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PET imaging in prostate cancer, future trends: PSMA ligands

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Abstract

Accurate staging is of utmost importance in patients with primary or recurrent prostate cancer. Current imaging techniques are unsuited for whole-body staging or limited by low sensitivity for small metastatic lesions. Prostate specific membrane antigen (PSMA) is over-expressed on prostate cancer cells. Thus, 68Ga-labelled small molecule PSMA ligands were developed to potentially overcome these limitations. A systematic search strategy was applied to review evidence for PSMA-directed imaging of prostate cancer. 175 publications were retrieved from The National Center for Biotechnology Information PubMed online database using the following search term: psma AND pet AND prostate cancer. Sixteen publications were included based on the following criteria: original research; cohort study; reported diagnostic accuracy at primary diagnosis or biochemical recurrence; high quality of data acquisition and analysis. 68Ga-PSMA PET/CT stages lymph node involvement with a higher accuracy than CT and 68Ga-PSMA PET/MRI more accurately localizes primary prostate cancer than MRI or PET alone. Especially in patients with serum PSA <1 ng/mL sites of biochemical recurrence were detected better with 68Ga-PSMA PET/CT than with any other imaging modality. In summary, PSMA imaging demonstrates high accuracy for prostate cancer staging at primary diagnosis and biochemical recurrence. Future trials need to determine whether this superior diagnostic performance translates into improved clinical outcomes.

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References

  1. Perner S, Hofer MD, Kim R, Shah RB, Li H, Moller P et al (2007) Prostate-specific membrane antigen expression as a predictor of prostate cancer progression. Hum Pathol 38:696–701

    Article  CAS  PubMed  Google Scholar 

  2. Mannweiler S, Amersdorfer P, Trajanoski S, Terrett JA, King D, Mehes G (2009) Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol Oncol Res 15:167–172

    Article  CAS  PubMed  Google Scholar 

  3. Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP (1998) Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer 82:2256–2261

    Article  CAS  PubMed  Google Scholar 

  4. Ross JS, Sheehan CE, Fisher HA, Kaufman RP Jr, Kaur P, Gray K et al (2003) Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res 9:6357–6362

    CAS  PubMed  Google Scholar 

  5. Murga JD, Moorji SM, Han AQ, Magargal WW, DiPippo VA, Olson WC (2015) Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer. Prostate 75:242–254

    Article  CAS  PubMed  Google Scholar 

  6. Meller B, Bremmer F, Sahlmann CO, Hijazi S, Bouter C, Trojan L et al (2015) Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy. EJNMMI Res 5:66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C (1997) Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81–85

    CAS  PubMed  Google Scholar 

  8. Ghosh A, Heston WD (2004) Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem 91:528–539

    Article  CAS  PubMed  Google Scholar 

  9. Schulke N, Varlamova OA, Donovan GP, Ma D, Gardner JP, Morrissey DM et al (2003) The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy. Proc Natl Acad Sci USA 100:12590–12595

    Article  PubMed  PubMed Central  Google Scholar 

  10. Rajasekaran SA, Anilkumar G, Oshima E, Bowie JU, Liu H, Heston W et al (2003) A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. Mol Biol Cell 14:4835–4845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eder M, Schafer M, Bauder-Wust U, Hull WE, Wangler C, Mier W et al (2012) 68 Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem 23:688–697

    Article  CAS  PubMed  Google Scholar 

  12. Afshar-Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA et al (2013) PET imaging with a [68 Ga] 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 40:486–495

    Article  CAS  PubMed  Google Scholar 

  13. Benesova M, Schafer M, Bauder-Wust U, Afshar-Oromieh A, Kratochwil C, Mier W et al (2015) Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med 56:914–920

    Article  CAS  PubMed  Google Scholar 

  14. Weineisen M, Schottelius M, Simecek J, Baum RP, Yildiz A, Beykan S et al (2015) 68 Ga- and 177Lu-Labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J Nucl Med 56:1169–1176

    Article  CAS  PubMed  Google Scholar 

  15. Mottet N, Bellmunt J, Briers E, Bergh RCNvd, Bolla M, Casteren NJV et al (2015) Guidelines on prostate cancer. European Association of Urology. https://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf

  16. Sonn GA, Chang E, Natarajan S, Margolis DJ, Macairan M, Lieu P et al (2014) Value of targeted prostate biopsy using magnetic resonance-ultrasound fusion in men with prior negative biopsy and elevated prostate-specific antigen. Eur Urol 65:809–815

    Article  PubMed  Google Scholar 

  17. Muller BG, Shih JH, Sankineni S, Marko J, Rais-Bahrami S, George A et al (2015) Prostate cancer: interobserver agreement and accuracy with the revised prostate imaging reporting and data system at multiparametric MR imaging. Radiology 277(3):741–750. doi:10.1148/radiol.2015142818

    Article  PubMed  Google Scholar 

  18. Mowatt G, Scotland G, Boachie C, Cruickshank M, Ford JA, Fraser C et al (2013) The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation. Health Technol Assess 17(vii–xix):1–281

    PubMed  PubMed Central  Google Scholar 

  19. Rowe SP, Gage KL, Faraj SF, Macura KJ, Cornish TC, Gonzalez-Roibon N et al (2015) 18F-DCFBC PET/CT for PSMA-based detection and characterization of primary prostate cancer. J Nucl Med 56:1003–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I et al (2016) Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer. Eur Urol. doi:10.1016/j.eururo.2015.12.053

  21. Ben Jemaa A, Bouraoui Y, Sallami S, Banasr A, Ben Rais N, Ouertani L et al (2010) Co-expression and impact of prostate specific membrane antigen and prostate specific antigen in prostatic pathologies. J Exp Clin Cancer Res 29:171

