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Feasibility and utility of re-treatment with 177Lu-DOTATATE in GEP-NENs relapsed after treatment with 90Y-DOTATOC

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 – 3 years. In the present study, we investigated the use of low dosage re-treatment with 177Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with 90Y-DOTATOC (Y-PRRT).

Methods

Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 – 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated.

Results

Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6 %, median PFS was 22 months (95 % CI 16 months – not reached) compared to 28 months (95 % CI 20 – 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re-treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity.

Conclusion

Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment.

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References

  1. Rindi G. The ENETS guidelines: the new TNM classification system. Tumori. 2010;96:806–9.

    PubMed  Google Scholar 

  2. Zaknun JJ, Bodei L, Mueller-Brand J, Pavel ME, Baum RP, Horsch D, 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;40:800–16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Forrer F, Valkema R, Kwekkeboom DJ, de Jong M, Krenning EP. Neuroendocrine tumors. Peptide receptor radionuclide therapy. Best Pract Res Clin Endocrinol Metab. 2007;21:111–29.

    Article  CAS  PubMed  Google Scholar 

  4. Bombardieri E, Ambrosini V, Aktolun C, Baum RP, Bishof-Delaloye A, Del Vecchio S, et al. 111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging. Oncology Committee of the EANM. Eur J Nucl Med Mol Imaging. 2010;37:1441–8.

    Article  PubMed  Google Scholar 

  5. Virgolini I, Ambrosini V, Bomanji JB, Baum RP, Fanti S, Gabriel M, et al. Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging. 2010;37:2004–10.

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Ambrosini V, Campana D, Bodei L, Nanni C, Castellucci P, Allegri V, et al. 68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors. J Nucl Med. 2010;51:669–73.

    Article  PubMed  Google Scholar 

  8. Oberg K. Molecular imaging radiotherapy: theranostics for personalized patient management of neuroendocrine tumors (NETs). Theranostics. 2012;2:448–58.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Kulkarni HR, Baum RP. Patient selection for personalized peptide receptor radionuclide therapy using Ga-68 somatostatin receptor PET/CT. PET Clin. 2014;9:83–90.

    Article  PubMed  Google Scholar 

  10. Reubi JC, Schär JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27:273–82.

    Article  CAS  PubMed  Google Scholar 

  11. Gabriel M, Andergassen U, Putzer D, Kroiss A, Waitz D, Von Guggenberg E, et al. Individualized peptide-related-radionuclide-therapy concept using different radiolabelled somatostatin analogs in advanced cancer patients. Q J Nucl Med Mol Imaging. 2010;54:92–9.

    CAS  PubMed  Google Scholar 

  12. Bodei L, Cremonesi M, Grana CM, Chinol M, Baio SM, Severi S, et al. Yttrium-labelled peptides for therapy of NET. Eur J Nucl Med Mol Imaging. 2012;39 Suppl 1:S93–102.

    Article  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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;29:2416–23.

    Article  CAS  PubMed  Google Scholar 

  15. 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;26:2124–30.

    Article  CAS  PubMed  Google Scholar 

  16. Hörsch D, Ezziddin S, Haug A, Gratz KF, Dunkelmann S, Krause BJ, et al. Peptide receptor radionuclide therapy for neuroendocrine tumors in Germany: first results of a multi-institutional cancer registry. Recent Results Cancer Res. 2013;194:457–65.

    Article  PubMed  Google Scholar 

  17. van der Zwan WA, Bodei L, Mueller-Brand J, de Herder WW, Kvols LK, Kwekkeboom DJ. GEPNETs update: radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol. 2015;172:R1–8.

    Article  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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;38:2125–35.

    Article  CAS  PubMed  Google Scholar 

  20. Sabet A, Ezziddin K, Pape UF, Ahmadzadehfar H, Mayer K, Pöppel T, et al. Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med. 2013;54:1857–61.

    Article  CAS  PubMed  Google Scholar 

  21. Sansovini M, Severi S, Ambrosetti A, Monti M, Nanni O, Sarnelli A, et al. Treatment with the radiolabelled somatostatin analog Lu-DOTATATE for advanced pancreatic neuroendocrine tumors. Neuroendocrinology. 2013;97:347–54.

    Article  CAS  PubMed  Google Scholar 

  22. 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;41:1845–51.

