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PSMA PET Imaging in Prostate Cancer: Staging for Unfavorable Intermediate and High-Risk Disease

Conventional imaging using CT and bone scan has limited sensitivity when staging men with high-risk localized prostate cancer. Findings of extraprostatic spread in the form of extraprostatic extension and/or lymph node, visceral, or bone metastasis can influence treatment planning, and thus, potentially, patient outcomes.
Written by: Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
References:

 

  1. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216.
  2. De Feria Cardet RE, Hofman MS, Segard T, et a. Is Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Imaging Cost-effective in Prostate Cancer: An Analysis Informed by the proPSMA Trial. Eur Urol. 2021;79(3):413-8.
  3. Hope TA, Eiber M, Armstrong WR, et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection: A Multicenter Prospective Phase 3 Imaging Trial. JAMA Oncol. 2021;7(11):1635-42.
  4. Van Kalmthout LWM, van Melick HHE, Lavalaye J, et al. Prospective Validation of Gallium-68 Prostate Specific Membrane Antigen-Positron Emission Tomography/Computerized Tomography for Primary Staging of Prostate Cancer. J Urol. 2020;203(3):537-45.
  5. Pienta KJ, Gorin MA, Rowe SP, et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate Specific Membrane Antigen PET/CT with 18 F-DCFPyL in Prostate Cancer Patients (OSPREY). J Urol 2021;206(1):52-61.
  6. Jansen BHE, Bodar YJL, Zwezerijnen GJC, et al. Pelvic lymph-node staging with 18F-DCFPyL PET/CT prior to extended pelvic lymph-node dissection in primary prostate cancer - the SALT trial. Eur J Nucl Med Mol Imaging. 2021;48(2):509-20.
  7. Prostate Cancer. https://uroweb.org/guidelines/prostate-cancer. Accessed on Aug 14, 2022
  8. Prostate Cancer. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed on August 27, 2022.

