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Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours

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Abstract

Purpose

The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with 177Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2).

Methods

We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with 177Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial 99mTc-DTPA clearance measurements.

Results

The median follow-up period was 58 months (range 4 – 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 – 42) and 53 months (95 % CI 46 – 60), respectively. A G1 proliferation status was associated with longer PFS (p = 0.04) and OS (p = 0.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤70 %, p = 0.007), a high hepatic tumour burden (≥25 % liver volume, p = 0.017), and an elevated plasma level of neuron-specific enolase (NSE >15 ng/ml, p = 0.035).

Conclusion

The outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient’s performance status, tumour burden and baseline plasma NSE level.

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References

  1. Kwekkeboom DJ, de Herder WW, van Eijck CH, Kam BL, van Essen M, Teunissen JJ, et al. Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2010;40:78–88.

    Article  PubMed  Google Scholar 

  2. Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. 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 

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

    PubMed  Google Scholar 

  6. Breeman WA, De Jong M, Visser TJ, Erion JL, Krenning EP. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. Eur J Nucl Med Mol Imaging. 2003;30:917–20.

    Article  CAS  PubMed  Google Scholar 

  7. Breeman WA, van der Wansem K, Bernard BF, van Gameren A, Erion JL, Visser TJ, et al. The addition of DTPA to [177Lu-DOTA0, Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity. Eur J Nucl Med Mol Imaging. 2003;30:312–5.

    Article  CAS  PubMed  Google Scholar 

  8. Kwekkeboom DJ, Bakker WH, Kam BL, Teunissen JJ, Kooij PP, de Herder WW, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA(0), Tyr3]octreotate. Eur J Nucl Med Mol Imaging. 2003;30:417–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. 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;23:2754–62.

    Article  CAS  PubMed  Google Scholar 

  10. Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs. 1992;10:239–53.

    Article  CAS  PubMed  Google Scholar 

  11. Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R, et al. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol. 2010;23:824–33.

    Article  CAS  PubMed  Google Scholar 

  12. Falconi M, Bartsch DK, Eriksson B, Klöppel G, Lopes JM, O'Connor JM, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology. 2012;95:120–34.

    Article  CAS  PubMed  Google Scholar 

  13. Kvols LK, Buck M. Chemotherapy of endocrine malignancies: a review. Semin Oncol. 1987;14:343–53.

    CAS  PubMed  Google Scholar 

  14. Murray-Lyon IM, Eddleston AL, Williams R, Brown M, Hogbin BM, Bennett A, et al. Treatment of multiple-hormone-producing malignant islet-cell tumour with streptozotocin. Lancet. 1968;2:895–8.

    Article  CAS  PubMed  Google Scholar 

  15. Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980;303:1189–94.

    Article  CAS  PubMed  Google Scholar 

  16. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519–23.

    Article  CAS  PubMed  Google Scholar 

  17. Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22:4762–71.

    Article  CAS  PubMed  Google Scholar 

  18. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401–6.

    Article  CAS  PubMed  Google Scholar 

  19. 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;71:663–70.

    Article  CAS  PubMed  Google Scholar 

  20. Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13:2986–91.

    Article  CAS  PubMed  Google Scholar 

  21. 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;117:268–75.

    Article  CAS  PubMed  Google Scholar 

  22. Zitzmann K, De Toni EN, Brand S, Göke B, Meinecke J, Spöttl G, et al. The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology. 2007;85:54–60.

    Article  CAS  PubMed  Google Scholar 

  23. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311–8.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Basu B, Sirohi B, Corrie P. Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin. Endocr Relat Cancer. 2010;17:R75–90.

    Article  CAS  PubMed  Google Scholar 

  25. Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95:1148–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Jensen RT, Delle FG. Promising advances in the treatment of malignant pancreatic endocrine tumors. N Engl J Med. 2011;364:564–5.

    Article  CAS  PubMed  Google Scholar 

  28. Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–10.

    Article  CAS  PubMed  Google Scholar 

  29. Shah MH, Young D, Kindler HL, Webb I, Kleiber B, Wright J, et al. Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res. 2004;10:6111–8.

    Article  CAS  PubMed  Google Scholar 

  30. 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;364:514–23.

    Article  CAS  PubMed  Google Scholar 

  31. 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;364:501–13.

    Article  CAS  PubMed  Google Scholar 

  32. 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;38:459–66.

    Article  CAS  PubMed  Google Scholar 

  33. Pape UF, Berndt U, Muller-Nordhorn J, Böhmig M, Roll S, Koch M, et al. Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2008;15:1083–97.

    Article  PubMed  Google Scholar 

  34. Pape UF, Jann H, Muller-Nordhorn J, Bockelbrink A, Berndt U, Willich SN, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer. 2008;113:256–65.

    Article  PubMed  Google Scholar 

  35. Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer. 2005;12:1083–92.

    Article  PubMed  Google Scholar 

  36. Bettini R, Boninsegna L, Mantovani W, Capelli P, Bassi C, Pederzoli P, et al. Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours. Ann Oncol. 2008;19:903–8.

    Article  CAS  PubMed  Google Scholar 

  37. Korse CM, Taal BG, Vincent A, van Velthuysen ML, Baas P, Buning-Kager JC, et al. Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments. Eur J Cancer. 2012;48:662–71.

    Article  CAS  PubMed  Google Scholar 

  38. Yao JC, Pavel M, Phan AT, Kulke MH, Hoosen S, St Peter J, et al. Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab. 2011;96:3741–9.

    Article  CAS  PubMed  Google Scholar 

  39. Baudin E, Gigliotti A, Ducreux M, Ropers J, Comoy E, Sabourin JC, et al. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer. 1998;78:1102–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38(12):2125–35.

    Google Scholar 

  41. Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group – E6282. Ann Oncol. 2001;12:1139–43.

    Article  CAS  PubMed  Google Scholar 

  42. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69–76.

    Article  CAS  PubMed  Google Scholar 

  43. Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012;30:2963–8.

    Article  CAS  PubMed  Google Scholar 

  44. Chan JA, Blaszkowsky L, Stuart K, Zhu AX, Allen J, Wadlow R, et al. A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer. 2013;119:3212–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nuclear Medicine, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Samer Ezziddin, Feras Khalaf, Maria Vanezi, Torjan Haslerud, Abdullah Al Zreiqat, Hans-Jürgen Biersack & Amir Sabet

  2. Department of Internal Medicine and Oncology, University Hospital, Bonn, Germany

    Karin Mayer

  3. Department of Radiology, University Hospital, Bonn, Germany

    Winfried Willinek

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  1. Samer Ezziddin
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  2. Feras Khalaf
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Correspondence to Samer Ezziddin.

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Ezziddin, S., Khalaf, F., Vanezi, M. 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 41, 925–933 (2014). https://doi.org/10.1007/s00259-013-2677-3

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