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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-03-2019 | Original Article

Salvage peptide receptor radionuclide therapy with [¹⁷⁷Lu-DOTA,Tyr³]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours

Authors: W. A. van der Zwan, T. Brabander, B. L. R. Kam, J. J. M. Teunissen, R. A. Feelders, J. Hofland, E. P. Krenning, W. W. de Herder

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2019

Abstract

Purpose

Therapy with [¹⁷⁷Lu-DOTA,Tyr³]octreotate is effective in patients with grade I/II metastasized and/or inoperable bronchial neuroendocrine tumour (NET) or gastroenteropancreatic NET (GEP-NET). In this study, we investigated the efficacy and safety of salvage treatment with [¹⁷⁷Lu-DOTA,Tyr³]octreotate.

Methods

Patients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [¹⁷⁷Lu-DOTA,Tyr³]octreotate over two cycles per retreatment with PRRT (R-PRRT) or re-retreatment with PRRT (RR-PRRT).

Results

The safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0–98.2). Median cumulative doses were 44.7 GBq (range 26.3–46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2–≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4–16.9) following R-PRRT and 14.2 months (95% CI 9.8–18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0–95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed.

Conclusion

A cumulative dose of up to 60.5 GBq salvage PRRT with [¹⁷⁷Lu-DOTA,Tyr³]octreotate is safe and effective in patients with progressive disease (relapse-PD) following I-PRRT with [¹⁷⁷Lu-DOTA,Tyr³]octreotate. Safety appears similar to that of I-PRRT as no higher incidence of AML or MDS was observed. No grade III/IV renal toxicity occurred after retreatment.

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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.

Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33. https://doi.org/10.1056/NEJMoa1316158.CrossRefPubMed

Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13. https://doi.org/10.1056/NEJMoa1003825.CrossRefPubMed

Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol. 2009;27(28):4656–63. https://doi.org/10.1200/JCO.2009.22.8510.CrossRefPubMed

Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23. https://doi.org/10.1056/NEJMoa1009290.CrossRefPubMedPubMedCentral

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(2):125–35. https://doi.org/10.1056/NEJMoa1607427.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124–30. https://doi.org/10.1200/JCO.2007.15.2553.CrossRefPubMed

Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, 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.CrossRefPubMed

10.

Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with (177)Lu-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.CrossRefPubMed

11.

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(1):5–19. https://doi.org/10.1007/s00259-014-2893-5.CrossRefPubMed

12.

Forrer F, Uusijarvi H, Storch D, Maecke HR, Mueller-Brand J. Treatment with 177Lu-DOTATOC of patients with relapse of neuroendocrine tumors after treatment with 90Y-DOTATOC. J Nucl Med. 2005;46(8):1310–6.PubMed

13.

Pach D, Sowa-Staszczak A, Kunikowska J, Krolicki L, Trofimiuk M, Stefanska A, et al. Repeated cycles of peptide receptor radionuclide therapy (PRRT) – results and side-effects of the radioisotope 90Y-DOTA TATE, 177Lu-DOTA TATE or 90Y/177Lu-DOTA TATE therapy in patients with disseminated NET. Radiother Oncol. 2012;102(1):45–50. https://doi.org/10.1016/j.radonc.2011.08.006.CrossRefPubMed

14.

Sabet A, Haslerud T, Pape UF, Sabet A, Ahmadzadehfar H, Grunwald F, et al. Outcome and toxicity of salvage therapy with 177Lu-octreotate in patients with metastatic gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41(2):205–10. https://doi.org/10.1007/s00259-013-2547-z.CrossRefPubMed

15.

Severi S, Sansovini M, Ianniello A, Bodei L, Nicolini S, Ibrahim T, et al. Feasibility and utility of re-treatment with (177)Lu-DOTATATE in GEP-NENs relapsed after treatment with (90)Y-DOTATOC. Eur J Nucl Med Mol Imaging. 2015;42(13):1955–63. https://doi.org/10.1007/s00259-015-3105-7.CrossRefPubMed

16.

van Essen M, Krenning EP, Kam BL, de Herder WW, Feelders RA, Kwekkeboom DJ. Salvage therapy with (177)Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2010;51(3):383–90. https://doi.org/10.2967/jnumed.109.068957.CrossRefPubMed

17.

Yordanova A, Mayer K, Brossart P, Gonzalez-Carmona MA, Strassburg CP, Essler M, et al. Safety of multiple repeated cycles of 177Lu-octreotate in patients with recurrent neuroendocrine tumour. Eur J Nucl Med Mol Imaging. 2017;44(7):1207–14. https://doi.org/10.1007/s00259-017-3652-1.CrossRefPubMed

18.

Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL, et al. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. Eur J Nucl Med. 2001;28(9):1319–25.CrossRefPubMed

19.

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(17):2416–23. https://doi.org/10.1200/JCO.2010.33.7873.CrossRefPubMed

20.

Bergsma H, van Lom K, Raaijmakers MHGP, Konijnenberg M, Kam BLBLR, Teunissen JJM, et al. Persistent hematologic dysfunction after peptide receptor radionuclide therapy with 177Lu-DOTATATE: incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2018;59(3):452–8. https://doi.org/10.2967/jnumed.117.189712.CrossRefPubMed

21.

Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, 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. Lancet. 2016;387(10022):968–77. https://doi.org/10.1016/S0140-6736(15)00817-X.CrossRefPubMed

22.

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(12):2754–62. https://doi.org/10.1200/JCO.2005.08.066.CrossRefPubMed

Title: Salvage peptide receptor radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours
Authors: W. A. van der Zwan
T. Brabander
B. L. R. Kam
J. J. M. Teunissen
R. A. Feelders
J. Hofland
E. P. Krenning
W. W. de Herder
Publication date: 01-03-2019
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2019
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-018-4158-1

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Salvage peptide receptor radionuclide therapy with [¹⁷⁷Lu-DOTA,Tyr³]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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