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Current Oncology Reports

, 18:7 | Cite as

Octreotide and Lanreotide in Gastroenteropancreatic Neuroendocrine Tumors

  • Venkata K. Pokuri
  • Mei Ka Fong
  • Renuka Iyer
Gastrointestinal Cancers (J Meyer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Gastrointestinal Cancers

Abstract

Neuroendocrine tumors are heterogeneous, rare malignancies that arise most commonly in the gastrointestinal tract and pancreas. They often secrete vasoactive substances resulting in carcinoid syndrome and the tumor cells exclusively express somatostatin receptors. Octreotide and lanreotide are the two synthetic somatostatin analogs used for the control of carcinoid symptoms and tumor progression in advanced inoperable disease. Recent pivotal trials (PROMID and CLARINET studies) established their antitumor activity. We discuss the available data to support their use as symptom controlling and antiproliferative agents. This article also reviews the guidelines (National Comprehensive Cancer Network and North American Neuro Endocrine Tumor Society), cost-analysis (suggesting the cost-effectiveness of lanreotide autogel compared to higher doses of octreotide long acting release formulation in refractory patients), and future directions of somatostatin analogs in the management of patients refractory to conventional doses of octreotide and lanreotide.

Keywords

Octreotide Lanreotide Synthetic Somatostatin Gastroenteropancreatic Neuroendocrine tumors Cost-analysis 

Notes

Compliance with Ethical Standards

Conflict of Interest

Venkata K. Pokuri declares that he has no conflict of interest. Mei Ka Fong participated in the advisory panel for lanreotide (Ipsen Pharmaceuticals) without financial compensation. Renuka Iyer has received compensation from Ipsen Pharmaceuticals for service as a consultant and has also received nonfinancial support from Ipsen for the review of manuscript content.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: ••Of major importance

  1. 1.
    Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40(1):1–18. vii.CrossRefGoogle Scholar
  3. 3.
    Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer. 2014;21(3):R153–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Frilling A, Akerstrom G, Falconi M, et al. Neuroendocrine tumor disease: an evolving landscape. Endocr Relat Cancer. 2012;19(5):R163–85.CrossRefPubMedGoogle Scholar
  5. 5.
    Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM. The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbeck’s Arch Surg. 2011;396(3):273–98.CrossRefGoogle Scholar
  6. 6.
    Cives M, Strosberg J. An update on gastroenteropancreatic neuroendocrine tumors. Oncology (Williston Park). 2014;28(9):749–56. 758.Google Scholar
  7. 7.
    Bousquet C, Puente E, Buscail L, Vaysse N, Susini C. Antiproliferative effect of somatostatin and analogs. Chemotherapy. 2001;47 Suppl 2:30–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Rinke A, Muller HH, Schade-Brittinger C, 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.CrossRefPubMedGoogle Scholar
  9. 9.••
    Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33. This is the phase 3 study establishing the anti-proliferative activity of Lanreotide, resulting in FDA approval of the first synthetic somatostatin analog for antitumor activity in gastro-entero-pancreatic neuroendocrine tumors.CrossRefPubMedGoogle Scholar
  10. 10.
    Oberg K. Future aspects of somatostatin-receptor-mediated therapy. Neuroendocrinology. 2004;80 Suppl 1:57–61.PubMedGoogle Scholar
  11. 11.
    Meier RF, Reichert MM. Octreotide: a clinical update. Saudi J Gastroenterol. 1998;4(3):147–55.PubMedGoogle Scholar
  12. 12.
    Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. 1996;334(4):246–54.CrossRefPubMedGoogle Scholar
  13. 13.
    Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. 1999;20(3):157–98.CrossRefPubMedGoogle Scholar
  14. 14.
    Kvols LK, Moertel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986;315(11):663–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Astruc B, Marbach P, Bouterfa H, et al. Long-acting octreotide and prolonged-release lanreotide formulations have different pharmacokinetic profiles. J Clin Pharmacol. 2005;45(7):836–44.CrossRefPubMedGoogle Scholar
  16. 16.
    Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17(2):600–6.PubMedGoogle Scholar
  17. 17.••
    Broder MS, Beenhouwer D, Strosberg JR, Neary MP, Cherepanov D. Gastrointestinal neuroendocrine tumors treated with high dose octreotide-LAR: a systematic literature review. World J Gastroenterol. 2015;21(6):1945–55. This is a systematic review of all the studies which utilized higher than conventional doses of Octreotide LAR formulation. Despite wide use of these higher doses in clinical practice, there are no large, randomized trials proving their superiority over conventional doses of Octreotide LAR. This review summarizes the benefit of higher dose Octreotide LAR in carcinoid symptom control along with its antitumor efficacy.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Woltering EA, Mamikunian PM, Zietz S, et al. Effect of octreotide LAR dose and weight on octreotide blood levels in patients with neuroendocrine tumors. Pancreas. 2005;31(4):392–400.CrossRefPubMedGoogle Scholar
  19. 19.
    Ruszniewski P, Ducreux M, Chayvialle JA, et al. Treatment of the carcinoid syndrome with the longacting somatostatin analogue lanreotide: a prospective study in 39 patients. Gut. 1996;39(2):279–83.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31(2):169–88.PubMedGoogle Scholar
  21. 21.
    O’Toole D, Ducreux M, Bommelaer G, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88(4):770–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Caron P, Beckers A, Cullen DR, et al. Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly. J Clin Endocrinol Metab. 2002;87(1):99–104.CrossRefPubMedGoogle Scholar
  23. 23.
    Lightman S. Somatuline autogel: an extended release lanreotide formulation. Hosp Med. 2002;63(3):162–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Bajetta E, Procopio G, Catena L, et al. Lanreotide autogel every 6 weeks compared with lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: a phase III study. Cancer. 2006;107(10):2474–81.CrossRefPubMedGoogle Scholar
  25. 25.
    Khan MS, El-Khouly F, Davies P, Toumpanakis C, Caplin ME. Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel). Aliment Pharmacol Ther. 2011;34(2):235–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Ruszniewski PCM, Valle J. Patient-reported satisfaction with symptom control during lanreotide Autogel/Depot treatment for carcinoid syndrome in gastroenteropancreatic neuroendocrine tumor patients: SymNET, a large multinational cross-sectional observational study. GI Cancers Symposium. 2014. Abstract No: 273.Google Scholar
  27. 27.
    Vinik AWE, Audry H. ELECT: a phase III study of efficacy and safety of lanreotide Autogel/depot (LAN) treatment for carcinoid syndrome in patients with neuroendocrine tumors (NETs). GI Cancers Symposium. 2014. Abstract No: 268.Google Scholar
  28. 28.
    Strosberg JR, Fisher GA, Benson AB, et al. Systemic treatment in unresectable metastatic well-differentiated carcinoid tumors: consensus results from a modified delphi process. Pancreas. 2013;42(3):397–404.CrossRefPubMedGoogle Scholar
  29. 29.
    Theodoropoulou M, Zhang J, Laupheimer S, et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res. 2006;66(3):1576–82.CrossRefPubMedGoogle Scholar
  30. 30.
    Strosberg J, Kvols L. Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol. 2010;16(24):2963–70.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Florio T. Molecular mechanisms of the antiproliferative activity of somatostatin receptors (SSTRs) in neuroendocrine tumors. Front Biosci. 2008;13:822–40.CrossRefPubMedGoogle Scholar
  32. 32.
    Sideris L, Dube P, Rinke A. Antitumor effects of somatostatin analogs in neuroendocrine tumors. Oncologist. 2012;17(6):747–55.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Arnold RWM, Rinke A, Schade-Brittinger C, Aminossadati B. E R. 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 (PROMID): results on long-term survival. Proc Am Soc Clin Oncol. 2013;31. Abstr: 4030.Google Scholar
  34. 34.••
    Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42(4):557–77. This article provides the guidelines (NANETS, North American Neuro Endocrine Tumor Society and NCCN, National Comprehensive Cancer Network) in the management of neuroendocrine tumors (NETs). Apart from identifying the applicability of synthetic somatostatin analogs in NETs, it also describe various other modalities of treatment for NETs and furnish guidelines to be used in day to day clinical practice.Google Scholar
  35. 35.••
    Kulke MH, Shah MH, Benson 3rd AB, et al. Neuroendocrine tumors, version 1.2015. J Natl Compr Cancer Netw. 2015;13(1):78–108. This article provides the guidelines (NANETS, North American Neuro Endocrine Tumor Society and NCCN, National Comprehensive Cancer Network) in the management of neuroendocrine tumors (NETs). Apart from identifying the applicability of synthetic somatostatin analogs in NETs, it also describe various other modalities of treatment for NETs and furnish guidelines to be used in day to day clinical practice.Google Scholar
  36. 36.
    Papotti M, Bongiovanni M, Volante M, et al. Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. 2002;440(5):461–75.CrossRefPubMedGoogle Scholar
  37. 37.
    de Herder WW, Hofland LJ, van der Lely AJ, Lamberts SW. Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. Endocr Relat Cancer. 2003;10(4):451–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Chadha MK, Lombardo J, Mashtare T, et al. High-dose octreotide acetate for management of gastroenteropancreatic neuroendocrine tumors. Anticancer Res. 2009;29(10):4127–30.PubMedGoogle Scholar
  39. 39.
    Anthony L, Vinik AI. Evaluating the characteristics and the management of patients with neuroendocrine tumors receiving octreotide LAR during a 6-year period. Pancreas. 2011;40(7):987–94.CrossRefPubMedGoogle Scholar
  40. 40.
    Ferolla P, Faggiano A, Grimaldi F, et al. Shortened interval of long-acting octreotide administration is effective in patients with well-differentiated neuroendocrine carcinomas in progression on standard doses. J Endocrinol Investig. 2012;35(3):326–31.Google Scholar
  41. 41.
    Edward M, Wolin MEC, Pavel ME, Cwikla JB, Phan AT, Markus R, et al. Lanreotide depot/autogel (LAN) in intestinal and pancreatic neuroendocrine tumors (NETs) according to body mass index (BMI): subgroup analyses from the CLARINET study. J Clin Oncol. 2015;33 (suppl; abstr e15182).Google Scholar
  42. 42.
    Nuria Buil-Bruna MJG, Marion D, Amandine M, Thi Xuan Quyen N, Gomez-Panzani EL, Troconiz IF. Population pharmacokinetic (PK) analysis of lanreotide autogel/depot in the treatment of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs): pooled analysis of four clinical trials. J Clin Oncol. 2015;33 suppl 3:abstr 397.Google Scholar
  43. 43.
    Eugene Woltering MAS, Boudreaux JP, Wang Y-Z, Pam R, Uhlhorn AP, Mamikunian G. Effect of sex, weight, and body mass index on plasma lanreotide levels. J Clin Oncol. 2015;33 (suppl; abstr e15189).Google Scholar
  44. 44.
    Bevan JS, Newell-Price J, Wass JA, et al. Home administration of lanreotide Autogel by patients with acromegaly, or their partners, is safe and effective. Clin Endocrinol. 2008;68(3):343–9.Google Scholar
  45. 45.
    Salvatori R, Nachtigall LB, Cook DM, et al. Effectiveness of self- or partner-administration of an extended-release aqueous-gel formulation of lanreotide in lanreotide-naive patients with acromegaly. Pituitary. 2010;13(2):115–22.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Adelman DT, Burgess A, Davies PR. Evaluation of long-acting somatostatin analog injection devices by nurses: a quantitative study. Med Devices (Auckl). 2012;5:103–9.CrossRefGoogle Scholar
  47. 47.
    Marty R, Roze S, Kurth H. Decision-tree model for health economic comparison of two long-acting somatostatin receptor ligand devices in France, Germany, and the UK. Med Devices (Auckl). 2012;5:39–44.Google Scholar
  48. 48.
    Schmid HA. Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol. 2008;286(1–2):69–4.CrossRefPubMedGoogle Scholar
  49. 49.
    Kvols LK, Oberg KE, O’Dorisio TM, et al. Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study. Endocr Relat Cancer. 2012;19(5):657–66.CrossRefPubMedGoogle Scholar
  50. 50.
    Cives M, Kunz PL, Morse B, et al. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr Relat Cancer. 2015;22(1):1–9.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Wolin EM JB, Eriksson B, Walter T, Toumpanakis C, Morse MTP, Weber M, et al. A multicenter, randomized, blinded, phase III study of pasireotide LAR versus octreotide LAR in patients with metastatic neuroendocrine tumors (NET) with disease-related symptoms inadequately controlled by somatostatin analogs [abstract]. In: 2013 American Society of Clinical Oncology Annual Meeting. J Clin Oncol. 2013;31(suppl):abstract 4031.Google Scholar
  52. 52.
    Kulke MH, O’Dorisio T, Phan A, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014;21(5):705–14.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Oberg K, Knigge U, Kwekkeboom D, Perren A. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii124–30.PubMedGoogle Scholar
  54. 54.
    Eriksson B, Kloppel G, Krenning E, et al. Consensus guidelines for the management of patients with digestive neuroendocrine tumors—well-differentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology. 2008;87(1):8–19.CrossRefPubMedGoogle Scholar
  55. 55.
    Xu C, Zhang H. Somatostatin receptor based imaging and radionuclide therapy. