Introduction. Neuroendocrine tumors (NETs) have increased expression of somatostatin receptors (SSTR), where subtype 2 and 5 are the most common. Overexpression of the SSTR is an outstanding molecular target for inoperable and metastatic NETs that enables a unique approach of targeted diagnosis and treatment. In addition to SSTRs, neuroendocrine tumors also express other receptors that can be suitable targets for visualization by nuclear medicine methods. Aim. This review paper is focused on the most common radiopharmaceuticals and their molecular targets that are used today based on theranostic approach in NETs. Results. In conventional nuclear medicine, the most important diagnostic radiopharmaceuticals are somatostatin analogs (SSA) labeled with 111 In and 99m Tc, however 99m Tc has advantages over 111 In based on better physical characteristics and better performance. In recent years, highly potent theranostic pairs have been created for the imaging and treatment of NETs, which can strongly bind SSTR. Derivatives of 68 Ga-labeled octreotide are recommended for diagnostics and follow-up of NENs. The great advantage of 68 Ga radiopharmaceuticals is that identical compounds can be labeled with therapeutic radionuclides 90 Y and 177 Lu. Conclusion. Peptide receptor radionuclide therapy is a systemic molecular target therapy that has proven to be safe and very effective in controlling the disease and prolonging the survival of patients with advanced and inoperable NETs. With a negligible number of adverse events, this therapy is safe and should be administered to all patients who meet the necessary criterias, primarily overexpression of the somatostatin receptor type 2.
References
1.
Kwekkeboom DJ, Kam BL, van Essen M, Teunissen JJM, van Eijck CHJ, Valkema R, et al. Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocrine-Related Cancer. 2010;17(1):R53–73.
2.
Otte A, Mueller-Brand J, Dellas S, Nitzsche E, Herrmann R, Maecke H. Yttrium-90-labelled somatostatin-analogue for cancer treatment. The Lancet. 1998;351(9100):417–8.
3.
Hofmann M, Maecke H, Börner A, Weckesser E, Schöffski P, Oei M, et al. Biokinetics and imaging with the somatostatin receptor PET radioligand 68Ga-DOTATOC: preliminary data. European Journal of Nuclear Medicine. 2001;28(12):1751–7.
4.
Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC, et al. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? European Journal of Nuclear Medicine and Molecular Imaging. 2007;34(7):982–93.
5.
Smith-Jones PM, Bischof C, Leimer M, Gludovacz D, Angelberger P, Pangerl T, et al. DOTA-Lanreotide: A Novel Somatostatin Analog for Tumor Diagnosis and Therapy1. Endocrinology. 1999;140(11):5136–48.
6.
Maina T, Nock B, Nikolopoulou A, Sotiriou P, Loudos G, Maintas D, et al. [99mTc]Demotate, a new 99mTc-based [Tyr3]octreotate analogue for the detection of somatostatin receptor-positive tumours: synthesis and preclinical results. European Journal of Nuclear Medicine and Molecular Imaging. 2002;29(6):742–53.
7.
Chiti A, Fanti S, Savelli G, Romeo A, Bellanova B, Rodari M, et al. Comparison of somatostatin receptor imaging, computed tomography and ultrasound in the clinical management of neuroendocrine gastro-entero-pancreatic tumours. European Journal of Nuclear Medicine and Molecular Imaging. 1998;25(10):1396–403.
8.
DE JONG M, BERNARD BF, BRUIN ED, VAN GAMEREN A, BAKKER WH, VISSER TJ, et al. Internalization of radiolabelled [DTPA0]octreotide and [DOTA0, Tyr3]octreotide. Nuclear Medicine Communications. 1998;19(3):283–8.
9.
Wild D, Schmitt JS, Ginj M, Mäcke HR, Bernard BF, Krenning E, et al. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. European Journal of Nuclear Medicine and Molecular Imaging. 2003;30(10):1338–47.
10.
Decristoforo C, Mather SJ, Cholewinski W, Donnemiller E, Riccabona G, Moncayo R. 99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours: first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives. European Journal of Nuclear Medicine. 2000;27(9):1318–25.