    Article  PubMed  PubMed Central  Google Scholar 

  22. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G et al (2015) 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 195(5):1436–1443. doi:10.1016/j.juro.2015.12.025

    Article  PubMed  Google Scholar 

  23. Mohler JL, Armstrong AJ, Bahnson RR, D’Amico AV, Davis BJ, Eastham JA et al (2016) Prostate cancer, version 1.2016. J Natl Compr Cancer Netw 14:19–30

    Google Scholar 

  24. Hovels AM, Heesakkers RA, Adang EM, Jager GJ, Strum S, Hoogeveen YL et al (2008) The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clin Radiol 63:387–395

    Article  CAS  PubMed  Google Scholar 

  25. Herlemann A, Wenter V, Kretschmer A, Thierfelder KM, Bartenstein P, Faber C et al (2016) 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. doi:10.1016/j.eururo.2015.12.051

  26. Kabasakal L, Demirci E, Ocak M, Akyel R, Nematyazar J, Aygun A et al (2015) Evaluation of PSMA PET/CT imaging using a 68 Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging. Nucl Med Commun 36:582–587

    Article  CAS  PubMed  Google Scholar 

  27. Han KR, Cohen JK, Miller RJ, Pantuck AJ, Freitas DG, Cuevas CA et al (2003) Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol 170:1126–1130

    Article  PubMed  Google Scholar 

  28. Zietman AL, Chung CS, Coen JJ, Shipley WU (2004) 10-year outcome for men with localized prostate cancer treated with external radiation therapy: results of a cohort study. J Urol 171:210–214

    Article  CAS  PubMed  Google Scholar 

  29. Agarwal PK, Sadetsky N, Konety BR, Resnick MI, Carroll PR (2008) Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes. Cancer 112:307–314

    Article  PubMed  Google Scholar 

  30. Kane CJ, Amling CL, Johnstone PA, Pak N, Lance RS, Thrasher JB et al (2003) Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology 61:607–611

    Article  PubMed  Google Scholar 

  31. Fuccio C, Castellucci P, Schiavina R, Guidalotti PL, Gavaruzzi G, Montini GC et al (2012) Role of 11C-choline PET/CT in the re-staging of prostate cancer patients with biochemical relapse and negative results at bone scintigraphy. Eur J Radiol 81:e893–e896

    Article  PubMed  Google Scholar 

  32. Krause BJ, Souvatzoglou M, Tuncel M, Herrmann K, Buck AK, Praus C et al (2008) 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 35:18–23

    Article  CAS  PubMed  Google Scholar 

  33. Tilki D, Reich O, Graser A, Hacker M, Silchinger J, Becker AJ et al (2013) 18F-fluoroethylcholine PET/CT identifies lymph node metastasis in patients with prostate-specific antigen failure after radical prostatectomy but underestimates its extent. Eur Urol 63:792–796

    Article  PubMed  Google Scholar 

  34. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG et al (2014) 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 41:11–20

    Article  CAS  PubMed  Google Scholar 

  35. Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q et al (2015) Prospective comparison of 18F-fluoromethylcholine versus 68 Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med 56:1185–1190

    Article  CAS  PubMed  Google Scholar 

  36. van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B et al (2015) (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 117(5):732–739. doi:10.1111/bju.13397

    Article  Google Scholar 

  37. Sterzing F, Kratochwil C, Fiedler H, Katayama S, Habl G, Kopka K et al (2016) (68)Ga-PSMA-11 PET/CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging 43:34–41

    Article  CAS  PubMed  Google Scholar 

  38. Bluemel C, Krebs M, Polat B, Linke F, Eiber M, Samnick S et al (2016) 68Ga-PSMA-PET/CT in patients with biochemical prostate cancer recurrence and negative 18F-Choline-PET/CT. Clin Nucl Med 41(7):515–521. doi:10.1097/RLU.0000000000001197

    Article  PubMed  Google Scholar 

  39. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B et al (2015) Evaluation of hybrid (6)(8)Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med 56:668–674

    Article  PubMed  Google Scholar 

  40. Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M et al (2015) 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 42:197–209

    Article  CAS  PubMed  Google Scholar 

  41. Castellucci P, Fuccio C, Rubello D, Schiavina R, Santi I, Nanni C et al (2011) Is there a role for (1)(1)C-choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase <1.5 ng/ml? Eur J Nucl Med Mol Imaging 38:55–63

    Article  PubMed  Google Scholar 

  42. Castellucci P, Fuccio C, Nanni C, Santi I, Rizzello A, Lodi F et al (2009) Influence of trigger PSA and PSA kinetics on 11C-choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy. J Nucl Med 50:1394–1400

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Wolfgang P. Fendler, Johannes Czernin & Ken Herrmann

  2. Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany

    Wolfgang P. Fendler

  3. Department of Nuclear Medicine, Julius-Maximilians-University of Würzburg, Würzburg, Germany

    Christina Bluemel & Ken Herrmann

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  1. Wolfgang P. Fendler
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  2. Christina Bluemel
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Correspondence to Wolfgang P. Fendler.

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No potential conflicts of interest were disclosed by WP Fendler, C Bluemel, J Czernin, and K Herrmann.

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Fendler, W.P., Bluemel, C., Czernin, J. et al. PET imaging in prostate cancer, future trends: PSMA ligands. Clin Transl Imaging 4, 467–472 (2016). https://doi.org/10.1007/s40336-016-0194-7

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  • DOI: https://doi.org/10.1007/s40336-016-0194-7

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