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Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis

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

A Correction to this article was published on 20 November 2017

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Abstract

Purpose

Grade 3 NENs are aggressive tumours with poor prognosis. PRRT+/− radiosensitising chemotherapy is a potential treatment for disease with high somatostatin receptor (SSTR) expression without spatially discordant FDG-avid disease. We retrospectively evaluated the efficacy of PRRT in G3 NEN.

Methods

Kaplan–Meier estimation was used to determine progression-free survival (PFS) and overall survival (OS) defined from start of PRRT. Subgroup analysis was performed for patients with Ki-67 ≤ 55% and >55%. Anatomical response (RECIST 1.1) and toxicity 3 months after PRRT was determined. Disease control rate (DCR) was defined as complete response (CR), partial response (PR) and stable disease (SD) of those with prior progression.

Results

28 patients (M = 17; age 16–78 years; Ki-67 ≤ 55% = 22) were reviewed. 17 patients had pancreatic, 5 small bowel, 3 large bowel, 2 bronchial and 1 unknown primary disease. 25/28 had significant FDG-avid disease prior to treatment. Most had 177Lu-DOTA-octreotate (median cumulative activity 24.4 GBq, median 4 cycles). Twenty patients had radiosensitising chemotherapy. 89% were treated for disease progression; 79% after prior chemotherapy. Median follow-up was 29 months. The median PFS was 9 months for all patients. 16 patients died (Ki-67 ≤ 55% = 11; Ki-67 > 55% = 5) with median OS of 19 months. For Ki-67 ≤ 55% (N = 22), the median PFS was 12 months and median OS 46 months. For Ki-67 > 55% (N = 6), the median PFS was 4 months and median OS 7 months. On CT imaging, DCR at 3 months post-PRRT was 74%, 35% (8/23) PR and 39% (9/23) SD. Eleven patients received further PRRT due to recrudescent disease after response. Five patients developed progression of discordant FDG-avid disease and were referred for targeted therapy/chemotherapy. Grade 3 and 4 lymphopenia and thrombocytopenia occurred in five and five patients, respectively. No renal or liver toxicity related to treatment was seen.

Conclusions

PRRT achieves clinically relevant disease control with acceptable toxicity in G3 NENs.

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Change history

  • 20 November 2017

    On page 4 of the original version of this article, the text “Eight (29%) of the patients had significant FDG-avid disease (i.e. with intensity above liver parenchyma) prior to treatment” needs to be corrected.

References

  1. Rindi G, Arnold R, Bosman FT, Bosman T, Carneiro F, Hruban R, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. WHO Classification of Tumours of the Digestive System 4th edn. Lyon: International Agency for Research on Cancer (IARC); 2010. 13–4.

  2. Öberg K, Knigge U, Kwekkeboom D, Perren A, ESMO Guidelines Working Group. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23:vii124–30.

    PubMed  Google Scholar 

  3. Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24:152–60. https://doi.org/10.1093/annonc/mds276.

    Article  CAS  PubMed  Google Scholar 

  4. Fazio N, Spada F, Giovannini M. Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view. Cancer Treat Rev. 2013;39:270–4. https://doi.org/10.1016/j.ctrv.2012.06.009.

    Article  CAS  PubMed  Google Scholar 

  5. Velayoudom-Cephise FL, Duvillard P, Foucan L, Hadoux J, Chougnet CN, Leboulleux S, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer. 2013;20:649–57. https://doi.org/10.1530/ERC-13-0027.

    Article  PubMed  Google Scholar 

  6. Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657–64.

    Article  CAS  PubMed  Google Scholar 

  7. Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, et al. The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology. 2017;104(1):85–93.

    Article  CAS  PubMed  Google Scholar 

  8. Tang LH, Basturk O, Sue JJ, Klimstra DS. A practical approach to the classification of WHO grade 3 (G3) well-differentiated Neuroendocrine tumor (WD-NET) and poorly differentiated Neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192–202. https://doi.org/10.1097/PAS.0000000000000662.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Tang LH, Untch BR, Reidy DL, O'Reilly E, Dhall D, Jih L, et al. Well-differentiated Neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated Neuroendocrine carcinomas. Clin Cancer Res. 2016;22(4):1011–7. https://doi.org/10.1158/1078-0432.CCR-15-0548.

    Article  CAS  PubMed  Google Scholar 

  10. Hofman MS, Hicks RJ. Changing paradigms with molecular imaging of neuroendocrine tumors. Discov Med. 2012;14(74):71–81.

    PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. Garin E, Le Jeune F, Devillers A, Cuggia M, de Lajarte-Thirouard AS, Bouriel C, et al. Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors. J Nucl Med. 2009;50(6):858–64. https://doi.org/10.2967/jnumed.108.057505.

    Article  CAS  PubMed  Google Scholar 

  13. 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: peptide receptor radionuclide therapy with Radiolabeled Somatostatin analogues. Neuroendocrinology. 2017; https://doi.org/10.1159/000475526.

  14. Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, et al. Favourable outcomes of (177)Lu-octreotate peptide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2015;42(2):176–85. https://doi.org/10.1007/s00259-014-2906-4.

    Article  CAS  PubMed  Google Scholar 

  15. Armaghany T, Vahdati G, Thamake S, Hamidi M, Amerinia R, Delpassand E. Treatment of high grade metastatic neuroendocrine tumor (mNET) with peptide receptor radionuclide therapy (PRRT): Retrospective analysis in a single referral center. J Clin Oncol 33, 2015 (suppl; abstr e15175).

  16. Ezziddin S, Opitz M, Attassi M, Biermann K, Sabet A, Guhlke S, et al. Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2011;38(3):459–66. https://doi.org/10.1007/s00259-010-1610-2.

    Article  CAS  PubMed  Google Scholar 

  17. Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103:186–94. https://doi.org/10.1159/000443172.

    Article  CAS  PubMed  Google Scholar 

  18. Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.

    Article  CAS  PubMed  Google Scholar 

  19. Hofman MS, Hicks RJ. Peptide receptor radionuclide therapy for neuroendocrine tumours: standardized and randomized, or personalized? Eur J Nucl Med Mol Imaging. 2014;41(2):211–3. https://doi.org/10.1007/s00259-013-2621-6.

    Article  PubMed  Google Scholar 

  20. Kong G, Callahan J, Hofman MS, Pattison DA, Akhurst T, Michael M, et al. High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2017;44(3):476–89. https://doi.org/10.1007/s00259-016-3527-x.

    Article  CAS  PubMed  Google Scholar 

  21. Hofman MS, Michael M, Hicks RJ. 177Lu-Dotatate for Midgut Neuroendocrine tumors. N Engl J Med. 2017;376(14):1390–1. https://doi.org/10.1056/NEJMc1701616.

    Article  PubMed  Google Scholar 

  22. Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O'Dorisio MS, 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(5):800–16. https://doi.org/10.1007/s00259-012-2330-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kashyap R, Jackson P, Hofman MS, Eu P, Beauregard JM, Zannino D, et al. Rapid blood clearance and lack of long-term renal toxicity of 177Lu-DOTATATE enables shortening of renoprotective amino acid infusion. Eur J Nucl Med Mol Imaging. 2013;40(12):1853–60. https://doi.org/10.1007/s00259-013-2504-x.

    Article  CAS  PubMed  Google Scholar 

  24. Kong G, Thompson M, Collins M, Herschtal A, Hofman MS, Johnston V, et al. Assessment of predictors of response and longterm survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Eur J Nucl Med Mol Imaging. 2014;41(10):1831–44. https://doi.org/10.1007/s00259-014-2788-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kong G, Johnston V, Ramdave S, Lau E, Rischin D, Hicks RJ. High-administered activity in-111 octreotide therapy with concomitant radiosensitizing 5FU chemotherapy for treatment of neuroendocrine tumors: preliminary experience. Cancer Biother Radiopharm. 2009;24(5):527–33. https://doi.org/10.1089/cbr.2009.0644.

    Article  CAS  PubMed  Google Scholar 

  26. Hubble D, Kong G, Michael M, Johnson V, Ramdave S, Hicks RJ. 177Lu-Octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide. Eur J Nucl Med Mol Imaging. 2010;37(10):1869–75. https://doi.org/10.1007/s00259-010-1483-4.

    Article  CAS  PubMed  Google Scholar 

  27. 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(2):302–11. https://doi.org/10.1007/s00259-010-1631-x.

    Article  CAS  PubMed  Google Scholar 

  28. Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the pancreas Center at Columbia University experience. Cancer Chemother Pharmacol. 2013;71(3):663–70. https://doi.org/10.1007/s00280-012-2055-z.

    Article  CAS  PubMed  Google Scholar 

  29. Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117(2):268–75. https://doi.org/10.1002/cncr.25425.

    Article  CAS  PubMed  Google Scholar 

  30. Claringbold PG, Price RA, Turner JH. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother Radiopharm. 2012;27(9):561–9. https://doi.org/10.1089/cbr.2012.1276.

    Article  CAS  PubMed  Google Scholar 

  31. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(Suppl 1):122S–50S. https://doi.org/10.2967/jnumed.108.057307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hicks RJ. The role of PET in monitoring therapy. Cancer Imaging. 2005;5:51–7.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.

    Article  CAS  PubMed  Google Scholar 

  34. Rindi G. The ENETS guidelines: the new TNM classification system. Tumori. 2010;96(5):806–9.

    PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. Strosberg JR, Coppola D, Klimstra DS, Phan AT, Kulke MH, Wiseman GA, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010;39:799–800. https://doi.org/10.1097/MPA.0b013e3181ebb56f.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 2011; 11: 4617–4622. doi: https://doi.org/10.1002/cncr.26124.

  38. Panzuto F, Rinzivillo M, Spada F, Antonuzzo L, Ibrahim T, Campana D, et al. Everolimus in pancreatic Neuroendocrine carcinomas G3. Pancreas. 2017;46(3):302–5. https://doi.org/10.1097/MPA.0000000000000762.

    Article  CAS  PubMed  Google Scholar 

  39. Kesavan M, Claringbold PG, Turner JH. Hematological toxicity of combined 177Lu-octreotate radiopeptide chemotherapy of gastroenteropancreatic neuroendocrine tumors in long-term follow-up. Neuroendocrinology. 2014;99(2):108–17. https://doi.org/10.1159/000362558.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Professor Hicks’ research is supported by a National Health and Medical Research Council of Australia Program grant and practitioner fellowship. We thank our radiopharmacists and radiochemists for their excellent support of our theranostics program and our dedicated nuclear medicine technologists and nursing staff for the care of our patients. Finally, we are grateful for the trust invested in us by our patients, their families and their managing clinicians.

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Correspondence to Rodney J. Hicks.

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All authors declare no conflicts of interest. No funding was received. All procedures performed were in accordance with the ethical standards of the institutional research committee and all patients provided informed consent for treatment.

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Sue Ping Thang and Mei Sim Lung are co-first authors.

A correction to this article is available online at https://doi.org/10.1007/s00259-017-3886-y.

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Thang, S.P., Lung, M.S., Kong, G. et al. Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. Eur J Nucl Med Mol Imaging 45, 262–277 (2018). https://doi.org/10.1007/s00259-017-3821-2

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