11.
Gabriel M, Muehllechner P, Decristoforo C. 99mTc-EDDA/HYNIC-Tyr(3)octreotide for staging and follow-up of patients with neuroendocrine gastro-entero-pancreatic tumors. QJ Nucl Med Mol Imag. 2005;49:237–44.
12.
Gabriel M, Decristoforo C, Donnemiller E. An intrapatient comparison of 99mTc-EDDA/HYNIC-TOC with 111In-DTPAoctreotide for diagnosis of somatostatin receptor-expressing tumors. J Nucl Med. 2003;44:708–16.
13.
Hubalewska-Dydejczyk A, Fröss-Baron K, Mikołajczak R, Maecke HR, Huszno B, Pach D, et al. 99mTc-EDDA/HYNIC-octreotate scintigraphy, an efficient method for the detection and staging of carcinoid tumours: results of 3 years’ experience. European Journal of Nuclear Medicine and Molecular Imaging. 2006;33(10):1123–33.
14.
Otte A, Jermann E, Behe M, Goetze M, Bucher HC, Roser HW, et al. DOTATOC: A powerful new tool for receptor-mediated radionuclide therapy. European Journal of Nuclear Medicine. 1997;24(7):792–5.
15.
Ambrosini V, Campana D, Tomassetti P, Fanti S. 68Ga-labelled peptides for diagnosis of gastroenteropancreatic NET. European Journal of Nuclear Medicine and Molecular Imaging. 2012;39(S1):52–60.
16.
Virgolini I, Raderer M, Kurtaran A, Angelberger P, Banyai S, Yang Q, et al. Vasoactive Intestinal Peptide-Receptor Imaging for the Localization of Intestinal Adenocarcinomas and Endocrine Tumors. New England Journal of Medicine. 1994;331(17):1116–21.
17.
Virgolini I, Kurtaran A, Raderer M. Vasoactive intestinal peptide receptor scintigraphy. J Nucl Med. 1995;36:1732–9.
18.
Virgolini I, Kurtaran A, Leimer M. Location of a VIPoma by 123iodine-vasoactive intestinal peptide scintigraphy. J Nucl Med. 1998;39:1575–9.
19.
Scopinaro F, Varvarigou AD, Ussof W, De Vincentis G, Sourlingas TG, Evangelatos GP, et al. Technetium Labeled Bombesin-like Peptide: Preliminary Report on Breast Cancer Uptake in Patients. Cancer Biotherapy and Radiopharmaceuticals. 2002;17(3):327–35.
20.
Breeman W, Jong M, Erion J. Preclinical comparison of 111In-labelled DTPA-or DOTAbombesin analogues for receptor-targeted scintigraphy and radionuclide therapy. J Nucl Med. 2002;43:1650–6.
21.
van Hagen PM, Breeman WAP, Reubi JC, Postema PTE, van den Anker-Lugtenburg PJ, Kwekkeboom DJ, et al. Visualization of the thymus by substance P receptor scintigraphy in man. European Journal of Nuclear Medicine. 1996;23(11):1508–13.
22.
Behr T, Behe M, Angerstein C. Cholecystokinin-B/gastrin receptor binding peptides: preclinical development and evaluation of their diagnostic and therapeutic potential. Clin Cancer Res. 1999;5:3124–38.
23.
Behr TM, Béhé MP. Cholecystokinin-B/gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies. Seminars in Nuclear Medicine. 2002;32(2):97–109.
24.
García-Garayoa E, Allemann-Tannahill L, Bläuenstein P, Willmann M, Carrel-Rémy N, Tourwé D, et al. In vitro and in vivo evaluation of new radiolabeled neurotensin(8–13) analogues with high affinity for NT1 receptors. Nuclear Medicine and Biology. 2001;28(1):75–84.
25.
Buchegger F, Bonvin F, Kosinski M. Radiolabelled neurotensin analogue, 99Tc-NT-XI, evaluated in ductal pancreatic adenocarcinoma patients. J Nucl Med. 2003;44:1649–54.
26.
