Петид-рецепторная радионуклидная терапия радиофармацевтическим лекарственным препаратом 177Lu-DOTA-TATE.

Введение: Пептид-рецепторная радионуклидная терапия (ПРРТ) меченными ¹⁷⁷Lu аналогами соматостатина давно стала признанным вариантом лечения во второй или третьей линии терапии пациентов с прогрессирующими дифференцированными (G1–2 степени) гастро-энтеро-панкреатическими нейроэндокринными опухолями (ГЭП-НЭО). На основании результатов исследования NETTER-II ПРРТ активно внедряется в качестве первой линии терапии гастроэнртеропанкретатическими нейроэндокринными опухолями (ГЭП-НЭО), в качестве неоадьювантного метода лечения. Цель: Анализ эффективности и безопасности метода пептид-рецепторной радионуклидной терапии ¹⁷⁷Lu-DOTA-TATЕ по данным мировой литературы. Материалы и методы: Поиск литературных источников выполнялся в период с 01.06.2024 по 12.12.2024 в базах данных: Pubmed, Google Scholar, ELibrary по поисковым запросам: ¹⁷⁷Lu-DOTA-TATE, ¹⁷⁷Lu and NET, peptid-receptor radionuclide therapy. Результаты: ¹⁷⁷Lu-DOTA-TATE является приоритетным РФЛП для радиотаргетной терапии больных метастатическими и неоперабельными нейроэндокринными опухолями (НЭО), и нейроэндокринными карциномами (НЭК) экспрессирующими соматостатиновые рецепторы 2-го типа (ССТР2) [1]. Рост заболеваемости на фоне улучшения диагностики НЭО, интенсивное развитие технологий ядерной медицины, в особенности методов радиотаргетной терапии, стали причиной повышенной заинтересованности в регистрации и широкомасштабном применении ¹⁷⁷Lu-DOTA-TATE [2]. Обсуждение: ¹⁷⁷Lu-DOTA-TATE был одобрен профильными зарубежными медицинскими организациями-регуляторами: Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов (FDA, USA) и Европейского медицинского агентства (EMA) [3, 4]. Анализ эффективности ПРРТ и нежелательных явлений характеризует данный вид радионуклидной терапии как безопасный и высокоэффективный. Заключение: Лечение пациентов с НЭО и НЭК, включающее ПРРТ, требует широкого набора специальных клинических знаний, что обусловливает необходимость обсуждения пациентов в экспертной мультидисциплинарной команде клиницистов (онкологи, эндокринологи, химиотерапевты, радиологи, радиотерапевты, патоморфологи и другие специалисты)

1. De Herder W, Hofland L, Van der Lely A-J, et al. Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. Endocr-Relat Cancer. 2003;(10):451-8. https://doi.org/10.1677/erc.0.0100451.

2. Fraenkel M, Kim M, Faggiano A, et al. Incidence of gastroenteropancreatic neuroendocrine tumours: A systematic review of the literature. Endocr-Relat Cancer. 2014;(21):R153-R163. https://doi.org/10.1530/ERC-13-0125.

3. FDA Letter of Approval for LUTATHERA®. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf (дата обращения 18.12.2024)

4. Authorization Details for Lutathera® in Europe. 2018. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/lutathera#authorisation-details-section (дата обращения 18.12.2024).

5. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177) Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;(376):125-35. https://doi.org/10.1056/NEJMoa1607427.

6. Lin E, Chen T, Little A, et al. Safety and outcomes of (177) Lu-DOTATATE for neuroendocrine tumours: Experience in New South Wales, Australia. Intern Med J. 2019;(49):1268-77. https://doi.org/10.1111/imj.14336.

7. Strosberg J, Caplin M, Kunz P, et al. NETTER-1 investigators. 177Lu-dotatate plus long-acting octreotide versus high−dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and longterm safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752-63. https://doi.org/10.1016/S1470-2045(21)00572-6.

