Assessing the Clinical Impact of Lutetium-177 DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) on Metastatic Neuroendocrine Tumors: A Multicenter Real-World Data from Türkiye

Caglar Unal¹, Nalan Alan Selcuk², Fatih Selcuk Biricik³, Ozkan Alan³, Cetin Ordu⁴, Oguzhan Selvi⁵, Abdullah Sakin⁵, Nadiye Sever⁶, Zeynep Alaca Topcu⁷, Arif Akyildiz⁸, Eyup Coban⁹, Turkan Evrensel⁹, Erkan Ozcan¹⁰, Bengu Dursun¹¹, Kadriye Bir Yucel¹², Haci Arak¹³, Sercan On¹⁴, Halil Goksel Guzel¹⁵, Derya Kivrak Salim¹⁵, Ziya Kalkan¹⁶, Zeynep Oruc¹⁶, Tomris Duymaz¹⁷, Mustafa Seyyar¹⁸, Gozde Agdas¹⁹, Melike Ozcelik²⁰, Nail Paksoy²¹, Bulent Cetin²², Kanay Yararbas²³, Sezer Saglam⁴

Show Less

¹ Division of Medical Oncology, Department of Internal Medicine, Kartal Dr. Lütfi Kırdar City Hospital, İstanbul, Türkiye

² Department of Nuclear Medicine, Faculty of Medicine, Yeditepe University, İstanbul, Türkiye

³ Division of Medical Oncology, Department of Internal Medicine, Koc University Hospital, İstanbul, Türkiye

⁴ Division of Medical Oncology, Department of Internal Medicine, Demiroglu Bilim University, İstanbul, Türkiye

⁵ Division of Medical Oncology, Department of Internal Medicine, Okmeydanı Research and Training Hospital, İstanbul, Türkiye

⁶ Division of Medical Oncology, Department of Internal Medicine, Marmara University Hospital, İstanbul, Türkiye

⁷ Division of Medical Oncology, Department of Internal Medicine, Göztepe Medeniyet University, İstanbul, Türkiye

⁸ Division of Medical Oncology, Department of Internal Medicine, Hacettepe University Institute of Oncology, Ankara, Türkiye

⁹ Division of Medical Oncology, Department of Internal Medicine, Uludağ Medicine Faculty Hospital, Bursa, Türkiye

¹⁰ Division of Medical Oncology, Department of Internal Medicine, Trakya University Medicine Faculy Hospital, Edirne, Türkiye

¹¹ Division of Medical Oncology, Department of Internal Medicine, Ankara University Hospital, Ankara, Türkiye

¹² Division of Medical Oncology, Department of Internal Medicine, Gazi University Medicine Faculty Hospital, Ankara, Türkiye

¹³ Division of Medical Oncology, Department of Internal Medicine, Gaziantep University Medicine Faculty Hospital, Gaziantep, Türkiye

¹⁴ Division of Medical Oncology, Department of Internal Medicine, Ege University Medicine Faculty Hospital, İzmir, Türkiye

¹⁵ Division of Medical Oncology, Department of Internal Medicine, Antalya Research and Training Hospital, Antalya, Türkiye

¹⁶ Division of Medical Oncology, Department of Internal Medicine, Dicle University Hospital, Diyarbakır, Türkiye

¹⁷ Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul Bilgi University, Istanbul, Türkiye

¹⁸ Division of Medical Oncology, Department of Internal Medicine, Kocaeli University Hospital, Kocaeli, Türkiye

¹⁹ Division of Medical Oncology, Department of Internal Medicine, Osmangazi University Hospital, Eskişehir, Türkiye

²⁰ Division of Medical Oncology, Department of Internal Medicine, Ümraniye Research and Training Hospital, İstanbul, Türkiye

²¹ Division of Medical Oncology, Department of Internal Medicine, Tekirdağ City Hospital, Tekirdağ, Türkiye

²² Division of Medical Oncology, Department of Internal Medicine, Ondokuz Mayıs University Medicine Faculty Hospital, Samsun, Türkiye

²³ Department of Medical Genetics, Demiroglu Bilim University, İstanbul, Türkiye

EJMO 2023, 7(3), 232–242; https://doi.org/10.14744/ejmo.2023.48337

Received: 10 August 2023 | Revised: 15 September 2023 | Accepted: 17 September 2023 | Published online: 6 October 2023

© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )

Download PDF

Cite

XML

Abstract

Objectives: This study aimed to evaluate the clinical outcomes, including progression-free survival (PFS), overall survival (OS), Objective Response Rate (ORR), and Disease Control Rate (DCR), in patients received Lutetium-177 (Lu-177) DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) for metastatic neuroendocrine tumors. This study further stratified outcomes based on tumor grade, Ki-67 status, primary tumor localization, number of treatment cycles, and associated adverse effects.

Methods: We conducted a multicenter retrospective study analyzing the data of 73 patients with metastatic NETs across 17 different hospitals in various regions of Türkiye. A total of 73 metastatic NET patients underwent Lu-177 DOTATATE PRRT between December 2013 and March 2023.

Results: Over a median follow-up of 52.7 months, patients showed a median PFS of 13.7 months and OS of 51.2 months. The ORR was 29.6%, and the DCR was 66.2%. Grade 1 and 2 tumor patients had superior outcomes (PFS: 16.9 months, OS: 55.5 months) compared to grade 3 tumor patients (PFS: 8.5 months, OS: 29.5 months). Based on their Ki-67 status, those ≤ 20% had prolonged PFS (16.9 months) and OS (55.5 months) than those between 21 and 55% (PFS: 5.9 months, OS: 41.3 months). Regarding primary tumor localization, the PFS values were 13.1, 15.3, 13.7, and 8.6 months for pancreatic, GIS, lung, and unknown origin tumors, respectively. The OS across tumor types fluctuated between 41.1 and 54.1 months. Patients who received more than four cycles demonstrated significantly improved median PFS (22.4 months) and OS (90.3 months) compared to those who received ≤ 4 cycles (median PFS: 9.3 months; median OS: 41.8 months). Grade 3-4 adverse effects were observed in 21.9% of patients.

Conclusion: Our findings affirm that PRRT is a potent and well-tolerated treatment for metastatic NETs. Notably, patients who received more than 4 cycles of PRRT experienced a markedly improved median PFS and OS compared to their counterparts who received ≤4 cycles.

Keywords

Lutetium-177

neuroendocrine tumors

neuroendocrine neoplasm

peptide receptor radionuclide therapy

PRRT

radiolabeled somatostatin analogues

Conflict of interest

None declared.

References

1. Pavel M, O’Toole D, Costa F, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology. 2016;103(2):172–85.
2. Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer. 2010;17:909–18.
3. Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40:1–18.
4. Unal Caglar, and Sezer Saglam. Metastatic neuroendocrine carcinoma: Liver metastases presenting with diffuse nodular calcifications on CT. Journal of Cancer Research and Therapeutics.2023.
5. Yao JC, Hassan M, Phan A, 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.
6. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–42.
7. Strosberg J, El-Haddad G, Wolin E, et al. NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.
8. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. The Lancet. 2016;387.10022): 968-977.
9. Solis-Hernandez, Mª Pilar, Fernandez del Valle, et al. Evaluating radiological response in pancreatic neuroendocrine tumours treated with sunitinib: comparison of Choi versus RECIST criteria (CRIPNET_ GETNE1504 study). British Journal of Cancer. 2019;121.7: 537-544.
10. Arrivi G, Verrico M, Roberto M, et al. Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs): A Systematic Review and Pooled Analysis.Cancer Management and Research. 2022:3507-3523.
11. Pasieka JL, McKinnon JG, Kinnear S, et al. Carcinoid syndrome symposium on treatment modalities for gastrointestinal carcinoid tumours: symposium summary. Can J Surg. 2001;44(1):25–32.
12. Sadowski SM, Neychev V, Millo C., et al. Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. Journal of Clinical Oncology.2016; 34.6: 588.
13. Lim LE, Chan DL, Thomas D, et al. Australian experience of peptide receptor radionuclide therapy in lung neuroendocrine tumours. Oncotarget.2020; 11.27: 2636.
14. Strosberg JR, Wolin EM, Chasen BA, et al. First update on overall survival, progression-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors. J Clin Oncol. 2018; 36:4099.
15. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-treatment-gep-nets. [Accessed 01 July 2023].
16. Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, GrozinskyGlasberg S, Arnold R, Borbath I, Cwikla J, Toumpanakis C, Kaltsas G, Davies P, Hörsch D, Tiensuu Janson E, Ramage J; Antibes Consensus Conference participants. 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.
17. Pusceddu S, Prinzi N, Tafuto S,et al. Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors. JAMA Netw Open. 2022 Feb 1;5(2):e220290.
18. Garske-Román U, Sandström M, Fröss Baron K, et al. Prospective observational study of 177 Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity." European journal of nuclear medicine and molecular imaging.2018;45: 970-988.
19. Raj N, Coffman K, Le T, et al. Treatment response and clinical outcomes of well-differentiated high-grade neuroendocrine tumors to lutetium-177-DOTATATE. Neuroendocrinology.2022; 112.12: 1177-1186.
20. Baum RP, Kluge AW, Kulkarni H, et al.[177Lu-DOTA](0)-DPhe(1)-Tyr(3)-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study. Theranostics. 2016; 6: 501–510.
21. Del Prete M, Buteau FA, Arsenault F, et al. Personalized 177Luoctreotate peptide receptor radionuclide therapy of neuroendocrine tumours: Initial results from the P-PRRT trial. Eur. J. Nucl. Med. Mol. Imaging. 2019; 46: 728–742.
22. Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: The IEO phase I-II study. Eur. J. Nucl. Med. Mol. Imaging. 2011; 38: 2125–2135.
23. Ezziddin S, Attassi M, Yong-Hing C J, et al. Predictors of longterm outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. Journal of nuclear medicine. 2014; 55.2: 183-190.
24. Zhang J, Song Q, Cai L, et al. The efficacy of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with
metastatic neuroendocrine tumours: a systematic review and meta-analysis. Journal of Cancer Research and Clinical Oncology.2020; 146.6: 1533-1543.
25. Papantoniou D, Grönberg M, Thiis-Evensen E,et al. Treatment efficacy in a metastatic small intestinal neuroendocrine tumour grade 2 cohort. Endocr Relat Cancer. 2023; 30(3):e220316.
26. McClellan K., Chen EY, Kardosh A, et al. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors.Cancers. 2022; 14.19: 4769.
27. Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39(5):683–90.
28. Waseem N, Aparici CM, Kunz PL. Evaluating the Role of Theranostics in Grade 3 Neuroendocrine Neoplasms. J Nucl Med Off Publ Soc Nucl Med. 2019;60(7):882–91.
29. Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103.2: 186-194.
30. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Annals of Oncology. 2013; 24: 152–160.
31. Vélayoudom-Céphise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous. Endocr Relat Cancer.2013; 20.5: 649-57.
32. Harris Philip E and Konstantin Zhernosekov. The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next?. Frontiers in Endocrinology.2022; 13: 941832.
33. Kunikowska J, Pawlak D, Bąk MI,.et al. Long-term results and tolerability of tandem peptide receptor radionuclide therapy with 90 Y/177 Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study. Annals of Nuclear Medicine.2017; 31: 347-356.
34. Brabander T, van der Zwan WA, Teunissen J J, et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0, Tyr3] octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clinical Cancer Research.2017; 23.16: 4617-4624.
35. Zandee WT, Brabander T, Blazevic A, et al. Symptomaticand Radiological Response to 177Lu-DOTATATE for the Treatment of Functioning Pancreatic Neuroendocrine Tumors. J. Clin. Endocrinol. Metab. 2019; 104: 1336–1344.
36. Ianniello A, Sansovini M, Severi S, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE in advanced bronchial carcinoids: Prognostic role of thyroid transcription factor 1 and 18F-FDG PET. Eur. J. Nucl. Med. Mol. Imaging. 2016; 43;1040–1046.
37. Kipnis ST, Hung M, Kumar S, Heckert JM, Lee H, Bennett B, Soulen MC, Pryma DA, Mankoff DA, Metz DC, Eads JR, Katona BW. Laboratory, Clinical, and Survival Outcomes Associated With Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors. JAMA Netw Open. 2021 Mar 1;4(3):e212274.
38. Swiha MM, Sutherland DE, Sistani G, et al. Survival predictors of 177Lu-Dotatate peptide receptor radionuclide therapy (PRRT) in patients with progressive well-differentiated neuroendocrine tumors (NETS). Journal of Cancer Research and Clinical Oncology.2022; 148.1: 225-236.
39. Das S, Chauhan A, Du L,et al. External Validation of a Clinical Score for Patients With Neuroendocrine Tumors Under Consideration for Peptide Receptor Radionuclide Therapy. JAMA Netw Open. 2022 Jan 4;5(1):e2144170.
40. Dumont RA, Seiler D, Marincek N, et al. Survival after somatostatin based radiopeptide therapy with 90Y-DOTATOC vs. 90Y-DOTATOC plus 177Lu-DOTATOC in metastasized gastrinoma. American journal of nuclear medicine and molecular imaging.2015; 5.1: 46.
41. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3] octreotate: toxicity, efficacy, and survival. Journal of Clinical Oncology.2008; 26: 2124–2130.
42. Kudo A, Tateishi U, Yoshimura R,et al.. Safety and response after peptide receptor radionuclide therapy with 177 Lu-DOTATATE for neuroendocrine tumors in phase 1/2 prospective Japanese trial. J Hepatobiliary Pancreat Sci. 2022 Apr; 29(4): 487-499.
43. Ryoo HG, Suh M, Kang KW, Lee DW, Han SW, Cheon GJ. Phase 1 Study of No-Carrier Added 177Lu-DOTATATE (SNU-KB-01)
in Patients with Somatostatin Receptor-Positive Neuroendocrine Tumors: The First Clinical Trial of Peptide Receptor Radionuclide Therapy in Korea. Cancer Res Treat. 2023 Jan;55(1):334-343.
44. Sundlöv A, Gleisner KS, Tennvall J,et al. Phase II trial demonstrates the efficacy and safety of individualized, dosimetrybased 177Lu-DOTATATE treatment of NET patients. Eur J Nucl Med Mol Imaging. 2022 Sep;49(11):3830-3840.
45. Ozonder Unal I, Ordu C. Alexithymia, Self-Compassion, Emotional Resilience, and Cognitive Emotion Regulation: Charting the Emotional Journey of Cancer Patients. Curr. Oncol. 2023;30(10):8872-8887.

Previous article in this issue

Next article in this issue

Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing