World J Mens Health.  2020 Jan;38(1):32-47. 10.5534/wjmh.180133.

Performance and Impact of Prostate Specific Membrane Antigen-Based Diagnostics in the Management of Men with Biochemical Recurrence of Prostate Cancer and its Role in Salvage Lymph Node Dissection

• Krimphove
• Theissen L
• Cole AP
• Preisser F
• Mandel PC
• Chun FK

• KMID: 2465408
• DOI: http://doi.org/10.5534/wjmh.180133

Abstract

Up to 50% of patients initially treated for prostate cancer in a curative intent experience biochemical recurrence, possibly requiring adjuvant treatment. However, salvage treatment decisions, such as lymph node dissection or radiation therapy, are typically based on prostate specific antigen (PSA) recurrence. Importantly, common imaging modalities (e.g., computed tomography [CT], magnetic resonance imaging, and bone scan) are limited and the detection of recurrent disease is particularly challenging if PSA is low. Prostate specific membrane antigen (PSMA) positron-emission tomography/computed tomography (PET/CT) is a novel and promising imaging modality which aims to overcome the incapability of early identification of distant and regional metastases. Within this review, we summarize the current evidence related to PSMA-PET/CT in prostate cancer men diagnosed with biochemical recurrence after local treatment with curative intent. We discuss detection rates of PSMA-PET/CT stratified by PSA-levels and its impact on clinical decision making. Furthermore, we compare different image-fusion techniques such as PSMA-PET vs. F-/C-Choline-PET scans vs. PSMA-single photon emission computed tomography/CT. Finally, we touch upon the contemporary role of radio-guided-PSMA salvage lymphadenectomy.

Keyword

Positron-emission tomography; Prostate-specific membrane antigen, human; Prostatic neoplasms; Salvage therapy

MeSH Terms

Clinical Decision-Making
Humans
Lymph Node Excision*
Lymph Nodes*
Magnetic Resonance Imaging
Male
Membranes*
Neoplasm Metastasis
Positron-Emission Tomography
Prostate*
Prostate-Specific Antigen
Prostatic Neoplasms*
Recurrence*
Salvage Therapy
Prostate-Specific Antigen

Figure

• 

  Fig. 1 Evidence acquisition. PSMA: prostate specific membrane antigen, PET: positron-emission tomography, BCR: biochemical recurrence, SPECT: single photon emission computed tomography, PSA: prostate specific antigen, CT: computed tomography.

Reference

1. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am. 2001; 28:555–565. PMID: 11590814.

2. Simmons MN, Stephenson AJ, Klein EA. Natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. Eur Urol. 2007; 51:1175–1184. PMID: 17240528.

3. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG Guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017; 71:630–642. PMID: 27591931.

4. Maurer T, Eiber M, Fanti S, Budäus L, Panebianco V. Imaging for prostate cancer recurrence. Eur Urol Focus. 2016; 2:139–150. PMID: 28723528.

5. Kosuri S, Akhtar NH, Smith M, Osborne JR, Tagawa ST. Review of salvage therapy for biochemically recurrent prostate cancer: the role of imaging and rationale for systemic salvage targeted anti-prostate-specific membrane antigen radioimmunotherapy. Adv Urol. 2012; 2012:921674. PMID: 22693495.

6. Meller B, Bremmer F, Sahlmann CO, Hijazi S, Bouter C, Trojan L, et al. Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy. EJNMMI Res. 2015; 5:66. PMID: 26576996.

7. Ruckle HC, Klee GG, Oesterling JE. Prostate-specific antigen: concepts for staging prostate cancer and monitoring response to therapy. Mayo Clin Proc. 1994; 69:69–79. PMID: 7505870.

8. Afshar-Oromieh A, Holland-Letz T, Giesel FL, Kratochwil C, Mier W, Haufe S, et al. Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients. Eur J Nucl Med Mol Imaging. 2017; 44:1258–1268. PMID: 28497198.

9. 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. PMID: 25411132.

10. 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; 45:2035–2044. PMID: 29922948.

11. Rauscher I, Düwel C, Haller B, Rischpler C, Heck MM, Gschwend JE, et al. Efficacy, predictive factors, and prediction nomograms for ⁶⁸Ga-labeled prostate-specific membrane antigen-ligand positron-emission tomography/computed tomography in early biochemical recurrent prostate cancer after radical prostatectomy. Eur Urol. 2018; 73:656–661. PMID: 29358059.

12. 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; 56:668–674. PMID: 25791990.