    Article  CAS  PubMed  Google Scholar 

  23. NICE. Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. Appendix D. Southwest Oncology Group (SWOG) criteria for assessing tumor response. London: National Institute for Health and Care Excellence; 2004. p. 35

  24. Bodei L, Cremonesi M, Grana C, Rocca P, Bartolomei M, Chinol M, et al. Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2004;31:1038–46.

    Article  CAS  PubMed  Google Scholar 

  25. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, version 3.0. Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH; 2006. http://ctep.cancer.gov.

  26. Forrer F, Uusijärvi 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;46:1310–6.

    CAS  PubMed  Google Scholar 

  27. Pach D, Sowa-Staszczak A, Kunikowska J, Królicki L, Trofimiuk M, Stefańska 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;102:45–50.

    Article  CAS  PubMed  Google Scholar 

  28. van Essen M, Krenning EP, Kam BL, de Herder W, Feelders RA, Kwekkeboom DJ. Salvage therapy with 177Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2010;51:383–90.

    Article  PubMed  Google Scholar 

  29. Sabet A, Haslerud T, Pape UF, Sabet A, Ahmadzadehfar H, Grünwald 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;41:205–10.

    Article  CAS  PubMed  Google Scholar 

  30. Prasad V, Brenner W, Modlin IM. How smart is peptide receptor radionuclide therapy of neuroendocrine tumors especially in the salvage setting? The clinician’s perspective. Eur J Nucl Med Mol Imaging. 2014;41:202–4.

    Article  PubMed  Google Scholar 

  31. de Jong M, Krenning EP. New advances in peptide receptor radionuclide therapy. J Nucl Med. 2002;43:617–20.

    PubMed  Google Scholar 

  32. Bernard BF, Krenning EP, Breeman WA, Rolleman EJ, Bakker WH, Visser TJ, et al. D-lysine reduction of indium-111 octreotide and yttrium-90 octreotide renal uptake. J Nucl Med. 1997;38:1929–33.

    CAS  PubMed  Google Scholar 

  33. 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;42:5–19.

    Article  CAS  PubMed  Google Scholar 

  34. Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15:e8–21.

    Article  PubMed  Google Scholar 

  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-ocreotate. J Nucl Med. 2014;55:183–90.

    Article  CAS  PubMed  Google Scholar 

  36. Pavel M, Baudin E, Couvelard A, Krenning E, Öberg K, Steinmüller T, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012;95:157–76.

    Article  CAS  PubMed  Google Scholar 

  37. McDermott EW, Guduric B, Brennan MF. Prognostic variables in patients with gastrointestinal carcinoid tumours. Br J Surg. 1994;81:1007–9.

    Article  CAS  PubMed  Google Scholar 

  38. Rindi G, D'Adda T, Froio E, Fellegara G, Bordi C. Prognostic factors in gastrointestinal endocrine tumors. Endocr Pathol. 2007;18:145–9.

    Article  PubMed  Google Scholar 

  39. Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A. 18Ffluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res. 2010;16:978–85.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Modlin IM, Drozdov I, Alaimo D, Callahan S, Teixiera N, Bodei L, et al. A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection. Endocr Relat Cancer. 2014;21:615–28.

    Article  CAS  PubMed  Google Scholar 

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Compliance with ethical standards

Funding

This study was funded by the Italian Association for Cancer Research (AIRC) (grant no. 10679).

Conflicts of interest

None.

Ethical approval

All procedures performed in the present study were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Acknowledgments

The authors thank Gráinne Tierney for editorial assistance.

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Authors and Affiliations

  1. Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, FC, Italy

    Stefano Severi, Maddalena Sansovini, Annarita Ianniello, Silvia Nicolini, Paola Caroli & Giovanni Paganelli

  2. Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy

    Lisa Bodei

  3. Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Toni Ibrahim

  4. Oncology Pharmacy Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Valentina Di Iorio

  5. Medical Physics Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Vincenzo D’Errico

  6. Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Manuela Monti

Authors
  1. Stefano Severi
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  4. Lisa Bodei
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  8. Vincenzo D’Errico
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  9. Paola Caroli
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  10. Manuela Monti
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  11. Giovanni Paganelli
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Correspondence to Stefano Severi.

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Severi, S., Sansovini, M., Ianniello, A. et al. Feasibility and utility of re-treatment with 177Lu-DOTATATE in GEP-NENs relapsed after treatment with 90Y-DOTATOC. Eur J Nucl Med Mol Imaging 42, 1955–1963 (2015). https://doi.org/10.1007/s00259-015-3105-7

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  • DOI: https://doi.org/10.1007/s00259-015-3105-7

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