Imaging in Prostate Cancer: An Update on a Rapidly Changing Space

An accurate assessment of the extent of disease is critical to the care of patients with cancer, across the natural history of disease including initial evaluation, following local treatment, and assessing response to systemic therapy. Thus, improvements in radiographic imaging may revolutionize the way we diagnose disease and the treatments we can offer.
Written by: Zachary Klaassen, MD, MSc
References:
  1. Shinohara K, Master VA, Chi T, et al. Prostate needle biopsy techniques and interpretation. In: Vogelzang NJ, Scardino PT, Shipley WU, et al., eds. Comprehensive textbook of genitourinary oncology (3rd ed.). Philadelphia Lippincott Williams & Wilkins; 2006.
  2. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol 2014; 65(1):124-37.
  3. Kongnyuy M, Sidana A, George AK, et al. The significance of anterior prostate lesions on multiparametric magnetic resonance imaging in African-American men. Urol Oncol 2016; 34(6):254.e15-21.
  4. Schouten MG, van der Leest M, Pokorny M, et al. Why and Where do We Miss Significant Prostate Cancer with Multi-parametric Magnetic Resonance Imaging followed by Magnetic Resonance-guided and Transrectal Ultrasound-guided Biopsy in Biopsy-naive Men? Eur Urol 2017; 71(6):896-903.
  5. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017; 71(4):618-629.
  6. Rifkin MD, Zerhouni EA, Gatsonis CA, et al. Comparison of magnetic resonance imaging and ultrasonography in staging early prostate cancer. Results of a multi-institutional cooperative trial. N Engl J Med 1990; 323(10):621-6.
  7. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015; 313(4):390-7.
  8. Vourganti S, Rastinehad A, Yerram NK, et al. Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies. J Urol 2012; 188(6):2152-7.
  9. Kasivisvanathan V, Stabile A, Neves JB, et al. Magnetic Resonance Imaging-targeted Biopsy Versus Systematic Biopsy in the Detection of Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2019.
  10. Eldred-Evans D, Burak P, Connor MJ, et al. Population-Based Prostate Cancer Screening With Magnetic Resonance Imaging or Ultrasonography: The IP1-PROSTAGRAM Study. JAMA Oncol 2021; 7(3):395-402.
  11. Callender T, Emberton M, Morris S, et al. Benefit, Harm, and Cost-effectiveness Associated With Magnetic Resonance Imaging Before Biopsy in Age-based and Risk-stratified Screening for Prostate Cancer. JAMA Netw Open 2021; 4(3):e2037657.
  12. Laurence Klotz CM. Can high resolution micro-ultrasound replace MRI in the diagnosis of prostate cancer? Eur Urol Focus 2019.
  13. Abouassaly R, Klein EA, El-Shefai A, et al. Impact of using 29 MHz high-resolution micro-ultrasound in real-time targeting of transrectal prostate biopsies: initial experience. World J Urol 2019.
  14. Heindel W, Gubitz R, Vieth V, et al. The diagnostic imaging of bone metastases. Dtsch Arztebl Int 2014; 111(44):741-7.
  15. Yang HL, Liu T, Wang XM, et al. Diagnosis of bone metastases: a meta-analysis comparing (1)(8)FDG PET, CT, MRI and bone scintigraphy. Eur Radiol 2011; 21(12):2604-17.
  16. Network NCC. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer - Version 1.2019. 2019.
  17. Namasivayam S, Martin DR, Saini S. Imaging of liver metastases: MRI. Cancer Imaging 2007; 7:2-9.
  18. Li R, Ravizzini GC, Gorin MA, et al. The use of PET/CT in prostate cancer. Prostate Cancer Prostatic Dis 2018; 21(1):4-21.
  19. Rayn KN, Elnabawi YA, Sheth N. Clinical implications of PET/CT in prostate cancer management. Transl Androl Urol 2018; 7(5):844-854.
  20. Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[(18)F]FACBC positron emission tomography-computerized tomography and (111)In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol 2014; 191(5):1446-53.
  21. Wondergem M, van der Zant FM, van der Ploeg T, et al. A literature review of 18F-fluoride PET/CT and 18F-choline or 11C-choline PET/CT for detection of bone metastases in patients with prostate cancer. Nucl Med Commun 2013; 34(10):935-45.
  22. Nanni C, Zanoni L, Pultrone C, et al. (18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging 2016; 43(9):1601-10.
  23. Jani AB, Schreibmann E, Goyal S, et al. (18)F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial. Lancet 2021.
  24. Calais J, Ceci F, Eiber M, et al. (18)F-fluciclovine PET-CT and (68)Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol 2019; 20(9):1286-1294.
  25. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet 2020; 395(10231):1208-1216.
  26. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic Performance of (18)F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase 3, Multicenter Study. Clin Cancer Res 2021.
  27. Pienta KJ, Gorin MA, Rowe SP, et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate-Specific Membrane Antigen PET/CT with (18)F-DCFPyL in Prostate Cancer Patients (OSPREY). J Urol 2021:101097JU0000000000001698.
  28. Eiber M, Weirich G, Holzapfel K, et al. Simultaneous (68)Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol 2016; 70(5):829-836.

The Current Landscape of PSMA PET Imaging in Prostate Cancer: Evaluating Men with Biochemical Recurrence

Although definitive local therapy in the form of radical prostatectomy or radiation therapy with or without ADT offers excellent long-term outcomes for the majority of patients with clinically localized prostate cancer, patients with high-risk disease experience primary treatment failure rates approaching 65%.1 Disease persistence/recurrence in such patients may be restricted to the prostatic fossa, pelvic lymph nodes, non-regional lymph nodes (M1a), bones (M1b), or the viscera (M1c).

Written by: Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
References:

 

  1. D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969-74.
  2. Jadvar H. Is There Utility for FDG PET in Prosate Cancer? Semin Nucl Med. 2016;46(6):502-506.
  3. Picchio M, Briganti A, Fanti S, et al. The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer. Eur Urol 2011;59:51-60.
  4. Krause BJ, Souvatzoglou M, Tuncel M, et al. The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:18-23.
  5. Rayn KN, Elnabawi YA, Sheth N. Clinical implications of PET/CT in prostate cancer management. Transl Androl Urol. 2018;7(5):844-54.
  6. Afshar-Oromieh A, Malcher A, Eder M, 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;40:486-95.
  7. Morigi JJ, Stricker PD, van Leewen PJ, 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(8):1185-90.
  8. Calais J, Ceci F, Eiber M, et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;20(9):1286-94.
  9. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer. JAMA Oncol. 2019; 5(6):856-63.
  10. Caroli P, Sandler I, Matteucci F, et al. 68 Ga-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(12):2035-44.
  11. Ceci F, Castellucci P, Graziani T, 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. 2019;46:31-39.
  12. Mazrani W, Cook GJR, Bomanji J. Role of 68Ga and 18F PSMA PET/CT and PET/MRI in biochemical recurrence of prostate cancer: a systematic review of prospective studies. Nucl Med Commun. 2022;43(6):631-7.
  13. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase 3, Multicenter Study. Clin Cancer Res. 2021;27(13):3674-82.
  14. Ong S, Pascoe C, Kelly BD, et al. PSMA PET-CT Imaging Predicts Treatment Progression in Men with Biochemically Recurrent Prostate Cancer-A Prospective Study of Men with 3 Year Follow Up. Cancers (Basel). 2022;14(11):2717.
  15. Emmett L , Tang R, Nandrukar R, et al. 3-Year Freedom from Progression After 68 Ga-PSMA PET/CT-Triaged Management in Men with Biochemical Recurrence After Radical Prostatectomy: Results of a Prospective Multicenter Trial. J Nucl Med. 2020;61(6):866-72.
  16. Pozdnyakov A, Kulanthaivelu R, Bauman G, et al. The impact of PSMA PET on the treatment and outcomes of men with biochemical recurrence of prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2022.

The Rapidly Evolving Role of PSMA In Prostate Cancer Diagnostics And Therapeutics

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein which functions as a zinc metalloenzyme and is found on prostatic epithelium. In normal prostate tissue, PSMA expression and localization focuses on the cytoplasm and apical side of the epithelium surrounding prostatic ducts. However, during prostate carcinogenesis, PSMA is transferred to the luminal surface of the ducts. 

Written by: Zachary Klaassen, MD MSc
References: 1. Heindel W, Gubitz R, Vieth V, Weckesser M, Schober O, Schafers M. The diagnostic imaging of bone metastases. Dtsch Arztebl Int. 2014;111(44):741-747.
2. Yang HL, Liu T, Wang XM, Xu Y, Deng SM. Diagnosis of bone metastases: a meta-analysis comparing (1)(8)FDG PET, CT, MRI and bone scintigraphy. Eur Radiol. 2011;21(12):2604-2617.
3. Network NCC. NCCN Clinical Practice Guideslines in Oncology: Prostate Cancer - Version 1.2019. 2019.
4. Li R, Ravizzini GC, Gorin MA, et al. The use of PET/CT in prostate cancer. Prostate cancer and prostatic diseases. 2018;21(1):4-21.
5. Wondergem M, van der Zant FM, van der Ploeg T, Knol RJ. A literature review of 18F-fluoride PET/CT and 18F-choline or 11C-choline PET/CT for detection of bone metastases in patients with prostate cancer. Nucl Med Commun. 2013;34(10):935-945.
6. Nanni C, Zanoni L, Pultrone C, et al. (18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging. 2016;43(9):1601-1610.
7. Calais J, Ceci F, Eiber M, et al. (18)F-fluciclovine PET-CT and (68)Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. The lancet oncology. 2019;20(9):1286-1294.
8. Zippel C, Ronski SC, Bohnet-Joschko S, Giesel FL, Kopka K. Current Status of PSMA-Radiotracers for Prostate Cancer: Data Analysis of Prospective Trials Listed on ClinicalTrials.gov. Pharmaceuticals (Basel). 2020;13(1).
9. Eiber M, Weirich G, Holzapfel K, et al. Simultaneous (68)Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. European urology. 2016;70(5):829-836.
10. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216.
11. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic Performance of (18)F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase 3, Multicenter Study. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021.
12. Pienta KJ, Gorin MA, Rowe SP, et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate-Specific Membrane Antigen PET/CT with (18)F-DCFPyL in Prostate Cancer Patients (OSPREY). The Journal of urology. 2021:101097JU0000000000001698.
13. Sartor O. Isotope Therapy for Castrate-Resistant Prostate Cancer: Unique Sequencing and Combinations. Cancer J. 2016;22(5):342-346.
14. Ye X, Sun D, Lou C. Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers. J Cancer Res Ther. 2018;14(Supplement):S36-S40.
15. James N, Pirrie S, Pope A, et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health technology assessment. 2016;20(53):1-288.
16. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. The New England journal of medicine. 2013;369(3):213-223.
17. Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer research. 2002;62(11):3120-3125.
18. Bruland OS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12(20 Pt 2):6250s-6257s.
19. Sadaghiania M., Sheikhbahaeia S., Werner R., et al., A Systematic Review and Meta-analysis of the Effectiveness and Toxicities of Lutetium-177–labeled Prostate-specific Membrane Antigen–targeted Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer. European Urology, 2021.
20. Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.

The Current Landscape of PSMA PET Imaging in Prostate Cancer: Evolution of Next Generation Imaging & PSMA PET for Primary Tumor Evaluation

Imaging plays a significant role in the diagnosis and management of prostate cancer. While transrectal ultrasound and, subsequently, multiparametric magnetic resonance imaging (mpMRI) have become well-established modalities in the initial diagnosis of prostate cancer, numerous techniques for the distant staging of prostate cancer have all suffered from significant limitations.

Written by: Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
References:
  1. Macedo F, Ladeira K, Pinho F, et al. Bone metastases: an overview. Oncol Rev. 2017;11(1):321.
  2. Heindel W, Gübitz R, Vieth V, et al. The diagnostic imaging of bone metastases. Dtsch Arztebl Int. 2014;111(44):741-7.
  3. Jadvar H. Is There Utility for FDG PET in Prosate Cancer? Semin Nucl Med. 2016;46(6):502-506.
  4. Picchio M, Briganti A, Fanti S, et al. The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer. Eur Urol 2011;59:51-60.
  5. Krause BJ, Souvatzoglou M, Tuncel M, et al. The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:18-23.
  6. Rayn KN, Elnabawi YA, Sheth N. Clinical implications of PET/CT in prostate cancer management. Transl Androl Urol. 2018;7(5):844-54.
  7. Schuste DM, Nieh PT, Jani AB, et al. Anti-3-[18F] FACBC positron emission tomography-computerized tomography and 111In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014;191(5):!446-53.
  8. Wondergem M, van der Zant FM, van der Ploeg T, Knol RJJ. A literature review of 18F-fluoride PET/CT and 18F-choline or 11C-choline PET/CT for detection of bone metastases in patients with prostate cancer. Nuclear medicine communications Nucl Med Commun. 2013;34(10):935-45.
  9. Nanni C, Zanoni L, Pultrone C, et al. 18 F-FACBC (anti1-amino-3-18 F-fluorocyclobutane-1-carboxylic acid) versus 11 C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging. 2016;43(9):1601-10.
  10. Afshar-Oromieh A, Malcher A, Eder M, 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;40:486-95.
  11. Chang SS. Overview of Prostate-Specific Membrane Antigen. Rev Urol. 2004;6(Suppl 10):S13-S18.
  12. Farolfi A, Calderoni L, Mattana F, et al. Current and Emerging Clinical Applications of PSMA PET Diagnostic Imaging for Prostate Cancer. J Nucl Med. 2021;62:596-604.
  13. Prostate Cancer. https://uroweb.org/guidelines/prostate-cancer. Accessed on Aug 14, 2022
  14. Ahmed HU, Bosaily AE, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;389(10071):815-822.
  15. Bodar YJL, Jansen BHE, van der Voorn JP, et al. Detection of prostate cancer with 18 F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial. World J Urol. 2021;39(7):2439-2446.
  16. Eiber M, Weirich G, Holzapfel K, et al. Simultaneous 68Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 2016;70(5):829-836.
  17. Emmett L, Buteau J, Papa N, et al. The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study. Eur Urol. 2021;80(6):682-9.
  18. Lopci E, Saita A, Lazzeri M, et al. 68 Ga-PSMA Positron Emission Tomography/Computerized Tomography for Primary Diagnosis of Prostate Cancer in Men with Contraindications to or Negative Multiparametric Magnetic Resonance Imaging: A Prospective Observational Study. J Urol. 2018;200(1):95-103.