13. Prado Júnior LM, Marino FM, Barra R, do Prado LFM, Barra Sobrinho A. One-year experience with ⁶⁸Ga-PSMA PET/CT: applications and results in biochemical recurrence of prostate cancer. Radiol Bras. 2018; 51:151–155. PMID: 29991835.

14. Ohri N, Dicker AP, Trabulsi EJ, Showalter TN. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012; 48:837–844. PMID: 21945099.

15. 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; 58:1081–1087. PMID: 28209912.

16. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018; 36:446–453. PMID: 29240541.

17. 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; 59:230–237. PMID: 29123013.

18. Farolfi A, Ceci F, Castellucci P, Graziani T, Siepe G, Lambertini A, et al. ⁶⁸Ga-PSMA-11 PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy and PSA <0.5 ng/ml. Efficacy and impact on treatment strategy. Eur J Nucl Med Mol Imagin. 2019; 46:11–19.

19. 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. PMID: 28747520.

20. Albisinni S, Artigas C, Aoun F, Biaou I, Grosman J, Gil T, et al. Clinical impact of ⁶⁸Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent: preliminary analysis of a multidisciplinary approach. BJU Int. 2017; 120:197–203. PMID: 27981732.

21. 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; 59:434–441. PMID: 29242398.

22. Henkenberens C, Derlin T, Bengel FM, Ross TL, Wester HJ, Hueper K, et al. Patterns of relapse as determined by ⁶⁸Ga-PSMA ligand PET/CT after radical prostatectomy: importance for tailoring and individualizing treatment. Strahlenther Onkol. 2018; 194:303–310. PMID: 29134231.

23. 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; 44:892–899. PMID: 30088720.

24. Zacho HD, Nielsen JB, Dettmann K, Haberkorn U, Langkilde NC, Jensen JB, et al. 68Ga-PSMA PET/CT in patients with biochemical recurrence of prostate cancer: a prospective, 2-center study. Clin Nucl Med. 2018; 43:579–585. PMID: 29916917.

25. 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; 117:732–739. PMID: 26683282.

26. Michalski JM, Lawton C, El Naqa I, Ritter M, O'Meara E, Seider MJ, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010; 76:361–368. PMID: 19394158.

27. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014; 65:467–479. PMID: 24321502.

28. Stish BJ, Pisansky TM, Harmsen WS, Davis BJ, Tzou KS, Choo R, et al. Improved metastasis-free and survival outcomes with early salvage radiotherapy in men with detectable prostate-specific antigen after prostatectomy for prostate cancer. J Clin Oncol. 2016; 34:3864–3871. PMID: 27480153.

29. Potters L, Kavanagh B, Galvin JM, Hevezi JM, Janjan NA, Larson DA, et al. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys. 2010; 76:326–332. PMID: 20117285.

30. Habl G, Straube C, Schiller K, Duma MN, Oechsner M, Kessel KA, et al. Oligometastases from prostate cancer: local treatment with stereotactic body radiotherapy (SBRT). BMC Cancer. 2017; 17:361. PMID: 28532400.

31. Tilki D, Reich O, Graser A, Hacker M, Silchinger J, Becker AJ, et al. 18F-Fluoroethylcholine PET/CT identifies lymph node metastasis in patients with prostate-specific antigen failure after radical prostatectomy but underestimates its extent. Eur Urol. 2013; 63:792–796. PMID: 22902037.

32. Ackerstaff E, Glunde K, Bhujwalla ZM. Choline phospholipid metabolism: a target in cancer cells? J Cell Biochem. 2003; 90:525–533. PMID: 14523987.

33. Kitajima K, Murphy RC, Nathan MA. Choline PET/CT for imaging prostate cancer: an update. Ann Nucl Med. 2013; 27:581–591. PMID: 23632880.

34. Pfister D, Bolla M, Briganti A, Carroll P, Cozzarini C, Joniau S, et al. Early salvage radiotherapy following radical prostatectomy. Eur Urol. 2014; 65:1034–1043. PMID: 23972524.

35. Castellucci P, Picchio M. 11C-choline PET/CT and PSA kinetics. Eur J Nucl Med Mol Imaging. 2013; 40(Suppl 1):S36–S40. PMID: 23579864.

36. Chiaravalloti A, Di Biagio D, Tavolozza M, Calabria F, Schillaci O. PET/CT with (18)F-choline after radical prostatectomy in patients with PSA ≤2 ng/ml. Can PSA velocity and PSA doubling time help in patient selection? Eur J Nucl Med Mol Imaging. 2016; 43:1418–1424. PMID: 26791373.

37. 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; 41:515–521. PMID: 26975008.

