ABSTRACT
Prostate cancer is the most common solid malignancy in men. The biochemical recurrence is defined as an increase in levels of prostate-specific antigen (PSA) after radical therapy. It is a common occurrence and occurs in about 20-30% of patients treated with radical prostatectomy and up to 60% in patients treated primary with external beam radiotherapy. Patients are therefore generally directed to a salvage radiotherapy on the prostate bed (suspicion of local recurrence) or to a systemic treatment with hormonal therapy. Conventional imaging, including computed tomography, bone scintigraphy and magnetic resonance, showed low accuracy values for restaging patients being biochemical recurrence. During the last decade, the nuclear medicine techniques such as positron emission tomography (PET), with F-18 choline, were found to be more accurate than conventional diagnostic tests for restaging patients with prostate cancer with progress in biochemical recurrence. However, the PET/computed tomography (CT) with choline showed a suboptimal sensitivity if performed in patients with early biochemical recurrence, in patients with low serum PSA (<0.2 ng/mL) after radical therapy. Recently, a new molecule has been developed that molecule that targets the prostate-specific membrane antigene (PSMA). The PSMA is a membrane enzyme that is mainly expressed in prostate cancer cells when compared with its expression in healthy prostate tissue. Preliminary studies with PSMA as a radiopharmaceutical for PET-CT imaging showed that its accuracy for the diagnosis of early disease recurrence was significantly higher than F-18 choline. Further studies conducted in larger patient populations with biochemical recurrence after radical therapy, showed excellent diagnostic power of Ga-68 PSMA PET/CT in restaging patients with biochemical recurrence of the disease even if serum PSA values very low. For the reasons explained above, the PSMA could be an excellent molecular target for the development of radiotracers for PET/CT imaging that could detect early relapse of disease.
References
1Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA: a cancer journal for clinicians. 2017;67:7-30.
2Rouviere O, Vitry T, Lyonnet D. Imaging of prostate cancer local recurrences: why and how? Eur Radiol 2010;20:1254-1266.
3Mease RC, Foss CA, Pomper MG. PET imaging in prostate cancer: focus on prostate specific membrane antigen. Current Topics in Medicinal Chemistry 2013;13:951-962.
4Vargas HA, Grimm J, O FD, Sala E, Hricak H. Molecular imaging of prostate cancer: translating molecular biology approaches into th clinical realm. Eur Radiol 2015;25:1294-1302.
5Eder M, Eisenhut M, Babich J, Haberkorn U. PSMA as a target for radiolabelled small molecules. Eur J Nucl Med Mol Imaging 2013;40:819-823.
6Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem 2004;91:528-539.
7Schafer M, Bauder-Wust U, Leotta K, et al. A dimerized ureabased inhibitor of the prostate-specific membrane antigen for Ga-68 PET imaging of prostate cancer. EJNMMI Res 2012;2:23.
8Afshar-Oromieh A, Avtzi E, Giesel FL, 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.
9Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid Ga-68 PSMA Ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med 2015;56:668-674.
10Morigi JJ, Stricker PD, Van Leeuwen PJ, et al. Prospective comparison of 18Ffluoromethylcholine 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.
11Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut M, Zechmann CM. [68Ga]Gallium labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. Eur J Nucl Med Mol Imaging 2012;39:1085-1086.
12Afshar-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.
13Yu CY, Desai B, Ji L, Groshen S, Jadvar H. Comparative performance of PET tracers in biochemical recurrence of prostate cancer: a critical analysis of literature. Am J Nucl Med Mol Imaging 2014;4:580-601.
14Maurer T, Gschwend JE, Rauscher I, et al. Diagnostic efficacy of 68Gallium-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;195:1436-1443.
15Perera M, Papa N, Christidis D, 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;70:926-937.
16Afshar-Oromieh A, Holland-Letz T, Giesel FL, et al. Diagnostic performance of 68GaPSMA-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.
17Ceci F, Uprimny C, Nilica B, 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;42:1284-1294.
18Demirkol MO, Acar O, Ucar B, Ramazanoglu SR, Saglican Y, Esen T. Prostate-specific membrane antigen-based imaging in prostate cancer: impact on clinical decision making process. Prostate 2015;75:748-757.
19Rauscher I, Düwel C, Haller B, et al. Efficacy, predictive factors, and prediction nomograms for Ga-68 labeled prostate-specific membrane antigen-ligand positron-emission tomography/computed tomography in early biochemical recurrent prostate cancer after radical prostatectomy. European Urology 2018
20Guidelines for imaging in patients with biochemical failure. https://uroweb.org/wp-content/uploads/EAUGuidelines-Prostate-Cancer-2016.pdf acessed 12.3.18.
