenter study. Int Braz J Urol. 2018; 44:892-9., 9595. McCarthy M, Francis R, Tang C, Watts J, Campbell A. A Multicenter Prospective Clinical Trial of 68Gallium PSMA HBED-CC PET-CT Restaging in Biochemically Relapsed Prostate Carcinoma: Oligometastatic Rate and Distribution Compared With Standard Imaging. Int J Radiat Oncol Biol Phys. 2019; 104:801-8., 9999. Walacides D, Meier A, Knöchelmann AC, Meinecke D, Derlin T, Bengel FM, et al. Comparison of 68 Ga-PSMA ligand PET/CT versus conventional cross-sectional imaging for target volume delineation for metastasis-directed radiotherapy for metachronous lymph node metastases from prostate cancer. Strahlenther Onkol. 2019; 195:420-9., 100100. Wondergem M, van der Zant FM, Knol RJJ, Lazarenko SV, Pruim J, de Jong IJ. 18F-DCFPyL PET/CT in the Detection of Prostate Cancer at 60 and 120 Minutes: Detection Rate, Image Quality, Activity Kinetics, and Biodistribution. J Nucl Med. 2017; 58:1797-804.), and one of them used cohort design (6565. Schwenck J, Rempp H, Reischl G, Kruck S, Stenzl A, Nikolaou K, et al. Comparison of 68Ga-labelled PSMA-11 and 11C-choline in the detection of prostate cancer metastases by PET/CT. Eur J Nucl Med Mol Imaging. 2017; 44:92-101.). Seven studies did not indicate how data were included or obtained (1616. Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I, et al. Simultaneous 68Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 2016; 70:829-36., 1717. Zamboglou C, Drendel V, Jilg CA, Rischke HC, Beck TI, Schultze-Seemann W, et al. 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. Theranostics. 2017; 7:228-237., 2020. Rhee H, Thomas P, Shepherd B, Gustafson S, Vela I, Russell PJ, et al. Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer. J Urol. 2016; 196:1261-7., 4242. Vinsensia M, Chyoke PL, Hadaschik B, Holland-Letz T, Moltz J, Kopka K, et al. 68Ga-PSMA PET/CT and Volumetric Morphology of PET-Positive Lymph Nodes Stratified by Tumor Differentiation of Prostate Cancer. J Nucl Med. 2017; 58:1949-55., 5050. Lengana T, Lawal IO, Boshomane TG, Popoola GO, Mokoala KMG, Moshokoa E, et al. 68Ga-PSMA PET/CT Replacing Bone Scan in the Initial Staging of Skeletal Metastasis in Prostate Cancer: A Fait Accompli? Clin Genitourin Cancer. 2018; 16:392-401., 6969. Pfister D, Porres D, Heidenreich A, Heidegger I, Knuechel R, Steib F, et al. Detection of recurrent prostate cancer lesions before salvage lymphadenectomy is more accurate with (68)Ga-PSMA-HBED-CC than with (18)F-Fluoroethylcholine PET/CT. Eur J Nucl Med Mol Imaging. 2016;43:1410-7., 8686. Dewes S, Schiller K, Sauter K, Eiber M, Maurer T, Schwaiger M, et al. Integration of (68)Ga-PSMA-PET imaging in planning of primary definitive radiotherapy in prostate cancer: a retrospective study. Radiat Oncol. 2016;11:73.).

While the patient selection was generally acceptable in most of the studies included, a few studies did not report the inclusion criteria clearly. All the studies reported methodology for the index test with clarity and were, thus, not considered a significant source of potential bias. There was a broad variability in the reference test: Prostate biopsy results were used in ten studies (1919. Fendler WP, Schmidt DF, Wenter V, Thierfelder KM, Zach C, Stief C, et al. 68Ga-PSMA PET/CT Detects the Location and Extent of Primary Prostate Cancer. J Nucl Med. 2016; 57:1720-5., 2121. Zamboglou C, Schiller F, Fechter T, Wieser G, Jilg CA, Chirindel A, et al. (68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison. Theranostics. 2016; 6:1619-28., 2323. Rahbar K, Weckesser M, Huss S, Semjonow A, Breyholz HJ, Schrader AJ, et al. Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer. J Nucl Med. 2016; 57:563-7., 3232. Zhang J, Shao S, Wu P, Liu D, Yang B, Han D, et al. Diagnostic performance of 68Ga-PSMA PET/CT in the detection of prostate cancer prior to initial biopsy: comparison with cancer-predicting nomograms. Eur J Nucl Med Mol Imaging. 2019; 46:908-20.

33. Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D, et al. 68Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging. 2017; 44:941-9.

34. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic Efficacy of (68)Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol. 2016; 195:1436-43. [Internet]. Available at. < https://www.sciencedirect.com/science/article/abs/pii/S0022534715053975?via%3Dihub>
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, 3939. Herlemann A, Wenter V, Kretschmer A, Thierfelder KM, Bartenstein P, Faber C, et al. 68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol. 2016; 70:553-7., 5454. Uprimny C, Svirydenka A, Fritz J, Kroiss AS, Nilica B, Decristoforo C, et al. Comparison of [68Ga]Ga-PSMA-11 PET/CT with [18F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy. Eur J Nucl Med Mol Imaging. 2018; 45:1873-83., 8383. Calais J, Czernin J, Cao M, Kishan AU, Hegde JV, Shaverdian N, et al. 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. J Nucl Med. 2018; 59:230-7.), histologic results from radical prostatectomy or lymphadenectomy in 35 studies (66. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014; 41:11-20., 1515. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88., 1616. Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I, et al. Simultaneous 68Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 2016; 70:829-36., 1818. Sachpekidis C, Kopka K, Eder M, Hadaschik BA, Freitag MT, Pan L, et al. 68Ga-PSMA-11 Dynamic PET/CT Imaging in Primary Prostate Cancer. Clin Nucl Med. 2016; 41:e473-9., 2020. Rhee H, Thomas P, Shepherd B, Gustafson S, Vela I, Russell PJ, et al. Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer. J Urol. 2016; 196:1261-7., 2222. Sahlmann CO, Meller B, Bouter C, Ritter CO, Ströbel P, Lotz J, et al. Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma. Eur J Nucl Med Mol Imaging. 2016; 43:898-905., 2424. Hijazi S, Meller B, Leitsmann C, Strauss A, Meller J, Ritter CO, et al. Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography. Prostate. 2015; 75:1934-40., 2525. Kabasakal L, Demirci E, Ocak M, Akyel R, Nematyazar J, Aygun A, et al. Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging. Nucl Med Commun. 2015; 36:582-7., 2727. Sanli Y, Kuyumcu S, Sanli O, Buyukkaya F, İribaş A, Alcin G, et al. Relationships between serum PSA levels, Gleason scores and results of 68Ga-PSMAPET/CT in patients with recurrent prostate cancer. Ann Nucl Med. 2017; 31:709-17., 2929. Hicks RM, Simko JP, Westphalen AC, Nguyen HG, Greene KL, Zhang L, et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET/MRI Compared with Multiparametric MRI in the Detection of Prostate Cancer. Radiology. 2018; 289:730-7., 3131. Wu SY, Boreta L, Shinohara K, Nguyen H, Gottschalk AR, Hsu IC, et al. Impact of Staging 68Ga-PSMA-11 PET Scans on Radiation Treatment Plansin Patients With Prostate Cancer. Urology. 2019; 125:154-62., 3434. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic Efficacy of (68)Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol. 2016; 195:1436-43. [Internet]. Available at. < https://www.sciencedirect.com/science/article/abs/pii/S0022534715053975?via%3Dihub>
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96. Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. 2015; 56:1185-90.
-9797. Rauscher I, Maurer T, Beer AJ, Graner FP, Haller B, Weirich G, et al. Value of 68Ga-PSMA HBED-CC PET for the Assessment of Lymph Node Metastases in Prostate Cancer Patients with Biochemical Recurrence: Comparison with Histopathology After Salvage Lymphadenectomy. J Nucl Med. 2016; 57:1713-9.) and combined outcomes using additional imaging with magnetic resonance imaging (MRI) or bone scan and/or clinical follow-up and/or response to treatment (mostly PSA testing courses over time) in 45 studies (1717. Zamboglou C, Drendel V, Jilg CA, Rischke HC, Beck TI, Schultze-Seemann W, et al. 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. Theranostics. 2017; 7:228-237., 2626. Gupta M, Choudhury PS, Hazarika D, Rawal S. A Comparative Study of 68Gallium-Prostate Specific Membrane Antigen Positron Emission Tomography-Computed Tomography and Magnetic Resonance Imaging for Lymph Node Staging in High Risk Prostate Cancer Patients: An Initial Experience. World J Nucl Med. 2017;16:186-91., 2828. Budäus L, Leyh-Bannurah SR, Salomon G, Michl U, Heinzer H, Huland H, et al. Initial Experience of (68)Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. Eur Urol. 2016; 69:393-6., 3030. Lopci E, Saita A, Lazzeri M, Lughezzani G, Colombo P, Buffi NM, et al. 68Ga-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. J Urol. 2018; 200:95-103., 3737. van Leeuwen PJ, Emmett L, Ho B, Delprado W, Ting F, Nguyen Q, et al. Prospective evaluation of 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer. BJU Int. 2017; 119:209-15., 4040. Giesel FL, Sterzing F, Schlemmer HP, Holland-Letz T, Mier W, Rius M, et al. Intra-individual comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:1400-6., 4747. Grubmüller B, Baltzer P, D'Andrea D, Korn S, Haug AR, Hacker M, et al. 68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making. Eur J Nucl Med Mol Imaging. 2018;45:235-42., 5050. Lengana T, Lawal IO, Boshomane TG, Popoola GO, Mokoala KMG, Moshokoa E, et al. 68Ga-PSMA PET/CT Replacing Bone Scan in the Initial Staging of Skeletal Metastasis in Prostate Cancer: A Fait Accompli? Clin Genitourin Cancer. 2018; 16:392-401., 5151. Soldatov A, von Klot CAJ, Walacides D, Derlin T, Bengel FM, Ross TL, et al. Patterns of Progression After 68Ga-PSMA-Ligand PET/CT-Guided Radiation Therapy for Recurrent Prostate Cancer. Int J Radiat Oncol Biol Phys. 2019; 103:95-104., 5353. Uprimny C, Kroiss AS, Fritz J, Decristoforo C, Kendler D, von Guggenberg E, et al. Early PET imaging with [68]Ga-PSMA-11 increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence. Eur J Nucl Med Mol Imaging. 2017; 44:1647-55., 5656. von Klot CJ, Merseburger AS, Böker A, Schmuck S, Ross TL, Bengel FM, et al. 68Ga-PSMA PET/CT Imaging Predicting Intraprostatic Tumor Extent, Extracapsular Extension and Seminal Vesicle Invasion Prior to Radical Prostatectomy in Patients with Prostate Cancer. Nucl Med Mol Imaging. 2017; 51:314-22.

57. Wong HS, Leung J, Bartholomeusz D, Sutherland P, Le H, Nottage M, et al. Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer. J Med Imaging Radiat Oncol. 2018; 62:816-22.
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64. Kabasakal L, Demirci E, Nematyazar J, Akyel R, Razavi B, Ocak M, et al. The role of PSMA PET/CT imaging in restaging of prostate cancer patients with low prostate-specific antigen levels. Nucl Med Commun. 2017; 38:149-55.

65. Schwenck J, Rempp H, Reischl G, Kruck S, Stenzl A, Nikolaou K, et al. Comparison of 68Ga-labelled PSMA-11 and 11C-choline in the detection of prostate cancer metastases by PET/CT. Eur J Nucl Med Mol Imaging. 2017; 44:92-101.

66. Hruby G, Eade T, Kneebone A, Emmett L, Guo L, Ho B,et al. Delineating biochemical failure with 68Ga-PSMA-PET following definitive external beam radiation treatment for prostate cancer. Radiother Oncol. 2017; 122:99-102.
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70. Sachpekidis C, Eder M, Kopka K, Mier W, Hadaschik BA, Haberkorn U, et al. (68)Ga-PSMA-11 dynamic PET/CT imaging in biochemical relapse of prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:1288-99.

71. Henkenberens C, von Klot CA, Ross TL, Bengel FM, Wester HJ, Merseburger AS, et al. (68)Ga-PSMA ligand PET/CT-based radiotherapy in locally recurrent and recurrent oligometastatic prostate cancer: Early efficacy after primary therapy. Strahlenther Onkol. 2016; 192:431-9.

72. van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B, et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int. 2016; 117:732-9.

73. Verburg FA, Pfister D, Heidenreich A, Vogg A, Drude NI, Vöö S, et al. Extent of disease in recurrent prostate cancer determined by [(68)Ga]PSMA-HBED-CC PET/CT in relation to PSA levels, PSA doubling time and Gleason score. Eur J Nucl Med Mol Imaging. 2016; 43:397-403.

74. Ceci F, Uprimny C, Nilica B, Geraldo L, Kendler D, Kroiss A, et al. (68)Ga-PSMA PET/CT for restaging recurrent prostate cancer: which factors are associated with PET/CT detection rate? Eur J Nucl Med Mol Imaging. 2015; 42:1284-94.

75. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. 2015;56:668-74.
-7676. Schmidt-Hegemann NS, Eze C, Li M, Rogowski P, Schaefer C, Stief C, et al. Impact of 68Ga-PSMA PET/CT on the Radiotherapeutic Approach to Prostate Cancer in Comparison to CT: A Retrospective Analysis. J Nucl Med. 2019; 60:963-70., 7979. Akdemir EN, Tuncel M, Akyol F, Bilen CY, Baydar DE, Karabulut E, et al. 68Ga-labelled PSMA ligand HBED-CC PET/CT imaging in patients with recurrent prostate cancer. World J Urol. 2019; 37:813-21.

80. Barbaud M, Frindel M, Ferrer L, Le Thiec M, Rusu D, Rauscher A, et al. 68Ga-PSMA-11 PET-CT study in prostate cancer patients with biochemical recurrence and non-contributive 18F-Choline PET-CT: Impact on therapeutic decision-making and biomarker changes. Prostate. 2019; 79:454-61.

81. Bashir U, Tree A, Mayer E, Levine D, Parker C, Dearnaley D, et al. Impact of Ga-68-PSMA PET/CT on management in prostate cancer patients with very early biochemical recurrence after radical prostatectomy. Eur J Nucl Med Mol Imaging. 2019; 46:901-7.
-8282. Calais J, Fendler WP, Eiber M, Gartmann J, Chu FI, Nickols NG, et al. Impact of 68Ga-PSMA-11 PET/CT on the Management of Prostate Cancer Patients with Biochemical Recurrence. J Nucl Med. 2018; 59:434-41., 8585. Ceci F, Castellucci P, Graziani T, Farolfi A, Fonti C, Lodi F, et al. 68Ga-PSMA-11 PET/CT in recurrent prostate cancer: efficacy in different clinical stages of PSA failure after radical therapy. Eur J Nucl Med Mol Imaging. 2019; 46:31-9., 8888. Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol. 2019; 5:856-63., 8989. Fennessy N, Lee J, Shin J, Ho B, Ali SA, Paschkewitz R, et al. Frusemide aids diagnostic interpretation of 68 Ga-PSMA positron emission tomography/CT in men with prostate cancer. J Med Imaging Radiat Oncol. 2017; 61:739-44., 9191. Hamed MAG, Basha MAA, Ahmed H, Obaya AA, Afifi AHM, Abdelbary EH. 68Ga-PSMA PET/CT in Patients with Rising Prostatic-Specific Antigen After Definitive Treatment of Prostate Cancer: Detection Efficacy and Diagnostic accuracy. Acad Radiol. 2019; 26:450-60., 9393. Jilg CA, Drendel V, Rischke HC, Beck T, Vach W, Schaal K, et al. Diagnostic Accuracy of Ga-68-HBED-CC-PSMA-Ligand-PET/CT before Salvage Lymph Node Dissection for Recurrent Prostate Cancer. Theranostics. 2017; 7:1770-80., 9494. Mattiolli AB, Santos A, Vicente A, Queiroz M, Bastos D, Herchenhorn D, et al. Impact of 68GA-PSMA PET / CT on treatment of patients with recurrent / metastatic high risk prostate cancer - a multicenter study. Int Braz J Urol. 2018; 44:892-9., 9898. Schmidkonz C, Cordes M, Beck M, Goetz TI, Schmidt D, Prante O, et al. SPECT/CT With the PSMA Ligand 99mTc-MIP-1404 for Whole-Body Primary Staging of Patients With Prostate Cancer. Clin Nucl Med. 2018; 43:225-31.

99. Walacides D, Meier A, Knöchelmann AC, Meinecke D, Derlin T, Bengel FM, et al. Comparison of 68 Ga-PSMA ligand PET/CT versus conventional cross-sectional imaging for target volume delineation for metastasis-directed radiotherapy for metachronous lymph node metastases from prostate cancer. Strahlenther Onkol. 2019; 195:420-9.
-100100. Wondergem M, van der Zant FM, Knol RJJ, Lazarenko SV, Pruim J, de Jong IJ. 18F-DCFPyL PET/CT in the Detection of Prostate Cancer at 60 and 120 Minutes: Detection Rate, Image Quality, Activity Kinetics, and Biodistribution. J Nucl Med. 2017; 58:1797-804.) (Tables 1 a-c).

Table 1a
Summary of contents of study design – Diagnosis.
Table 1b
Summary of contents of study design – Staging.
Table 1c
Summary of contents of study design – Recurrence.

Pooled sensitivity, specificity, and diagnostic odds ratios; likelihood ratios

The availability of original data and the possibility of constructing a two-by-two table were minimum requirements (66. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014; 41:11-20., 1515. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88., 1717. Zamboglou C, Drendel V, Jilg CA, Rischke HC, Beck TI, Schultze-Seemann W, et al. 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. Theranostics. 2017; 7:228-237., 1818. Sachpekidis C, Kopka K, Eder M, Hadaschik BA, Freitag MT, Pan L, et al. 68Ga-PSMA-11 Dynamic PET/CT Imaging in Primary Prostate Cancer. Clin Nucl Med. 2016; 41:e473-9., 2222. Sahlmann CO, Meller B, Bouter C, Ritter CO, Ströbel P, Lotz J, et al. Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma. Eur J Nucl Med Mol Imaging. 2016; 43:898-905.

23. Rahbar K, Weckesser M, Huss S, Semjonow A, Breyholz HJ, Schrader AJ, et al. Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer. J Nucl Med. 2016; 57:563-7.
-2424. Hijazi S, Meller B, Leitsmann C, Strauss A, Meller J, Ritter CO, et al. Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography. Prostate. 2015; 75:1934-40., 3232. Zhang J, Shao S, Wu P, Liu D, Yang B, Han D, et al. Diagnostic performance of 68Ga-PSMA PET/CT in the detection of prostate cancer prior to initial biopsy: comparison with cancer-predicting nomograms. Eur J Nucl Med Mol Imaging. 2019; 46:908-20., 3333. Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D, et al. 68Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging. 2017; 44:941-9., 3636. Zang S, Shao G, Cui C, Li TN, Huang Y, Yao X, et al. 68Ga-PSMA-11 PET/CT for prostate cancer staging and risk stratification in Chinese patients. Oncotarget. 2017; 8:12247-58. [Internet]. Available at. <http://www.oncotarget.com/abstract/14691>
http://www.oncotarget.com/abstract/14691...
, 3737. van Leeuwen PJ, Emmett L, Ho B, Delprado W, Ting F, Nguyen Q, et al. Prospective evaluation of 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer. BJU Int. 2017; 119:209-15., 3939. Herlemann A, Wenter V, Kretschmer A, Thierfelder KM, Bartenstein P, Faber C, et al. 68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol. 2016; 70:553-7.

40. Giesel FL, Sterzing F, Schlemmer HP, Holland-Letz T, Mier W, Rius M, et al. Intra-individual comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:1400-6.

