Skip to main content
Top
Published in: European Journal of Nuclear Medicine and Molecular Imaging 6/2016

01-06-2016 | Original Article

Peptide receptor radionuclide therapy with 177Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and 18F-FDG PET

Authors: Annarita Ianniello, Maddalena Sansovini, Stefano Severi, Silvia Nicolini, Chiara Maria Grana, Katrin Massri, Alberto Bongiovanni, Lorenzo Antonuzzo, Valentina Di Iorio, Anna Sarnelli, Paola Caroli, Manuela Monti, Emanuela Scarpi, Giovanni Paganelli

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 6/2016

Login to get access

Abstract

Purpose

Typical and atypical carcinoids (TC and AC) represent 20 – 25 % of all neuroendocrine tumours. No standard therapeutic approach is available for patients with advanced disease. The aim of this phase II study was to investigate the efficacy and safety of peptide receptor radionuclide therapy with 177Lu-DOTATATE (Lu-PRRT) and the role of thyroid transcription factor 1 (TTF-1) and 18F-FDG PET as prognostic factors in patients with advanced TC or AC.

Methods

A total of 34 consecutive patients with radiologically documented progressive disease were treated with Lu-PRRT at a therapeutic cumulative activity of 18.5 or 27.8 GBq in four or five cycles according to the patient’s kidney function and bone marrow reserve. Information on TTF-1 was available in all patients. FDG PET studies prior to Lu-PRRT were available in 29 patients.

Results

The median follow-up was 29 months (range 7 – 69 months). The disease control rate (DCR) in patients with TC was 80 %: 6 % complete response, 27 % partial response and 47 % stable disease. The median progression-free survival (mPFS) was 20.1 months (95 % CI 11.8 – 26.8 months). Stable disease was achieved in 47 % of patients with AC with a mPFS of 15.7 months (95 % CI 10.6 – 25.9 months). No major acute or delayed toxicity occurred in either group or with either cumulative activity. mPFS in patients with TTF-1-negative TC was 26.3 months (95 % CI 12.9 – 45.2 months), but in patients with TTF-1-positive TC mPFS was 7.2 months (4.2 – 14.0 months; p = 0.0009). FDG PET was negative in 13 patients (10 TC and 3 AC) and positive in 16 patients (4 TC and 12 AC). The mPFS in the FDG PET-negative group was 26.4 months (95 % CI 14.2 – 48.9 months) and 15.3 months (11.7 – 31.1 months) in the FDG PET-positive group.