21Pfister D, Bolla M, Briganti A, et al. Early salvage radiotherapy following radical prostatectomy. Eur Urol 2014;65:1034-1043.
22King CR. The timing of salvage radiotherapy after radical prostatectomy: a systematic review.Int J Radiat Oncol Biol Phys 2012;84:104-111.
23Bluemel C, Krebs M, Polat B, et al. HerrmannK. Ga-68 PSMA-PET/CT in patients with biochemical prostate cancer recurrence and negative 18F-Choline-PET/CT. Clin Nucl Med 2016;41:515–521.
24Rauscher I, Maurer T, Fendler WP, et al. Ga-68 PSMA ligand PET/CT in patients with prostate cancer: how we review and report. Cancer Imaging 2016;8;16:14.
25Schwenck J, Tabatabai G, Skardelly M, et al. In vivo visualization of prostatespecific membrane antigen in glioblastoma. Eur J Nucl Med Mol Imaging 2015;42:170-171.
26Verburg FA, Krohn T, Heinzel A, et al. First evidence of PSMA expression in differentiated thyroid cancer using [Ga-68]PSMA-HBED-CC PET/CT. Eur J Nucl Med Mol Imaging 2015;42:1622–1623.
27Rowe SP, Gorin MA, Hammers HJ, et al. Imaging of metastatic clear cell renal cell carcinoma with PSMA targeted (18)F-DCFPyL PET/CT. Ann Nucl Med 2015;29:877-882.
28Pyka T, Weirich G, Einspieler I, et al. Ga-68 PSMA HBED PET for differential diagnosis of suspicious lung lesions in patients with prostate cancer. J Nucl Med 2016;57:367-371.
29Sasikumar A, Joy A, Nanabala R, et al. (68)Ga-PSMA PET/CT imaging in primary hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2016;43:795-796.
30Gykiere P, Goethals L, Everaert H. Healing sacral fracture masquerading as metastatic bone disease on a 68Ga-PSMA PET/CT. Clin Nucl Med 2016;41:e346-347.
31Kanthan GL, Drummond J, Schembri GP, et al. Follicular thyroid adenoma showing avid uptake on 68Ga PSMAHBED-CC PET/CT. Clin Nucl Med 2016;41:331-332.
32Kobe C, Maintz D, Fischer T, et al. Prostate-specific membrane antigen PET/CT in splenic sarcoidosis. Clin Nucl Med 2015;40:897-898.
33Rischpler C, Maurer T, Schwaiger M, et al. Intense PSMA-expression using (68)Ga-PSMA PET/CT in a paravertebral schwannoma mimicking prostate cancer metastasis. Eur J Nucl Med Mol Imaging 2016;43:193–194.
34Beheshti M, Rezaee A, Langsteger W. 68Ga-PSMAHBED uptake on cervicothoracic (Stellate) -ganglia, a common pitfall on PET/CT. Clin Nucl Med 2017;42:195-196.
35Rischpler C, Beck TI, Okamoto S, et al. 68Ga-PSMAHBED-CC uptake in cervical, coeliac and sacral ganglia as an important pitfall in prostate cancer PET imaging. J Nucl Med 2018;59:1406-1411.
36Pfob CH, Ziegler S, Graner FP, et al. Biodistribution and radiation dosimetry of (68)Ga-PSMA HBED CC-a PSMA specific probe for PET imaging of prostate cancer. Eur J Nucl Med Mol Imaging 2016;43:1962-1970.
37Nielsen JB, Zacho HD, Haberkorn U, et al. A comprehensive safety evaluation of 68Ga-labeled ligand prostate-specific membrane antigen 11 PET/CT in prostate cancer: the results of 2 prospective, multicenter trials. Clin Nucl Med 2017;42:520-524.
38Fennessy N, Lee J, Shin J, 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;61:739–744.
39Freitag MT, Radtke JP, Afshar-Oromieh A, et al. Local recurrence of prostate cancer after radical prostatectomy is at risk to be missed in 68Ga-PSMA-11-PET of PET/CT and PET/MRI: comparison with mpMRI integrated in simultaneous PET/MRI. Eur J Nucl Med Mol Imaging 2017;44:776–787.
40Uprimny C, Kroiss AS, Decristoforo C, 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;44:765-775.
41Uprimny C, Kroiss AS, Fritz J, 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;44:1647-1655.
42Hijazi S, Meller B, Leitsmann C, et al. Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography. Prostate 2015;75:1934–1940.
43Giesel FL, Fiedler H, Stefanova M, et al. PSMA PET/CT with Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)] versus 3D CT volumetric lymph node assessment in recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2015;42:1794–1800.
44Rauscher I, Maurer T, Beer AJ, et al. Value of Ga-68 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.
45Hijazi S, Meller B, Leitsmann C, et al. See the unseen: mesorectal lymph node metastases in prostate cancer. Prostate 2016;76:776-780.
46Queiroz MA, Viana P, Santos A, et al. Clinical impact of 68Ga-PSMA PET/CT in a patient with biochemical recurrence of prostate cancer. Clin Nucl Med 2016;41:e417-419.
47Janssen JC, Woythal N, Meißner S, et al. [68Ga]PSMAHBED-CC uptake in osteolytic, osteoblastic, and bone marrow metastases of prostate cancer patients. Mol Imaging Biol 2017;19:933–943.
48Sachpekidis C, Bäumer P, Kopka K, et al. 68Ga-PSMA PET/CT in the evaluation of bone metastases in prostate cancer. Eur J Nucl Med Mol Imaging 2018;45:904-912.
49Pyka TJ, Weirich G, Einspieler I, et al. 68Ga-PSMAHBED-CC PET for differential diagnosis of suggestive lung lesions in patients with prostate cancer. Nucl Med 2016;57:367-371.
50Große Hokamp N, Kobe C, Linzenich E, et al. Solitary PSMA-positive pulmonary metastasis in biochemical relapse of prostate cancer. Clin Nucl Med 2017;42: 406-407.
51Rauscher I, Düwel C, Haller B, 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.
52Ceci F, Uprimny C, Nilica B, 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;42:1284-1294.
53Bluemel C, Krebs M, Polat B, et al. Ga-68 PSMA-PET/CT in patients with biochemical prostate cancer recurrence and negative 18F-choline-PET/CT. Clin Nucl Med 2016;41:515-521.
54Afaq A, Alahmed S, Chen SH, et al. Impact of Ga-68 prostate-specific membrane antigen PET/CT on prostate cancer management. J Nucl Med 2018;59:89–92.
55Einspieler I, Rauscher I, Düwel C, 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.
56Sterzing F, Kratochwil C, Fiedler H, et al. (68)GaPSMA-11 PET/CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging 2016;43:34-41.
57Van Leeuwen PJ, Stricker P, Hruby G, et al. (68) GaPSMA 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.
58Bluemel C, Linke F, Herrmann K, et al. Impact of Ga-68 PSMA PET/CT on salvage radiotherapy planning in patients with prostate cancer and persisting PSA values or biochemical relapse after prostatectomy. EJNMMI Res 2016;6:78.
59Albisinni S, Artigas C, Aoun F, et al. Clinical impact of Ga-68 prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/ CT) in patients with prostate cancer with rising prostatespecific antigen after treatment with curative intent:preliminary analysis of a multidisciplinary approach. BJU Int 2017;120:197-203.
60Habl G, Sauter K, Schiller K, et al. 68 Ga-PSMA-PET for radiation treatment planning in prostate cancer recurrences after surgery: Individualized medicine or new standard in salvage treatment. Prostate 2017;77:920-927.
61Roach PJ, Francis R, Emmett L, et al. The impact of Ga-68 PSMA PET/CT on management intent in prostate cancer: results of an Australian prospective multicenter study. J Nucl Med 2018;59:82-88.
62Calais J, Czernin J, Cao M, 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.
63Calais J, Fendler WP, Eiber M, et al. Impact of 68GaPSMA-11 PET/CT on the management of prostate cancer patients with biochemical recurrence. J Nucl Med 2018;59:434-441.
64Fendler WP, Eiber M, Beheshti M, et al. 68Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for prostate cancer imaging: version 1.0. Eur J Nucl Med Mol Imaging 2017;44:1014–1024.
65Berliner C, Tienken M, Frenzel T, 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;44:670-677.
66Derlin T, Schmuck S, Juhl C, et al. Imaging characteristics and first experience of [68Ga]THP-PSMA, a novel probe for rapid kit-based Ga-68 labeling and PET imaging: comparative analysis with[68Ga]PSMA I&T. Mol Imaging Biol 2018; doi:10.1007/s11307-018-1160-1168.
67Giesel FL , Knorr K , Spohn F, Will L, Maurer T, Flechsig P , et al. Detection efficacy of [18F]PSMA-1007 PET/CT in 251 Patients with biochemical recurrence after radical prostatectomy. J Nucl Med 2018. pii: jnumed.118.212233.
68Afshar-Oromieh A, Holland-Letz T, Giesel FL, et al. Diagnostic performance of 6868Ga-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.
69Henkenberens C, von Klot CA, Ross TL, et al. (68)GaPSMA ligand PET/CT-based radiotherapy in locally recurrent and recurrent oligometastatic prostate cancer: early efficacy after primary therapy. Strahlenther Onkol 2016;192:431-439.