41. Bräuer A, Rahbar K, Konnert J, Bögemann M, Stegger L. Diagnostic value of additional 68Ga-PSMA-PET before 223Ra-dichloride therapy in patients with metastatic prostate carcinoma. Nuklearmedizin. 2017; 56:14-22.

42. Vinsensia M, Chyoke PL, Hadaschik B, Holland-Letz T, Moltz J, Kopka K, et al. 68Ga-PSMA PET/CT and Volumetric Morphology of PET-Positive Lymph Nodes Stratified by Tumor Differentiation of Prostate Cancer. J Nucl Med. 2017; 58:1949-55.

43. Afshar-Oromieh A, Sattler LP, Mier W, Hadaschik BA, Debus J, Holland-Letz T, et al. The Clinical Impact of Additional Late PET/CT Imaging with 68Ga-PSMA-11 (HBED-CC) in the Diagnosis of Prostate Cancer. J Nucl Med. 2017; 58:750-5.

44. Demirkol MO, Acar Ö, Uçar B, Ramazanoğlu SR, Sağlıcan Y, Esen T. Prostate-specific membrane antigen-based imaging in prostate cancer: impact on clinical decision making process. Prostate. 2015; 75:748-57.

45. Dyrberg E, Hendel HW, Huynh THV, Klausen TW, Løgager VB, Madsen C, et al. 68Ga-PSMA-PET/CT in comparison with 18F-fluoride-PET/CT and whole-body MRI for the detection of bone metastases in patients with prostate cancer: a prospective diagnostic accuracy study. Eur Radiol. 2019; 29:1221-30.

46. Ergül N, Yilmaz Güneş B, Yücetaş U, Toktaş MG, Çermik TF. 68Ga-PSMA-11 PET/CT in Newly Diagnosed Prostate Adenocarcinoma. Clin Nucl Med. 2018; 43:e422-7.

47. Grubmüller B, Baltzer P, D'Andrea D, Korn S, Haug AR, Hacker M, et al. 68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making. Eur J Nucl Med Mol Imaging. 2018;45:235-42.

48. Hruby G, Eade T, Emmett L, Ho B, Hsiao E, Schembri G, et al. 68 Ga-PSMA-PET/CT staging prior to definitive radiation treatment for prostate cancer. Asia Pac J Clin Oncol. 2018; 14:343-6.
-4949. Kuten J, Mabjeesh NJ, Lerman H, Levine C, Barnes S, Even-Sapir E. Ga-PSMA PET/CT Staging of Newly Diagnosed Intermediate- and High-Risk Prostate Cancer. Isr Med Assoc J. 2019; 21:100-4.). We excluded studies that did not provide us with enough data in terms of sensitivity, specificity, diagnostic odds ratios, and likelihood ratios analyses to create a 2X2 Table. Overall, 34 studies met the criteria for this meta-analysis, comprehending a total of 4532 patients submitted to 68Ga-PSMA PET; among those, nine studies (287 patients) in diagnostic setting and four studies for staging purposes, and 22 studies for restaging, in a total of 4050 patients (note that 1 study included staging and restaging patients). For diagnosis, the sensitivity was 0.90 (0.86 to 0.93), with an inconsistency of 75.1% and a specificity of 0.90 (0.82 to 0.96), not considering case-only confirmed patients (Figure-2).

Figure 2
Pooled sensibility and specificity in diagnosis scenario, considering only studies which included possible non-cancer cases (false positive).

We carried out a secondary analysis, withdrawing studies, one by one, in order to identify which study generated such heterogeneity. Recalling Budaus, L 2015 study, we obtained a pooled sensitivity of 0.92 (0.89 to 0.95) with 2.6% heterogeneity (Figure-3).

Figure 3
A secondary analysis, when Budaus, L. Study was withdraw from the pool, the inconsistency became much lower, not changing, substantially, the sensitivity of the method.