Wang L fan, Lin L, Wang M jiao, Li Y. The therapeutic efficacy of 177Lu-DOTATATE/DOTATOC in advanced neuroendocrine tumors. Medicine. 99(10):e19304.
27.
Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71.
28.
Laschinsky C, Herrmann K, Fendler W, Nader M, Lahner H, Hadaschik B, et al. Onkologische Theranostik in der Nuklearmedizin. Die Radiologie. 2022;62(10):875–84.
29.
Velikyan I. (Radio)Theranostic Patient Management in Oncology Exemplified by Neuroendocrine Neoplasms, Prostate Cancer, and Breast Cancer. Pharmaceuticals. 13(3):39.
30.
Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012;61(1):6–32.
31.
Pavel M, Öberg K, Falconi M, Krenning EP, Sundin A, Perren A, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2020;31(7):844–60.
32.
Lloyd RV, Osamura RY, Klöppel G. Neoplasms of the neuroendocrine pancreas. In: WHO Classification of Tumors of Endocrine Organs. 2017. p. 209–40.
33.
Halperin DM, Shen C, Dasari A, Xu Y, Chu Y, Zhou S, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. The Lancet Oncology. 2017;18(4):525–34.
34.
Patel YC. Somatostatin and Its Receptor Family. Frontiers in Neuroendocrinology. 1999;20(3):157–98.
35.
Pencharz D, Gnanasegaran G, Navalkissoor S. Theranostics in neuroendocrine tumours: somatostatin receptor imaging and therapy. The British Journal of Radiology. 2018;91(1091):20180108.
36.
Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncology. 2017;3(10):1335.
37.
Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD, __. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocrine-Related Cancer. 2014;21(3):R153–63.
38.
Leoncini E, Boffetta P, Shafir M, Aleksovska K, Boccia S, Rindi G. Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms. Endocrine. 2017;58(2):368–79.
39.
Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, et al. TNM Staging of Neoplasms of the Endocrine Pancreas: Results From a Large International Cohort Study. JNCI: Journal of the National Cancer Institute. 2012;104(10):764–77.
40.
Yordanova A, Eppard E, Kürpig S, Bundschuh R, Schönberger S, Gonzalez-Carmona M, et al. Theranostics in nuclear medicine practice. OncoTargets and Therapy. Volume 10:4821–8.
41.
Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Annals of Translational Medicine. 2018;6(12):252–252.
42.
Erickson LA, Lloyd RV. Practical Markers Used in the Diagnosis of Endocrine Tumors. Advances in Anatomic Pathology. 2004;11(4):175–89.
43.
Gould VE, Lee I, Wiedenmann B, Moll R, Chejfec G, Franke WW. Synaptophysin: A novel marker for neurons, certain neuroendocrine cells, and their neoplasms. Human Pathology. 1986;17(10):979–83.
44.
Klimstra DS, Pitman MB, Hruban RH. An Algorithmic Approach to the Diagnosis of Pancreatic Neoplasms. Archives of Pathology & Laboratory Medicine. 2009;133(3):454–64.
45.
La Rosa S, Sessa F, Uccella S. Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms. Endocrine Pathology. 2016;27(4):284–311.
46.
Kontogianni K, Nicholson AG, Butcher D, Sheppard MN. CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact. Journal of Clinical Pathology. 2005;58(9):978–80.
47.
Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. The Lancet. 1998;352(9130):799–805.
48.
Davis Z, Moertel CG, McIlrath DC. The malignant carcinoid syndrome. Surg Gynecol Obstet. 1973;137:637–44.
49.
Reubi J, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. European Journal of Nuclear Medicine. 2001;28(7):836–46.
50.
Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WAP, Kooij PPM, Oei HY, et al. Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. European Journal of Nuclear Medicine. 1993;20(8):716–31.
51.
KRENNING EP, KOOIJ PPM, BAKKER WH, BREEMAN WAP, POSTEMA PTE, KWEKKEBOOM DJ, et al. Radiotherapy with a Radiolabeled Somatostatin Analogue, [111In‐DTPA‐<scp>d</scp>‐Phe1]‐Octreotide. Annals of the New York Academy of Sciences. 1994;733(1):496–506.
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