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Clinical Applications of Nuclear Medicine Targeted Therapy pp 207–234Cite as

Radiopharmaceuticals for Treatment of NETs

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Abstract

Neuroendocrine tumours (NETs) are a group of unusual cancers which develop from cells of the diffuse endocrine system. They are found most commonly in lungs or gastrointestinal system, but they can also originate in other tissues such as pancreas, ovary and testes. A common feature of NETs is that they almost all overexpress somatostatin receptors. For this reason somatostatin receptors have been considered as a target for radiolabelled radiopharmaceuticals. These molecules are constituted by a peptide chain (i.e. a somatostatin-like structure), a partially or totally electron emitter radionuclide and a suitable bifunctional chelator able both to firmly complex the radionuclide as well as to be connected to the peptide chain by means of proper molecular spacers. Nowadays, the most used radiopharmaceuticals for treatments of NETs are [DOTA]0-Tyr3-octreotide (DOTATOC) and [DOTA0]-Tyr3-octreotate (DOTATATE) labelled with yttrium-90 and lutetium-177.

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References

  1. Gudkov SV, Shilyagina NY, Vodeneev VA, et al. Targeted radionuclide therapy of human tumors. Int J Mol Sci. 2016;17:33.

    Article  Google Scholar 

  2. De Jong M, Breeman WA, Kwekkeboom DJ, et al. Tumor imaging and therapy using radiolabeled somatostatin analogues. Acc Chem Res. 2009;42:873–80.

    Article  PubMed  Google Scholar 

  3. Ambrosini V, Fani M, Fanti S, et al. Radiopeptide imaging and therapy in Europe. J Nucl Med. 2011;52:42S–55S.

    Article  CAS  PubMed  Google Scholar 

  4. Gabriel M, Oberauer A, Dobrozemsky G, et al. 68Ga-DOTA-Tyr3 octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy. J Nucl Med. 2009;50:1427–34.

    Article  CAS  PubMed  Google Scholar 

  5. Kwekkeboom DJ, Krenning EP. Peptide receptor radionuclide therapy in the treatment of neuroendocrine tumors. Hematol Oncol Clin North Am. 2016;30:179–91.

    Article  PubMed  Google Scholar 

  6. Sabet A, Biersack HJ, Ezziddin S. Advances in peptide receptor radionuclide therapy. Semin Nucl Med. 2016;46:40–6.

    Google Scholar 

  7. Patel YC. General aspects of the biology and function of somatostatin. In:Somatostatin, Basic and clinical aspects of neuroscience, vol. 4. Berlin: Springer; 1992.

    Chapter  Google Scholar 

  8. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. 1999;20(3):157–98.

    Article  CAS  PubMed  Google Scholar 

  9. Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24(4):389–427.

    Article  CAS  PubMed  Google Scholar 

  10. Froidevaux S, Eberle AN. Somatostatin analogs and radiopeptides in cancer therapy. Biopolymers. 2002;66:161–83.

    Article  CAS  PubMed  Google Scholar 

  11. van der Lely AJ, de Herder WW, Krenning EP, et al. Octreoscan radioreceptor imaging. Endocrine. 2003;20(3):307–11.

    Article  PubMed  Google Scholar 

  12. Delacroix D, Guerre JP, Leblanc P, et al. Radionuclide and radiation protection data handbook 2nd edition (2002). Radiat Prot Dosim. 2002;98:9–168.

    Article  CAS  Google Scholar 

  13. Barone R, Borson-Chazot F, Valkema R, et al. Patient-specific dosimetry in predicting renal toxicity with 90Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose–effect relationship. J Nucl Med. 2005;46:99S–106S.

    CAS  PubMed  Google Scholar 

  14. Hind E, Zanotti-Fregonara P, Quinto MA, et al. Dose deposits from 90Y, 177Lu, 111In, and 161Tb in micrometastases of various sizes: implications for radiopharmaceutical therapy. J Nucl Med. 2016;57:759. https://doi.org/10.2967/jnumed.115.170423.

    Article  Google Scholar 

  15. Smith-Jones PM, Stolz B, Albert R, et al. Synthesis and characterisation of [90Y]-Bz-DTPA-oct: a yttrium-90-labelled octreotide analogue for radiotherapy of somatostatin receptor-positive tumours. Nucl Med Biol. 1998;25(3):181–8.