38. 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. PMID: 27557844.

39. 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; 56:1185–1190. PMID: 26112024.

40. 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. PMID: 24072344.

41. Hlatky MA, Shilane D, Hachamovitch R, Dicarli MF. Economic outcomes in the study of myocardial perfusion and coronary anatomy imaging roles in coronary artery disease registry: the SPARC study. J Am Coll Cardiol. 2014; 63:1002–1008. PMID: 24636556.

42. Mariani G, Bruselli L, Kuwert T, Kim EE, Flotats A, Israel O, et al. A review on the clinical uses of SPECT/CT. Eur J Nucl Med Mol Imaging. 2010; 37:1959–1985. PMID: 20182712.

43. Schmidkonz C, Hollweg C, Beck M, Reinfelder J, Goetz TI, Sanders JC, et al. ^99mTc-MIP-1404-SPECT/CT for the detection of PSMA-positive lesions in 225 patients with biochemical recurrence of prostate cancer. Prostate. 2018; 78:54–63. PMID: 29105797.

44. Liu C, Zhu Y, Su H, Xu X, Zhang Y, Ye D, et al. Relationship between PSA kinetics and Tc-99m HYNIC PSMA SPECT/CT detection rates of biochemical recurrence in patients with prostate cancer after radical prostatectomy. Prostate. 2018; 78:1215–1221. PMID: 30027591.

45. Reinfelder J, Kuwert T, Beck M, Sanders JC, Ritt P, Schmidkonz C, et al. First experience with SPECT/CT using a ^99mTc-labeled inhibitor for prostate-specific membrane antigen in patients with biochemical recurrence of prostate cancer. Clin Nucl Med. 2017; 42:26–33. PMID: 27775936.

46. Su HC, Zhu Y, Ling GW, Hu SL, Xu XP, Dai B, et al. Evaluation of ^99mTc-labeled PSMA-SPECT/CT imaging in prostate cancer patients who have undergone biochemical relapse. Asian J Androl. 2017; 19:267–271. PMID: 27976632.

47. Rauscher I, Maurer T, Souvatzoglou M, Beer AJ, Vag T, Wirtz M, et al. Intrapatient comparison of 111In-PSMA I&T SPECT/CT and hybrid 68Ga-HBED-CC PSMA PET in patients with early recurrent prostate cancer. Clin Nucl Med. 2016; 41:e397–e402. PMID: 27276206.

48. 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; 70:553–557. PMID: 26810345.

49. 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; 7:1770–1780. PMID: 28529650.

50. Mandel P, Tilki D, Chun FK, Pristupa E, Graefen M, Klutmann S, et al. Accuracy of ⁶⁸Ga-Prostate-specific membrane antigen positron emission tomography for the detection of lymph node metastases before salvage lymphadenectomy. Eur Urol Focus. 2018; DOI: 10.1016/j.euf.2018.07.025. .

51. 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; 43:1410–1417. PMID: 26993315.

52. 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; 57:1713–1719. PMID: 27261524.

53. Tilki D, Mandel P, Seeliger F, Kretschmer A, Karl A, Ergün S, et al. Salvage lymph node dissection for nodal recurrence of prostate cancer after radical prostatectomy. J Urol. 2015; 193:484–490. PMID: 25180792.

54. Xu X, Zhang J, Hu S, He S, Bao X, Ma G, et al. ^99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen. Nucl Med Biol. 2017; 48:69–75. PMID: 28273495.

55. Rauscher I, Düwel C, Wirtz M, Schottelius M, Wester HJ, Schwamborn K, et al. Value of ¹¹¹In-prostate-specific membrane antigen (PSMA)-radioguided surgery for salvage lymphadenectomy in recurrent prostate cancer: correlation with histopathology and clinical follow-up. BJU Int. 2017; 120:40–47. PMID: 27862863.

56. Maurer T, Robu S, Schottelius M, Schwamborn K, Rauscher I, van den Berg NS, et al. ^99mTechnetium-based prostate-specific membrane antigen-radioguided surgery in recurrent prostate cancer. Eur Urol. 2019; 75:659–666. PMID: 29625755.

57. Knipper S, Tilki D, Mansholt J, Berliner C, Bernreuther C, Steuber T, et al. Metastases-yield and prostate-specific antigen kinetics following salvage lymph node dissection for prostate cancer: a comparison between conventional surgical approach and prostate-specific membrane antigen-radioguided surgery. Eur Urol Focus. 2019; 5:50–53. PMID: 30292421.

58. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018; 378:1767–1777. PMID: 29552975.