Abstract
Purpose
In March 2014, we reported the activity and safety of 177Lu-DOTA-octreotate peptide receptor radionuclide therapy (Lu-PRRT) at two different dosages (18.5 GBq and 27.5 GBq in 5 cycles) in patients with progressive metastatic gastrointestinal neuroendocrine tumors (GI-NETs). Disease control rate (DCR) and toxicity were addressed. Herein, we report the late toxicity, progression-free survival (PFS), and overall survival (OS) in the same cohort after a 10-year follow-up.
Methods
We conducted an open-label, disease-oriented prospective phase II trial. From March 2008 to June 2011, 43 patients received 3.7 GBq or 5.5 GBq of Lu-PRRT every 6 to 8 weeks, each cycle repeated 5 times. All patients showed 68Gallium-DOTA-peptide PET/Octreoscan® positivity (score 3–4 Rotterdam scale) in known lesions. Tumor burden was estimated radiologically. Time-to-event data (PFS and OS) were described using Kaplan-Meier curves and compared with the log-rank test.
Results
Forty-three patients (28 males and 15 females) were evaluable and were monitored for a median period of 118 months (range 12.6–139.6). Median PFS in patients receiving 18.5 GBq was 59.8 months (95% confidence interval [95% CI] 14.3–79.6), identical to that of patients treated with 27.5 GBq (59.8 months, 95% CI 23.4–82.0). Median OS was 71.0 months (95% CI 46.1–107.3) in the group who received 18.5 GBq and 97.6 months (95% CI 64.3-not reached) in the group treated with 27.5 GBq (P = 0.22). Patients with progression limited to lymph nodes showed significantly longer median PFS and OS than those with hepatic lesions (P = 0.02 for PFS and P = 0.04 for OS). Age over 65 years at the time of PRRT was also significant for OS. Of note, no late hematological or renal toxicity was observed in either group.
Conclusions
The long-term follow-up of the IRST phase II study shows that Lu-PRRT is a safe and effective therapy for patients with advanced GI-NET, the most important prognostic factor being tumor burden, hepatic lesions, and age. We believe that Lu-PRRT should be offered to patients with early-stage disease.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, 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. https://doi.org/10.1159/000443167.
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. https://doi.org/10.1677/ERC-10-0152.
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, vii. https://doi.org/10.1016/j.ecl.2010.12.005.
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. https://doi.org/10.1200/JCO.2007.15.4377.
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 Oncol. 2017;3(10):1335–42. https://doi.org/10.1001/jamaoncol.2017.0589.
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, 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. https://doi.org/10.1056/NEJMoa1607427.
Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]ocreotate: toxicity, efficacy and survival. J Clin Oncol. 2008;26(13):2124–30. https://doi.org/10.1200/JCO.2007.15.2553.
Severi S, Grassi I, Nicolini S, Sansovini M, Bongiovanni A, Paganelli G. Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life. Onco Targets Ther. 2017;10:551–7. https://doi.org/10.2147/OTT.S97584.
Paganelli G, Sansovini M, Ambrosetti A, Severi S, Monti M, Scarpi E, et al. 177Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study. Eur J Nucl Med Mol Imaging. 2014;41(10):1845–51. https://doi.org/10.1007/s00259-014-2735-5.
Bosman F, Carneiro F, editors. World Health Organization classification of tumours, pathology and genetics of tumours of the digestive system. Lyon: IARC Press; 2010.
Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A. 18F-Fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res. 2010;16(3):978–85. https://doi.org/10.1158/1078-0432.CCR-09-1759.
Severi S, Nanni O, Bodei L, Sansovini M, Ianniello A, Nicoletti S, et al. Role of 18FDG PET/CT in patients treated with 177Lu-DOTATATE for advanced differentiated neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013;40(6):881–8. https://doi.org/10.1007/s00259-013-2369-z.
Bahri H, Laurence L, Edeline J, Leghzali H, Devillers A, Raoul JL, et al. High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation. J Nucl Med. 2014;55(11):1786–90. https://doi.org/10.2967/jnumed.114.144386.
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 90 Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging. 2008;35(10):1847–56. https://doi.org/10.1007/s00259-008-0778-1.
Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with 1Lu-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.
Capdevila J, Hernando J, Perez-Hoyos S, Roman-Gonzalez A, Grande E. Meta-analysis of randomized clinical trials comparing active treatment with placebo in metastatic neuroendocrine tumors. Oncologist. 2019;24(12):e1315–20.
Sansovini M, Severi S, Ianniello A, Nicolini S, Fantini L, Mezzenga E, et al. Long-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with 177Lu-D OTATATE. Eur J Nucl Med Mol Imaging. 2017;44(3):490–9. https://doi.org/10.1007/s00259-016-3533-z.
Ngo H, Tortorella SM, Ververis K, Karagiannis TC. The Warburg effect: molecular aspects and therapeutic possibilities. Mol Biol Rep. 2015;42(4):825–34. https://doi.org/10.1007/s11033-014-3764-7.
Claringbold PG, Brayshaw PA, Price RA, Turner JH. Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 38(2):302–11. https://doi.org/10.1007/s00259-010-1631-x.
Veenendaal LM, Borel Rinkes IHM, Lips CJM, van Hillegersberg R. Liver metastases of neuroendocrine tumours; early reduction of tumour load to improve life expectancy. World J Surg Oncol. 2006;4:35. https://doi.org/10.1186/1477-7819-4-35.
Ezziddin S, Attassi M, Yong-Hing CJ, Ahmadzadehfar H, Willinek W, Grünwald F, et al. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med. 2014;55(2):183–90. https://doi.org/10.2967/jnumed.113.125336.
Panzuto F, Merola E, Pavel ME, Rinke A, Kump P, Partelli S, et al. Stage IV gastro-entero-pancreatic neuroendocrine neoplasms: a risk score to predict clinical outcome. Oncologist. 2017;22(4):409–15. https://doi.org/10.1634/theoncologist.2016-0351.
Bertani E, Fazio N, Radice D, Zardini C, Spinoglio G, Chiappa A, et al. Assessing the role of primary tumour resection in patients with synchronous unresectable liver metastases from pancreatic neuroendocrine tumour of the body and tail. A propensity score survival evaluation. Eur J Surg Oncol. 2017;43(2):372–9. https://doi.org/10.1016/j.ejso.2016.09.011.
Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: peptidereceptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology. 2017;105(3):295–309. https://doi.org/10.1159/000475526.
Acknowledgments
The authors thank Gráinne Tierney for the English revision of the manuscript. We also thank Monica Golinucci and the other members of the Nuclear Medicine and Radiometabolic Medicine Unit team for their support and assistance.
Funding
This study was partially supported by AIRC (Associazione Italiana per la Ricerca sul Cancro).
Author information
Authors and Affiliations
Contributions
Giovanni Paganelli: study concept and design, manuscript drafting; Stefano Severi: coordinated the different tasks of the project and worked on preparation, treatment, and follow-up of patients; Maddalena Sansovini, Silvia Nicolini, Grassi Ilaria, and Luca Urso: worked on enrolment, preparation, treatment, and follow-up of patients; Elena Amadori: reviewed morphological imaging during enrolment, treatment, and follow-up; Federica Matteucci: worked on the diagnostic and therapeutic scintigraphy examinations of the patients; Corrado Cittanti: reviewed the manuscript; Mattia Altini: reviewed the manuscript; Valentina Di Iorio: prepared the radiopharmaceutical drug; Toni Ibrahim and Alberto Bongiovanni: worked on enrolment and follow-up of patients; Emanuela Scarpi: data analysis; Manuela Monti: data collection; Giovanni Paganelli: coordinated and supervised the different tasks of the project. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The protocol was approved by the Area Vasta Romagna Ethics Committee (approval no. 2007-005517-20 of October 31, 2007), and by the competent Italian Regulatory Authorities. The study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and with Good Clinical Practice (GCP) guidelines.
Informed consent
All patients gave informed consent. Having an 18FDG-PET scan before PRRT was not a prerequisite for the study but was taken into account as a prognostic factor when available.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Oncology - Digestive tract
Rights and permissions
About this article
Cite this article
Paganelli, G., Sansovini, M., Nicolini, S. et al. 177Lu-PRRT in advanced gastrointestinal neuroendocrine tumors: 10-year follow-up of the IRST phase II prospective study. Eur J Nucl Med Mol Imaging 48, 152–160 (2021). https://doi.org/10.1007/s00259-020-04873-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00259-020-04873-0