    Article  CAS  PubMed  Google Scholar 

  16. Otte A, Jermann E, Behe M, et al. DOTATOC: a powerful new tool for receptor-mediated radionuclide therapy. Eur J Nucl Med. 1997;24(7):792–5.

    CAS  PubMed  Google Scholar 

  17. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.

    Article  CAS  PubMed  Google Scholar 

  18. Schuchardt C, Kulkarni HR, Prasad V, et al. The bad berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using 177Lu-DOTATATE, 177Lu-DOTANOC, and 177Lu-DOTATOC. In: Baum R, Rösch F, editors. Theranostics, gallium-68, and other radionuclides, Recent results in cancer research, vol. 194. Berlin: Springer; 2013.

    Google Scholar 

  19. Esser JP, Krenning EP, Teunissen JJ, et al. Comparison of [(177) Lu-OTA(0), Tyr(3)] octreotate and [(177) Lu-DOTA(0), Tyr(3)] octreotide: which peptide is preferable for PRRT? Eur J Nucl Med Mol Imaging. 2006;33:1346–51.

    Article  CAS  PubMed  Google Scholar 

  20. Antunes P, Ginj M, Zhang H, et al. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging. 2007;34:982–93.

    Article  CAS  PubMed  Google Scholar 

  21. Förster GJ, Engelbach M, Brockmann J, et al. Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of 86Y-DOTATOC and 111In-DTPA-octreotide. Eur J Nucl Med. 2001;28(12):1743–50.

    Article  PubMed  Google Scholar 

  22. De Jong M, Bakker WH, Krenning EP, et al. Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA0,d-Phe1,Tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy. Eur J Nucl Med. 1997;24:368–71.

    PubMed  Google Scholar 

  23. Breeman WA, Chan HS, de Zanger RM, et al. Overview of development and formulation of 177Lu-DOTA-TATE for PRRT. Curr Radiopharm. 2016;9(1):8–18.

    Article  CAS  PubMed  Google Scholar 

  24. Breeman WA, van der Wansem K, Bernard BF, et al. The addition of DTPA to [177Lu-DOTA0,Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity. Eur J Nucl Med Mol Imaging. 2003;30(2):312–5.

    Article  CAS  PubMed  Google Scholar 

  25. Breeman WA, De Jong MT, De Blois E, et al. Reduction of skeletal accumulation of radioactivity by co-injection of DTPA in [90Y-DOTA0,Tyr3]octreotide solutions containing free 90Y3+. Nucl Med Biol. 2004;31(6):821–4.

    Article  CAS  PubMed  Google Scholar 

  26. Scott PJ, Hockley BG, Kung HF, et al. Studies into radiolytic decomposition of fluorine-18 labeled radiopharmaceuticals for positron emission tomography. Appl Radiat Isot. 2009;67(1):88–94.

    Article  CAS  PubMed  Google Scholar 

  27. Asti M, Atti G, Iori M, et al. Semi-automated labelling and fractionation of yttrium-90 and lutetium-177 somatostatin analogues using disposable syringes and vials. Nucl Med Commun. 2012;33:1144–52.

    Article  CAS  PubMed  Google Scholar 

  28. European Directorate for the Quality of Medicines & Healthcare (EDQM). Gallium (68Ga) edotreotide injection. European Pharmacopoeia 7.6. 2013;2482:4847–48.

    Google Scholar 

  29. European Directorate for the Quality of Medicines & Healthcare (EDQM). Extemporaneous preparation of radiopharmaceutical preparations. Chapter 5.19. In:European pharmacopoeia. 8th ed. Strasbourg: EDQM; 2016.

    Google Scholar 

  30. Elsinga P, Todde S, Penuelas I, et al. Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals. Eur J Nucl Med Mol Imaging. 2010;37:1049–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zaknun JJ, Bodei L, Mueller-Brand J, et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013;40(5):800–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. International Atomic Energy Agency. Therapeutic radionuclide generators: 90Sr/90Y and 188W/188Re generators, Technical Reports Series No. 470. Vienna: International Atomic Energy Agency; 2009.

    Google Scholar 

  33. Castillo AX, Pérez-Malo M, Isaac-Olivé K, et al. Production of large quantities of 90Y by ion-exchange chromatography using an organic resin and a chelating agent. Nucl Med Biol. 2010;37(8):935–42.

    Article  CAS  PubMed  Google Scholar 

  34. Dash A, Pillai MR, Knapp FF Jr. Production of (177)Lu for targeted radionuclide therapy: available options. Nucl Med Mol Imaging. 2015;49(2):85–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tarasov VA, Andreev OI, Romanov EG, et al. Production of no-carrier added lutetium-177 by irradiation of enriched ytterbium-176. Curr Radiopharm. 2015;8(2):95–106.

    Article  CAS  PubMed  Google Scholar 

  36. Williams K. Endotoxins. 3rd ed. New York: Informa Healthcare; 2007. p. 27–90.

    Google Scholar 

  37. Cooper JF, Thoma LA. Screening extemporaneously compounded intraspinal injections with the bacterial endotoxins test. Am J Health Syst Pharm. 2002;59:2426–33.

    CAS  PubMed  Google Scholar 

  38. Dragotakes SC, Cooper JF, Hubers D. A new system for the rapid detection of endotoxin in PET radiopharmaceuticals. (abstract). 2005. Society of Nuclear Medicine. Toronto.

    Google Scholar 

  39. Biasiotto G, Bertagna F, Zanella I, et al. Production and quality control of [(90)Y]DOTATOC for treatment of metastatic neuroendocrine tumors: results of 85 syntheses. Nucl Med Commun. 2013;34(3):265–70.

    Article  CAS  PubMed  Google Scholar 

  40. Kunikowska J, Królicki L, Dydejczyk AH, et al. Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option? Eur J Nucl Med Mol Imaging. 2011;38(10):1788–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Petrik M, Knetsch PA, Knopp R, et al. Radiolabelling of peptides for PET, SPECT and therapeutic applications using a fully automated disposable cassette system. Nucl Med Commun. 2011;32:887–95.

    Article  PubMed  Google Scholar 

  42. Mukherjee A, Lohar S, Dash A, et al. Single vial kit formulation of DOTATATE for preparation of (177) Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy. J Label Compd Radiopharm. 2015;58(4):166–72.

    Article  CAS  Google Scholar 

  43. Taşdelen B, Ergun A, Büyükkaya F, et al. Rapid isocratic HPLC investigation of radiochemical purity for 90Y-DOTATATE. J Radioanal Nucl Chem. 2011;289(2):573–5.

    Article  Google Scholar 

  44. Breeman WAP, Chan HS, de Blois E. Determination of peptide content and purity of DOTA-peptides by metal ion titration and UPLC: an alternative method to monitor quality of DOTA-peptides. J Radioanal Nucl Chem. 2004;302(2):825–30.

    Article  Google Scholar 

  45. Asti M, Tegoni M, Farioli D, et al. Influence of cations on complexation yield of DOTATATE with yttrium and lutetium: a perspective study for enhancing the 90Y and 177Lu labeling conditions. Nucl Med Biol. 2012;39(4):509–17.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author thanks Coruzzi Chiara for the work on the raw material, the proofs for correction and for the bibliographic research.

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Authors and Affiliations

  1. Nuclear Medicine Unit, Oncology and Advanced Technologies Department, Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, Italy

    Mattia Asti, Michele Iori, Pier Cesare Capponi & Sara Rubagotti

Authors
  1. Mattia Asti
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  2. Michele Iori
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  3. Pier Cesare Capponi
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  4. Sara Rubagotti
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Corresponding author

Correspondence to Mattia Asti .

Editor information

Editors and Affiliations

  1. Department of Nuclear Medicine, Humanitas Gavazzeni Hospital, Bergamo, Italy

    Emilio Bombardieri

  2. Nuclear Medicine Therapy and Endocrinology, Istituto Nazionale dei Tumori, Milano, Italy

    Ettore Seregni

  3. Nuclear Medicine and Molecular Imaging Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy

    Laura Evangelista

  4. Nuclear Medicine Division, Istituto Nazionale dei Tumori, Milano, Italy

    Carlo Chiesa

  5. Nuclear Medicine, Humanitas Research Hospital, Rozzano, Milano, Italy

    Arturo Chiti

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Asti, M., Iori, M., Capponi, P.C., Rubagotti, S. (2018). Radiopharmaceuticals for Treatment of NETs. In: Bombardieri, E., Seregni, E., Evangelista, L., Chiesa, C., Chiti, A. (eds) Clinical Applications of Nuclear Medicine Targeted Therapy . Springer, Cham. https://doi.org/10.1007/978-3-319-63067-0_17

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  • DOI: https://doi.org/10.1007/978-3-319-63067-0_17

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