Conclusion

Lu-PRRT showed antitumour activity in terms of DCR and PFS and proved safe, even in patients with a higher risk of side effects. TTF-1 would appear to be a prognostic factor. FDG PET positivity in bronchial carcinoids is a hallmark of aggressive tumour and is more frequent in patients with AC than in those with TC.
Literature
2.
go back to reference Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604–20.CrossRefPubMed Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604–20.CrossRefPubMed
3.
go back to reference Sturm N, Lantuéjoul S, Laverrière MH, Papotti M, Brichon PY, Brambilla C, et al. Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34betaE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung. Hum Pathol. 2001;32:918–25.CrossRefPubMed Sturm N, Lantuéjoul S, Laverrière MH, Papotti M, Brichon PY, Brambilla C, et al. Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34betaE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung. Hum Pathol. 2001;32:918–25.CrossRefPubMed
4.
go back to reference Folpe AL, Gown AM, Lamps LW, Garcia R, Dail DH, Zarbo RJ, et al. Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors. Mod Pathol. 1999;12:5–8.PubMed Folpe AL, Gown AM, Lamps LW, Garcia R, Dail DH, Zarbo RJ, et al. Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors. Mod Pathol. 1999;12:5–8.PubMed
5.
go back to reference Righi L, Volante M, Tavaglione V, Billè A, Daniele L, Angusti T, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol. 2010;21:548–55.CrossRefPubMed Righi L, Volante M, Tavaglione V, Billè A, Daniele L, Angusti T, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol. 2010;21:548–55.CrossRefPubMed
6.
go back to reference Granberg D, Sundin A, Janson ET, Oberg K, Skogseid B, Westlin JE. Octreoscan in patients with bronchial carcinoid tumors. Clin Endocrinol. 2003;59:793–9.CrossRef Granberg D, Sundin A, Janson ET, Oberg K, Skogseid B, Westlin JE. Octreoscan in patients with bronchial carcinoid tumors. Clin Endocrinol. 2003;59:793–9.CrossRef
7.
go back to reference Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007;48:508–18.CrossRefPubMed Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007;48:508–18.CrossRefPubMed
8.
go back to reference Rivera MP, Detterbeck F, Mehta AC. Diagnosis of lung cancer: the guidelines. Chest. 2003;123(1 Suppl):129S–36. Rivera MP, Detterbeck F, Mehta AC. Diagnosis of lung cancer: the guidelines. Chest. 2003;123(1 Suppl):129S–36.
9.
go back to reference Lim E, Goldstraw P, Nicholson AG, Travis WD, Jett JR, Ferolla P, et al. Proceedings of the IASLC International Workshop on Advances in Pulmonary Neuroendocrine Tumors 2007. J Thorac Oncol. 2008;3:1194–201.CrossRefPubMed Lim E, Goldstraw P, Nicholson AG, Travis WD, Jett JR, Ferolla P, et al. Proceedings of the IASLC International Workshop on Advances in Pulmonary Neuroendocrine Tumors 2007. J Thorac Oncol. 2008;3:1194–201.CrossRefPubMed
10.
go back to reference Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005–12.CrossRefPubMed Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005–12.CrossRefPubMed
11.
go back to reference 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–6. 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–6.
12.
go back to reference Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.CrossRefPubMed Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference Ezziddin S, Khalaf F, Vanezi M, Haslerud T, Mayer K, Al Zreiqat A, et al. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41:925–33.CrossRefPubMed Ezziddin S, Khalaf F, Vanezi M, Haslerud T, Mayer K, Al Zreiqat A, et al. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41:925–33.CrossRefPubMed
15.
go back to reference Sabet A, Dautzenberg K, Haslerud T, Aouf A, Sabet A, Simon B, et al. Specific efficacy of peptide receptor radionuclide therapy with (177)Lu-octreotate in advanced neuroendocrine tumours of the small intestine. Eur J Nucl Med Mol Imaging. 2015;42:1238–46.CrossRefPubMed Sabet A, Dautzenberg K, Haslerud T, Aouf A, Sabet A, Simon B, et al. Specific efficacy of peptide receptor radionuclide therapy with (177)Lu-octreotate in advanced neuroendocrine tumours of the small intestine. Eur J Nucl Med Mol Imaging. 2015;42:1238–46.CrossRefPubMed
16.
go back to reference Sabet A, Ezziddin K, Pape UF, Reichman K, Haslerud T, Ahmadzadehfar H, et al. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with (177)Lu-octreotate. Eur J Nucl Med Mol Imaging. 2014;41:505–10.CrossRefPubMed Sabet A, Ezziddin K, Pape UF, Reichman K, Haslerud T, Ahmadzadehfar H, et al. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with (177)Lu-octreotate. Eur J Nucl Med Mol Imaging. 2014;41:505–10.CrossRefPubMed
17.
go back to reference van Essen M, Krenning EP, Bakker WH, de Herder WW, van Aken MO, Kwekkeboom DJ. Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumors of bronchial, gastric and thymic origin. Eur J Nucl Med Mol Imaging. 2007;34:1219–27.CrossRefPubMed van Essen M, Krenning EP, Bakker WH, de Herder WW, van Aken MO, Kwekkeboom DJ. Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumors of bronchial, gastric and thymic origin. Eur J Nucl Med Mol Imaging. 2007;34:1219–27.CrossRefPubMed
18.
go back to reference Bodei L, Cremonesi M, Kidd M, Grana CM, Severi S, Modlin IM, et al. Peptide receptor radionuclide therapy for advanced neuroendocrine tumors. Thorac Surg Clin. 2014;24:333–49.CrossRefPubMed Bodei L, Cremonesi M, Kidd M, Grana CM, Severi S, Modlin IM, et al. Peptide receptor radionuclide therapy for advanced neuroendocrine tumors. Thorac Surg Clin. 2014;24:333–49.CrossRefPubMed
19.
go back to reference 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;16:978–85.CrossRefPubMed 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;16:978–85.CrossRefPubMed
20.
go back to reference 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;40:881–8.CrossRefPubMed 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;40:881–8.CrossRefPubMed
21.
go back to reference Sandström M, Garske-Román U, Granberg D, Johansson S, Widström C, Eriksson B, et al. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. J Nucl Med. 2013;54(1):33–41.CrossRefPubMed Sandström M, Garske-Román U, Granberg D, Johansson S, Widström C, Eriksson B, et al. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. J Nucl Med. 2013;54(1):33–41.CrossRefPubMed
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference Bergsma H, Konijnenberg MW, Kam BL, Teunissen JJ, Kooij PP, de Herder WW, et al. Subacute haematotoxicity after PRRT with 177Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2015. doi:10.1007/s00259-015-3193-4 Bergsma H, Konijnenberg MW, Kam BL, Teunissen JJ, Kooij PP, de Herder WW, et al. Subacute haematotoxicity after PRRT with 177Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2015. doi:10.​1007/​s00259-015-3193-4
24.
go back to reference Breeman WA, de Blois E, Bakker WH. Radiolabeling DOTA peptides with 90Y and 177Lu to a high specific activity. In: Chinol M, Paganelli G, editors. Radionuclide peptide cancer therapy. New York: Taylor & Francis; 2006. p. 119–26.CrossRef Breeman WA, de Blois E, Bakker WH. Radiolabeling DOTA peptides with 90Y and 177Lu to a high specific activity. In: Chinol M, Paganelli G, editors. Radionuclide peptide cancer therapy. New York: Taylor & Francis; 2006. p. 119–26.CrossRef
25.
go back to reference Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs. 1992;10:239–53.CrossRefPubMed Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs. 1992;10:239–53.CrossRefPubMed
26.
go back to reference van Vliet EI, Krenning EP, Teunissen JJ, Bergsma H, Kam BL, Kwekkeboom DJ. Comparison of response evaluation in patients with gastroenteropancreatic and thoracic neuroendocrine tumors after treatment with [177Lu-DOTA0, Tyr3] octreotate. J Nucl Med. 2013;54:1689–96.CrossRefPubMed van Vliet EI, Krenning EP, Teunissen JJ, Bergsma H, Kam BL, Kwekkeboom DJ. Comparison of response evaluation in patients with gastroenteropancreatic and thoracic neuroendocrine tumors after treatment with [177Lu-DOTA0, Tyr3] octreotate. J Nucl Med. 2013;54:1689–96.CrossRefPubMed
28.
go back to reference Kaplan EL, Meier P. Nonparametric estimation for incomplete observation. J Am Stat Assoc. 1958;53:457–81.CrossRef Kaplan EL, Meier P. Nonparametric estimation for incomplete observation. J Am Stat Assoc. 1958;53:457–81.CrossRef
29.
go back to reference Lawless JS. Statistical models and methods for life-time data. New York: Wiley; 1982. Lawless JS. Statistical models and methods for life-time data. New York: Wiley; 1982.
30.
go back to reference Granberg D, Eriksson B, Wilander E, Grimfjärd P, Fjällskog ML, Oberg K, et al. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol. 2001;12:1383–91.CrossRefPubMed Granberg D, Eriksson B, Wilander E, Grimfjärd P, Fjällskog ML, Oberg K, et al. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol. 2001;12:1383–91.CrossRefPubMed
31.
go back to reference 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. 2011;38:302–11.CrossRefPubMed 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. 2011;38:302–11.CrossRefPubMed
32.
go back to reference Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, et al. Favourable outcomes of 177Lu-octreotate peptide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2015;42(2):176–85.CrossRefPubMed Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, et al. Favourable outcomes of 177Lu-octreotate peptide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2015;42(2):176–85.CrossRefPubMed
Metadata
Title
Peptide receptor radionuclide therapy with 177Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and 18F-FDG PET
Authors
Annarita Ianniello
Maddalena Sansovini
Stefano Severi
Silvia Nicolini
Chiara Maria Grana
Katrin Massri
Alberto Bongiovanni
Lorenzo Antonuzzo
Valentina Di Iorio
Anna Sarnelli
Paola Caroli
Manuela Monti
Emanuela Scarpi
Giovanni Paganelli
Publication date
01-06-2016
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 6/2016
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-015-3262-8

Other articles of this Issue 6/2016

European Journal of Nuclear Medicine and Molecular Imaging 6/2016 Go to the issue