The group of studies that enrolled patients for staging indication, resulted in a sensitivity of 0.93 (0.86-0.98), with a low inconsistency, and a specificity of 0.96 (0.92-0.99), but with a significant inconsistency (Figure-4). After a secondary analysis, when Herlermann, the study found to be responsible for the inconsistency, was withdrawn from the pool, the specificity was 0.99 (0.96-1.00) (Figure-5). A summary ROC (sROC) curve confirmed the high value for this imaging modality in the staging setting with an area under the curve of 0.9731 (Figure-6).

Figure 4
Sensitivity and Specificity analysis in staging prostate cancer patients. Note in specificity analysis the high inconsistency among these studies.
Figure 5
Specificity analysis in staging prostate cancer patients, after secondary analysis that showed Herlermann, A. study was responsible for the great inconsistency. Recalling the study, the specificity was 0.99 (0.96 to 1.00) with no inconsistency between the studies.
Figure 6
ROC curve for 68Ga-PSMA-PET in diagnosis setting, showing an area under the curve of 0.9731.

The pool of studies that analyzed the power of 68Ga-PSMA PET in restaging recurrent prostate cancer resulted in a sensitivity of 0.76 (0.74 to 0.78), with heterogeneity of 96.7% (Figure-7). The specificity of the method, calculated based on the data available from the pool of studies, was 0.42 (0.27-0.58), and, again, a great inconsistency was noted (Figure-8). An sROC curve was plotted for those results, and the calculated area under the curve resulted in 0.73 (Figure-9).

Figure 7
68Ga-PSMA-PET sensitivity for restating patients with biochemical recurrence of prostate cancer.
Figure 8
68Ga-PSMA-PET specificity for restating patients with biochemical recurrence of prostate cancer.
Figure 9
SROC curve for the pooled sensitivities and specificities on restating scenario, showing an area under the curve of 0.73.

When assessing biochemical recurrence, we observed that the higher the PSA level, the higher was the ability of the study to accurately demonstrate sites of accumulation of PSMA, positive for prostate cancer involvement. For patients with PSA LEVEL <0.5ng/mL, the positive LR pool estimation was 1.17 (0.37-3.73) and the sensitivity was 56% (0.42-0.68), increasing to 1.04 (0.38-2.85) and 58% (0.47-0.68), respectively, in patients with PSA between 0.5 and 1ng/mL. The positive probable pool ratio is 1.44 (0.59-3.51) and the sensibility is 81% (0.74-0.87) for patients with PSA 1 to<2ng/mL and, for patients with a PSA level higher than 2ng/mL, LR ratio is 1.78 (0.66-4.77), with sensitivity of 96% (0.93-0.97).

DISCUSSION

Early biochemical recurrence represents the most clinically relevant subgroup of patients with relapsed prostate cancer, offering the possibility of potential curative salvage therapy concepts that might have a major impact on the outcome of patients. In biochemical recurrence, traditional imaging approaches (MRI, CT, and choline-based PET-CT) often fail to localize disease, mainly when the PSA level ranges lower than 2ng/mL. In our meta-analysis, we defined 4 subgroups based on PSA level: very low (<0.5ng/mL), low (0.5-1.0ng/mL), intermediate (1-2.0ng/mL), and high (>2.0ng/mL). We confirmed the value of 68Ga-PSMA-PET in all subgroups. Detection rates are indeed higher when PSA levels are higher; however, the 68Ga-PSMA-PET may have the greatest clinical impact in very low and low PSA level subgroups. To date, choline-based PET/CT is not recommended for patients with recurrent cancer and PSA level below 2ng/mL. Compared to choline-based PET/CT, evidence suggests that the 68Ga-PSMA PET has better sensitivity in detecting prostate cancer recurrence. On pooled analysis, the 68Ga-PSMA PET sensitivity was 56% for PSA under 0.5ng/mL. Our results for diagnostic accuracy are according to a recently published meta-analysis, reporting similar pooled sensitivity and specificity (33. Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, et al. Sensitivity, Specificity, and Predictors of Positive 68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016; 70:926-37.). To the date, most of the data outlining the utility of the 68Ga-PSMA PET is in the restaging for biochemical recurrence after definitive therapy.

Thus far, the value of 68Ga-PSMA PET in the accurate detection and delineation of intraprostatic tumor burden, which is important for diagnosis and treatment planning for patients with primary prostate cancer, is poorly explored. Although prostate cancer is mostly a multifocal disease, there is growing evidence that dominant intraprostatic lesions (DILs) may be responsible for metastatic and recurrent prostate cancer. Most of the ongoing studies use multiparametric magnetic resonance imaging (mpMRI); however, Zamboglou et al. compared seven patients who underwent mpMRI and 68Ga-PSMA PET before radical prostatectomy with co-registration between 68Ga-PSMA PET, mpMRI and histopathology. The sensitivity and specificity for 68Ga-PSMA PET were 75% and 87% and for mpMRI were 70% and 82%, respectively.

The present study highlights the possibility of improvement in evaluating prostate cancer, supporting the use of 68Ga-PSMA PET for diagnosing and staging. Traditionally, the primary staging of lymph nodes is performed using CT or MRI, but this relies on pathologic changes in lymph node morphology and size criteria. However, up to 80% of metastasis-involved nodes are smaller than the threshold limit of 8mm, typically used in clinical practice. Meta-analytical data for the traditional CT and MRI imaging approaches suggest sensitivity and specificity be 39-42% and 82%, respectively. A recent meta-analysis of choline-based tracers for PET-CT reviewed sensitivity of 49.2% and specificity of 95% for the detection of lymph nodes. Maurer et al. (3434. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic Efficacy of (68)Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol. 2016; 195:1436-43. [Internet]. Available at. < https://www.sciencedirect.com/science/article/abs/pii/S0022534715053975?via%3Dihub>
https://www.sciencedirect.com/science/ar...
) performed a retrospective review of 130 patients undergoing high-risk prostate cancer, with a sensitivity of 65.9% and specificity of 98.9%. In our meta-analysis, the pool of studies showed the sensitivity and specificity were 93% and 87%, respectively, in detecting positive lymph nodes. As these are superior to those for traditional imaging, 68Ga-PSMA PET could allow complete and accurate diagnosing in primary staging compared to the current practice and potential improvement in patient care.

Despite significant advances, there is considerable scope for further research based on the use of 68Ga-PSMA PET. There is a need for more robust sensitivity and specificity data. In this meta-analysis, much of the histopathological correlation data available were not suitable for inclusion in our analysis for biopsy was performed according to clinician discretion. Selective lesion biopsy did not provide meaningful false-negative rates or specificity. Several groups reported the use of the 68Ga-PSMA PET for localization of intraprostatic malignancies, particularly in the context of focal therapies (5050. Lengana T, Lawal IO, Boshomane TG, Popoola GO, Mokoala KMG, Moshokoa E, et al. 68Ga-PSMA PET/CT Replacing Bone Scan in the Initial Staging of Skeletal Metastasis in Prostate Cancer: A Fait Accompli? Clin Genitourin Cancer. 2018; 16:392-401.).

There are several limitations to this study. Firstly, most of the articles used for meta-analysis were derived from not measurable, retrospective, and single-institutional studies. The absence of more comprehensive studies could be justified as this technique is new and is still being explored for its inclusion in recent prostate cancer guidelines. Secondly, the heterogeneous nature of patient cohorts, treatment protocols, and studies used to pool sensitivity and specificity data, in particular, because most of the studies were carried with small sample size and patients were assessed in primary staging settings. Researchers should be encouraged to agree on data acquisition protocols and data analysis algorithms to increase the comparability of studies, which is one of the major issues in achieving evidence. Careful reporting of those methods may help evaluation to the extent that the results found to be applicable in other clinical settings.

68Ga-PSMA PET seems to provide higher sensitivity and specificity compared to alternative techniques. Our results reinforce the current evidence of the usefulness of 68Ga-PSMA PET, whereby the diagnostic evidence is more substantial in restaging with biochemical recurrence. The main applicability of 68Ga-PSMA PET certainly relies on restaging patients with biochemical recurrence after local treatment with curative intent.

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Publication Dates

  • Publication in this collection
    30 July 2021
  • Date of issue
    Jul-Aug 2021

History

  • Received
    26 Feb 2020
  • Accepted
    14 July 2020
  • Published
    10 Nov 2020
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