8. Brabander T, van der Zwan W, Teunissen J, et al. Long-Term Efficacy, Survival, and Safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017;(23):4617-24. https://doi.org/10.1158/1078-0432.CCR-16-2743.

9. Baudin E, Walter T, Beron A, et al. First multicentric randomized phase II trial investigating the antitumor efficacy of peptide receptor radionucleide therapy with 177lutetium–octreotate (OCLU) in unresectable progressive neuroendocrine pancreatic tumor: results of the OCLURANDOM trial. Ann Oncol. 2020;(31):844-60. https://doi.org/10.1016/j.annonc.2022.07.1013.

10. Hertelendi M, Belguenani O, Cherfi A, et al. Systematic Review Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review. Biomedicines. 2023;(11):1024. https://doi.org/10.3390/biomedicines11041024.

11. Velikyan I. (Radio)Theranostic Patient Management in Oncology Exemplified by Neuroendocrine Neoplasms, Prostate Cancer, and Breast Cancer. Pharmaceuticals. 2020; 13(3):39. https://doi.org/10.3390/ph13030039.

12. Kwekkeboom D, de Herder W, Kam B, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;(26):2124-30. https://doi.org/10.1200/JCO.2007.15.2553.

13. NCCN Guidelines Neuroendocrine and Adrenal Tumors (Version 1.2018 and Version 2.2024), NCCN Clinical Practice Guidelines in Oncology. Available at: https://www.nccn.org/guidelines/guidelines-detail.

14. Hope T, Abbott A, Colucci K, et al. NANETS/SNMMI Procedure Standard for Somatostatin Receptor-Based Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE. Nucl Med. 2019;60(7):937-43. https://doi.org/10.2967/jnumed.118.230607.

15. Singh S, Halperin D, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024; 29;403(10446):2807-17. https://doi.org/10.1016/S0140-6736(24)00701-3.

16. Partelli S, Landoni L, Bartolomei M, et al. Neoadjuvant 177Lu-DOTA-TATE for non-functioning pancreatic neuroendocrine tumours (NEOLUPANET): multicentre phase II study. Br J Surg. 2024;30;111(9):178. https://doi.org/10.1093/bjs/znae178.

17. Приказ Министерства здравоохранения Российской Федерации от 31.07.2020 № 780н «Об утверждении видов аптечных организаций» (Зарегистрирован 17.09.2020 № 59929). Доступно по ссылке: http://www.publication.pravo.gov.ru/Document/View/

18. Румянцев П, Сергунова Е, Коневега А, и др. Тераностика в ядерной медицине. Российские нанотехнологии. 2023;18(4):486-94. https://doi.org/10.56304/S1992722323040155.e. Russian Nanotechnologies 2023;18(4): 486-94. (In Russ).

19. Gains J, Bomanji J, Fersht N, et al. 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. J Nucl Med. 2011;52(7):1041-7 https://doi.org/10.2967/jnumed.110.085100.

20. Fathpour G, Jafari E, Hashemi A, et al. Feasibility and Therapeutic Potential of Combined Peptide Receptor Radionuclide Therapy With Intensive Chemotherapy for Pediatric Patients With Relapsed or Refractory Metastatic Neuroblastoma. Clin Nucl Med. 2021;46(7):540-8. https://doi.org/10.1097/RLU.0000000000003577.

21. Malcolm J, Falzone N, Gains J, et al. Impact of cyclic changes in pharmacokinetics and absorbed dose in pediatric neuroblastoma patients receiving [177Lu]Lu-DOTATATE. EJNMMI Phys. 2022;9(1):24. https://doi.org/10.1186/s40658-022-00436-4.

22. Castle J, Levy B, Chauhan A. Pediatric Neuroendocrine Neoplasms: Rare Malignancies with Incredible Variability. Cancers (Basel). 2022;14(20):5049. https://doi.org/10.3390/cancers14205049.

