Nuclear Medicine and Molecular Imaging

, Volume 52, Issue 3, pp 208–215 | Cite as

Lu-177-Based Peptide Receptor Radionuclide Therapy for Advanced Neuroendocrine Tumors

Review

Abstract

Peptide receptor radionuclide therapy (PRRT) is a systemic cytotoxic radiation therapy using a compound of β-emitting radionuclide chelated to a peptide for the treatment of tumor with overexpressed specific cell receptor such as somatostatin receptor subtype 2 (SSTR2) of neuroendocrine tumor (NET). Surgical resection should be performed for the curative treatment for NETs when it is feasible; however, a multi-disciplinary approach is needed when locally advanced or metastasized disease. PRRT with lutetium-177 (Lu-177)-labeled somatostatin analogues, as a new treatment modality targeting metastatic or inoperable NETs expressing the SSTR2, have been developed and successfully used for the past two decades. As Lu-177 emits both β- and γ-radiation, it has the ability as a theragnostic agent for NETs compared with only β-emitting yttrium-90 labeled PRRT. Several recent studies reported that Lu-177 gave an overall positive response and improved the patients’ quality of life. To fully exploit its potential, large comparative studies are needed for the assessment of distinct efficacies of Lu-177 labeled PRRT. Additionally, for extending the indications and developing new regimens of Lu-177-based PRRT, more dedicated clinical research is required.

Keywords

Peptide receptor radionuclide therapy Neuroendocrine tumors Radiolabeled somatostatin analogues Lu-177 

Notes

Compliance with Ethical Standards

Conflict of Interest

Keunyoung Kim and Seong-Jang Kim have no conflicts of interest related to the current study.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors.

Informed Consent

This article does not contain any studies with human participants performed by any of the authors.

References

  1. 1.
    Fraenkel M, Kim MK, Faggiano A, Valk GD. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26:691–703.CrossRefPubMedGoogle Scholar
  2. 2.
    Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72.CrossRefPubMedGoogle Scholar
  3. 3.
    Moller LN, Stidsen CE, Hartmann B, Holst JJ. Somatostatin receptors. Biochim Biophys Acta. 1616;2003:1–84.Google Scholar
  4. 4.
    Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Horsch D, O’Dorisio MS, 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;40:800–16.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kulke MH, Shah MH, Benson AB III, Bergsland E, Berlin JD, Blaszkowsky LS, et al. Neuroendocrine tumors, version 1.2015. J Natl Compr Cancer Netw. 2015;13:78–108.CrossRefGoogle Scholar
  6. 6.
    Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54(Suppl 4):iv1–16.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–92.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol. 2006;17:1733–42.CrossRefPubMedGoogle Scholar
  10. 10.
    Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32:225–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Kwekkeboom DJ, Bakker WH, Kam BL, Teunissen JJ, Kooij PP, de Herder WW, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA(0),Tyr3]octreotate. Eur J Nucl Med Mol Imaging. 2003;30:417–22.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Okarvi SM. Recent developments in 99Tcm-labelled peptide-based radiopharmaceuticals: an overview. Nucl Med Commun. 1999;20:1093–112.CrossRefPubMedGoogle Scholar
  13. 13.
    de Jong M, Breeman WA, Bernard BF, Bakker WH, Schaar M, van Gameren A, et al. [177Lu-DOTA(0),Tyr3] octreotate for somatostatin receptor-targeted radionuclide therapy. Int J Cancer. 2001;92:628–33.CrossRefPubMedGoogle Scholar
  14. 14.
    Delpassand ES, Samarghandi A, Zamanian S, Wolin EM, Hamiditabar M, Espenan GD, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience. Pancreas. 2014;43:518–25.CrossRefPubMedGoogle Scholar
  15. 15.
    Maecke HR, Reubi JC. Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment. J Nucl Med. 2011;52:841–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols LK, et al. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med. 2005;46(Suppl 1):62s–6s.PubMedGoogle Scholar
  17. 17.
    Cremonesi M, Botta F, Di Dia A, Ferrari M, Bodei L, De Cicco C, et al. Dosimetry for treatment with radiolabelled somatostatin analogues. A review. Q J Nucl Med Mol Imaging. 2010;54:37–51.PubMedGoogle Scholar
  18. 18.
    Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, et al. Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012;39(Suppl 1):S103–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Kulkarni HR, Schuchardt C, Baum RP. Peptide receptor radionuclide therapy with (177)Lu labeled somatostatin analogs DOTATATE and DOTATOC: contrasting renal dosimetry in the same patient. Recent Results Cancer Res. 2013;194:551–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Bodei L, Cremonesi M, Ferrari M, Pacifici M, Grana CM, Bartolomei M, et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging. 2008;35:1847–56.CrossRefPubMedGoogle Scholar
  21. 21.
    Watkins J. Reactions to gelatin plasma expanders. Lancet. 1994;344:328–9. author reply 9-30CrossRefPubMedGoogle Scholar
  22. 22.
    Rolleman EJ, Melis M, Valkema R, Boerman OC, Krenning EP, de Jong M. Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues. Eur J Nucl Med Mol Imaging. 2010;37:1018–31.CrossRefPubMedGoogle Scholar
  23. 23.
    Barron ME, Wilkes MM, Navickis RJ. A systematic review of the comparative safety of colloids. Arch Surg. 2004;139:552–63.CrossRefPubMedGoogle Scholar
  24. 24.
    Wehrmann C, Senftleben S, Zachert C, Muller D, Baum RP. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DOTA-NOC. Cancer Biother Radiopharm. 2007;22:406–16.CrossRefPubMedGoogle Scholar
  25. 25.
    Bakker WH, Breeman WA, Kwekkeboom DJ, De Jong LC, Krenning EP. Practical aspects of peptide receptor radionuclide therapy with [177Lu][DOTA0, Tyr3]octreotate. Q J Nucl Med Mol Imaging. 2006;50:265–71.PubMedGoogle Scholar
  26. 26.
    Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with (1)(7)(7)Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Calais PJ, Turner JH. Radiation safety of outpatient 177Lu-octreotate radiopeptide therapy of neuroendocrine tumors. Ann Nucl Med. 2014;28:531–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Olmstead C, Cruz K, Stodilka R, Zabel P, Wolfson R. Quantifying public radiation exposure related to lutetium-177 octreotate therapy for the development of a safe outpatient treatment protocol. Nucl Med Commun. 2015;36:129–34.CrossRefPubMedGoogle Scholar
  29. 29.
    Schuchardt C, Kulkarni HR, Prasad V, Zachert C, Muller D, Baum RP. The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC. Recent Results Cancer Res. 2013;194:519–36.CrossRefPubMedGoogle Scholar
  30. 30.
    Valkema R, Pauwels SA, Kvols LK, Kwekkeboom DJ, Jamar F, de Jong M, et al. Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate. J Nucl Med. 2005;46(Suppl 1):83s–91s.PubMedGoogle Scholar
  31. 31.
    Bergsma H, Konijnenberg MW, Kam BL, Teunissen JJ, Kooij PP, de Herder WW, et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2016;43:453–63.CrossRefPubMedGoogle Scholar
  32. 32.
    Garkavij M, Nickel M, Sjogreen-Gleisner K, Ljungberg M, Ohlsson T, Wingardh K, et al. 177Lu-[DOTA0,Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: analysis of dosimetry with impact on future therapeutic strategy. Cancer. 2010;116:1084–92.CrossRefPubMedGoogle Scholar
  33. 33.
    Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging. 2015;42:5–19.CrossRefPubMedGoogle Scholar
  34. 34.
    Bodei L, Ferone D, Grana CM, Cremonesi M, Signore A, Dierckx RA, et al. Peptide receptor therapies in neuroendocrine tumors. J Endocrinol Investig. 2009;32:360–9.CrossRefGoogle Scholar
  35. 35.
    Kwekkeboom DJ, Kam BL, van Essen M, Teunissen JJ, van Eijck CH, Valkema R, et al. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17:R53–73.CrossRefPubMedGoogle Scholar
  36. 36.
    Kwekkeboom DJ, Teunissen JJ, Bakker WH, Kooij PP, de Herder WW, Feelders RA, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23:2754–62.CrossRefPubMedGoogle Scholar
  37. 37.
    Bodei L, Cremonesi M, Zoboli S, Grana C, Bartolomei M, Rocca P, et al. Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: a phase I study. Eur J Nucl Med Mol Imaging. 2003;30:207–16.CrossRefPubMedGoogle Scholar
  38. 38.
    Pfeifer AK, Gregersen T, Gronbaek H, Hansen CP, Muller-Brand J, Herskind Bruun K, et al. Peptide receptor radionuclide therapy with Y-DOTATOC and (177)Lu-DOTATOC in advanced neuroendocrine tumors: results from a Danish cohort treated in Switzerland. Neuroendocrinology. 2011;93:189–96.CrossRefPubMedGoogle Scholar
  39. 39.
    Sabet A, Ezziddin K, Pape UF, Ahmadzadehfar H, Mayer K, Poppel T, et al. Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med. 2013;54:1857–61.CrossRefPubMedGoogle Scholar
  40. 40.
    Gupta SK, Singla S, Bal C. Renal and hematological toxicity in patients of neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-DOTATATE. Cancer Biother Radiopharm. 2012;27:593–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.CrossRefPubMedGoogle Scholar
  42. 42.
    Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29:2416–23.CrossRefPubMedGoogle Scholar
  43. 43.
    Svensson J, Berg G, Wangberg B, Larsson M, Forssell-Aronsson E, Bernhardt P. Renal function affects absorbed dose to the kidneys and haematological toxicity during (1)(7)(7)Lu-DOTATATE treatment. Eur J Nucl Med Mol Imaging. 2015;42:947–55.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Karmy-Jones R, Vallieres E. Carcinoid crisis after biopsy of a bronchial carcinoid. Ann Thorac Surg. 1993;56:1403–5.CrossRefPubMedGoogle Scholar
  45. 45.
    Kharrat HA, Taubin H. Carcinoid crisis induced by external manipulation of liver metastasis. J Clin Gastroenterol. 2003;36:87–8.CrossRefPubMedGoogle Scholar
  46. 46.
    de Keizer B, van Aken MO, Feelders RA, de Herder WW, Kam BL, van Essen M, et al. Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate. Eur J Nucl Med Mol Imaging. 2008;35:749–55.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376:125–35.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Paganelli G, Sansovini M, Ambrosetti A, Severi S, Monti M, Scarpi E, et al. 177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study. Eur J Nucl Med Mol Imaging. 2014;41:1845–51.CrossRefPubMedGoogle Scholar
  49. 49.
    Bartolomei M, Bodei L, De Cicco C, Grana CM, Cremonesi M, Botteri E, et al. Peptide receptor radionuclide therapy with (90)Y-DOTATOC in recurrent meningioma. Eur J Nucl Med Mol Imaging. 2009;36:1407–16.CrossRefPubMedGoogle Scholar
  50. 50.
    Bodei L, Handkiewicz-Junak D, Grana C, Mazzetta C, Rocca P, Bartolomei M, et al. Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas. Cancer Biother Radiopharm. 2004;19:65–71.CrossRefPubMedGoogle Scholar
  51. 51.
    Iten F, Muller B, Schindler C, Rasch H, Rochlitz C, Oertli D, et al. [(90)Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term results of a phase 2 clinical trial. Cancer. 2009;115:2052–62.CrossRefPubMedGoogle Scholar
  52. 52.
    Iten F, Muller B, Schindler C, Rochlitz C, Oertli D, Macke HR, et al. Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clin Cancer Res. 2007;13:6696–702.CrossRefPubMedGoogle Scholar
  53. 53.
    Villard L, Romer A, Marincek N, Brunner P, Koller MT, Schindler C, et al. Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol. 2012;30:1100–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Kunikowska J, Krolicki L, Hubalewska-Dydejczyk A, Mikolajczak R, Sowa-Staszczak A, Pawlak D. 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;38:1788–97.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom DJ, Breeman WA, et al. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med. 2002;32:133–40.CrossRefPubMedGoogle Scholar
  56. 56.
    Claringbold PG, Price RA, Turner JH. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother Radiopharm. 2012;27:561–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Claringbold PG, Turner JH. NeuroEndocrine tumor therapy with Lutetium-177-octreotate and Everolimus (NETTLE): a phase I study. Cancer Biother Radiopharm. 2015;30:261–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Kamp K, Gumz B, Feelders RA, Kwekkeboom DJ, Kaltsas G, Costa FP, et al. Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate. Endocr Relat Cancer. 2013;20:825–31.CrossRefPubMedGoogle Scholar
  59. 59.
    Barber TW, Hofman MS, Thomson BN, Hicks RJ. The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroendocrine tumours resectable. Eur J Surg Oncol. 2012;38:64–71.CrossRefPubMedGoogle Scholar
  60. 60.
    Cescato R, Waser B, Fani M, Reubi JC. Evaluation of 177Lu-DOTA-sst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro. J Nucl Med. 2011;52:1886–90.CrossRefPubMedGoogle Scholar
  61. 61.
    Fani M, Braun F, Waser B, Beetschen K, Cescato R, Erchegyi J, et al. Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications. J Nucl Med. 2012;53:1481–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Wild D, Fani M, Fischer R, Del Pozzo L, Kaul F, Krebs S, et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med. 2014;55:1248–52.CrossRefPubMedGoogle Scholar
  63. 63.
    Todorovic-Tirnanic M, Kaemmerer D, Prasad V, Hommann M, Baum RP. Intraoperative somatostatin receptor detection after peptide receptor radionuclide therapy with (177)Lu- and (90)Y-DOTATOC (tandem PRRNT) in a patient with a metastatic neuroendocrine tumor. Recent Results Cancer Res. 2013;194:487–96.CrossRefPubMedGoogle Scholar
  64. 64.
    Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24:389–427.CrossRefPubMedGoogle Scholar

Copyright information

© Korean Society of Nuclear Medicine 2017

Authors and Affiliations

  1. 1.Department of Nuclear Medicine and Biomedical Research InstitutePusan National University HospitalBusanSouth Korea
  2. 2.Department of Nuclear Medicine and Research Institute for Convergence of Biomedical Science and TechnologyPusan National University Yangsan HospitalYangsanSouth Korea

Personalised recommendations