23. Aggarwal P, Satapathy S, Sood A, et al. Safety and Efficacy of 177Lu-DOTATATE in Children and Young Adult Population: A Single-Center Experience. Clin Nucl Med. 2024;49(7):e312-e318. https://doi.org/10.1097/RLU.0000000000005233

24. Becx M, Minczeles N, Brabander T, et al. A Clinical Guide to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients. Cancers (Basel). 2022;14(23):5792. https://doi.org/10.3390/cancers14235792.

25. Peterson A, Wang C, Wong K, et al. 177Lu-DOTATATE Theranostics: Predicting Renal Dosimetry From Pretherapy 68Ga-DOTATATE PET and Clinical Biomarkers. Clin Nucl Med. 2023;48(5):393-9. https://doi.org/10.1097/RLU.0000000000004599.

26. Strosberg J, El-Haddad G, Wolin, E, et al. Phase 3 Trial of (177) Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376(2):125-35. https://doi.org/10.1056/NEJMoa1607427.

27. Brabander T, van der Zwan W, Teunissen, et al. Long-Term Efficacy, Survival, and Safety of [(177)Lu-DOTA(0),Tyr(3)] octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017;23(16):4617-24. https://doi.org/10.1158/1078-0432.CCR-16-2743.

28. Vegt E, de Jong M, Wetzels J, et al. Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention. J Nucl Med. 2010;51(7):1049-58. https://doi.org/10.2967/jnumed.110.075101.

29. Bodei L, Mueller-Brand J, Baum R, 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. https://doi.org/10.1007/s00259-012-2330-6.

30. Yordanova A, Wicharz M, Mayer K, et al. The Role of Adding Somatostatin Analogues to Peptide Receptor Radionuclide Therapy as a Combination and Maintenance Therapy. Clin Cancer Res. 2018;24(19):4672-9. https://doi.org/10.1158/1078-0432.CCR-18-0947.

31. Syguła A, Ledwon A, Hasse-Lazar K, et al. In patients with well-differentiated neuroendocrine tumours, there is no apparent benefit of somatostatin analogues after disease control by peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2022; 49(11):3841-51. https://doi.org/10.1007/s00259-022-05792-y.

32. Приказ Министерства здравоохранения Российской федерации № 249н от 22 мая 2023 г. «Об утверждении правил изготовления и отпуска лекарственных препаратов для медицинского применения аптечными организациями, имеющими лицензию на фармацевтическую деятельность» от 22 мая 2023 г. № 249н. Доступно по ссылке: http://publication.pravo.gov.ru/document/0001202305300017?ysclid=lw3cm0srg3931881778.

33. Peterson A, Wang C, Wong K, et al. 177Lu-DOTATATE Theranostics: Predicting Renal Dosimetry From Pretherapy 68Ga-DOTATATE PET and Clinical Biomarkers. Clin Nucl Med. 2023;48(5):393-9. https://doi.org/10.1097/RLU.0000000000004599

34. Kwekkeboom D, Krenning E. Peptide Receptor Radionuclide Therapy in the Treatment of Neuroendocrine Tumors. Hematol Oncol Clin North Am. 2016;30(1):179-91. https://doi.org/10.1016/j.hoc.2015.09.009.

35. Minczeles N, de Herder W, Konijnenberg M, et al. Dose-Limiting Bone Marrow Toxicities After Peptide Receptor Radionuclide Therapy Are More Prevalent in Women Than in Men. Clin Nucl Med. 2022;47(7):599-605. https://doi.org/10.1097/RLU.0000000000004203.

36. Kong G, Callahan J, Hofman M, et al. High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2017;44(3):476-89. https://doi.org/10.1007/s00259-016-3527-x.

37. Bodei L, Cremonesi M, Grana C, et al. Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38(12):2125-35. https://doi.org/10.1007/s00259-011-1902-1.

38. Brabander T, Hofland H. Radionuclide therapy in the time of COVID-19. Eur J Nucl Med Mol Imaging. 2020;47(9):2066-7. https://doi.org/10.1007/s00259-020-04921-9.

39. Bodei L, Kidd M, Paganelli G, 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(1):5-19. https://doi.org/10.1007/s00259-014-2893-5.

40. Singh A, Mencia-Trinchant N, Griffiths E, et al. Mutant PPM1D and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy. JCO Precis Oncol. 2022;(6):e2100309. https://doi.org/10.1200/PO.21.00309.

41. Delpassand E, Samarghandi A, Zamanian S, 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(4):518-25. https://doi.org/10.1097/MPA.0000000000000113.

42. Bergsma H, Konijnenberg M, Kam B, et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2016;43(3):453-63. https://doi.org/10.1007/s00259-015-3193-4.

43. Geenen L, Nonnekens J, Konijnenberg M, et al. Overcoming nephrotoxicity in peptide receptor radionuclide therapy using [177Lu]Lu-DOTA-TATE for the treatment of neuroendocrine tumours. Nucl Med Biol. 2021;(102-103):1-11. https://doi.org/10.1016/j.nucmedbio.2021.06.006.

44. Тищенко В, Петриев В, Крылов В и др. Аналоги соматостатина, меченные радионуклидами, для терапии онкологических заболеваний. Обзор. Радиация и риск. 2022;31(2):76-96. Tishchenko V, Petriev V, Krylov V, et al. Radionuclide-labeled somatostatin analogues for cancer therapy. Review. Radiation and Risk. 2022;31(2):76-96. (In Russ.). https://doi.org/10.21870/0131-3878-2022-31-2-76-96

45. Geenen L, Nonnekens J, Konijnenberg M, et al. Overcoming nephrotoxicity in peptide receptor radionuclide therapy using [177Lu]Lu-DOTA-TATE for the treatment of neuroendocrine tumours. Nucl Med Biol. 2021;(102-103):1-11. https://doi.org/10.1016/j.nucmedbio.2021.06.006.

46. Rolleman J, Valkema R, de Jong M, et al. Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. Eur J Nucl Med Mol Imaging. 2003;30(1):9-15. https://doi.org/10.1007/s00259-002-0982-3.

47. De Jong M, Krenning E. New advances in peptide receptor radionuclide therapy. J Nucl Med. 2002;43(5):617-20. PMID: 11994523.

48. Moll S, Nickeleit V, Mueller-Brand J, et al. A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy // Am J Kidney Dis. 2001 Apr;37(4):847-51. https://doi.org/10.1016/s0272-6386(01)80135-9.

49. Bergsma H, Konijnenberg M, van der Zwan W, et al. Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate // Eur J Nucl Med Mol Imaging. 2016;43(10):1802-11. https://doi.org/10.1007/s00259-016-3382-9.

50. Stolniceanu C, Nistor I, Bilha S, et al. Nephrotoxicity/renal failure after therapy with 90Yttrium and 177Lutetium-radiolabeled somatostatin analogs in different types of neuroendocrine tumors: a systematic review. Nucl Med Commun. 2020; 41(7):601‑17. https://doi.org/10.1097/MNM.0000000000001198.

51. Daskalakis K, Karakatsanis A, Stålberg P, et al. Clinical signs of fibrosis in small intestinal neuroendocrine tumours. Br J Surg. 2017;104(1):69-75. https://doi.org/10.1002/b

52. Hofman M, Hicks R. Gallium-68 EDTA PET/CT for Renal Imaging // Semin Nucl Med. 2016;46(5):448-61. https://doi.org/10.1053/j.semnuclmed.2016.04.002.

53. Van Binnebeek S, Baete K, Vanbilloen B, et al. Individualized dosimetry-based activity reduction of ⁹⁰Y-DOTATOC prevents severe and rapid kidney function deterioration from peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2014;41(6):1141-57. https://doi.org/10.1007/s00259-013-2670-x.

54. Krajewski W, Wojciechowska J, Dembowski J, et al. Hydronephrosis in the course of ureteropelvic junction obstruction: An underestimated problem? Current opinions on thepathogenesis, diagnosis and treatment. Adv Clin Exp Med. 2017;26(5):857-64. https://doi.org/10.17219/acem/59509.

55. Lin E, Chen T, Little A, et al. Safety and outcomes of 177 Lu-DOTATATE for neuroendocrine tumours: experience in New South Wales, Australia. Intern Med J. 2019;49(10):1268-77. https://doi.org/10.1111/imj.14336.

56. Hamiditabar M, Ali M, Roys J, et al. Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years’ Assessment. Clin Nucl Med. 2017;42(6):436-43. https://doi.org/10.1097/RLU.0000000000001629.

57. Smits M, Nijsen J, van den Bosch M, et al. Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. Lancet Oncol. 2012;13(10):1025-34. https://doi.org/10.1016/S1470-2045(12)70334-0.

58. Braat A, Ahmadzadehfar H, Kappadath S, et al. Radioembolization with 90Y Resin Microspheres of Neuroendocrine Liver Metastases After Initial Peptide Receptor Radionuclide Therapy. Cardiovasc Intervent Radiol. 2020;43(2):246-53. https://doi.org/10.1007/s00270-019-02350-2.

59. Ezziddin S, Meyer C, Kahancova S, et al. 90Y Radioembolization after radiation exposure from peptide receptor radionuclide therapy. J Nucl Med. 2012;53(11):1663-9. https://doi.org/10.2967/jnumed.112.107482.

60. Del Olmo-García M, Muros M, López-de-la-Torre M, et al. Prevention and Management of Hormonal Crisis during Theragnosis with LU-DOTA-TATE in Neuroendocrine Tumors. A Systematic Review and Approach Proposal. J Clin Med. 2020;9(7):2203. https://doi.org/10.3390/jcm9072203.

61. De Keizer B, van Aken M, Feelders R, 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(4):749-55. https://doi.org/10.1007/s00259-007-0691-z.

62. Hlatky R, Suki D, Sawaya R. Carcinoid metastasis to the brain. Cancer. 2004;101(11):2605-13. https://doi.org/10.1002/cncr.20659.

63. Pavel M, Grossman A, Arnold R, et al. Palma de Mallorca Consensus Conference Participants. ENETS consensus guidelines for the management of brain, cardiac and ovarian metastases from neuroendocrine tumors. Neuroendocrinology. 2010;91(4):326-32. https://doi.org/10.1159/000287277.

64. Scharf M, Petry V, Daniel H, et al. Bone Metastases in Patients with Neuroendocrine Neoplasm: Frequency and Clinical, Therapeutic, and Prognostic Relevance. Neuroendocrinology. 2018;106(1):30-7. https://doi.org/10.1159/000457954.

65. Cecchin D, Schiavi F, Fanti S, et al. Peptide receptor radionuclide therapy in a case of multiple spinal canal and cranial paragangliomas. J Clin Oncol. 2011;29(7):e171-4. https://doi.org/10.1200/JCO.2010.31.7131.

66. Zaknun J, 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. https://doi.org/10.1007/s00259-012-2330-6.

67. Hicks R, Kwekkeboom D, Krenning E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology. 2017;105(3):295-309. https://doi.org/10.1159/000475526.

68. Schwartz L, Litière S, de Vries E, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016;62:132-7. https://doi.org/10.1016/j.ejca.2016.03.081.

69. Deshayes E, Assenat E, Meignant L, et al. A prospective, randomized, phase II study to assess the schemas of retreatment with Lutathera® in patients with new progression of an intestinal, well-differentiated neuroendocrine tumor (ReLUTH). BMC Cancer. 2022;22(1):1346. https://doi.org/10.1186/s12885-022-10443-4.

70. Fayers P, Bottomley A; EORTC Quality of Life Group; Quality of Life Unit. Quality of life research within the EORTC-the EORTC QLQ-C30. European Organisation for Research and Treatment of Cancer. Eur J Cancer. 2002;(38):125-33. https://doi.org/10.1016/s0959-8049(01)00448-8.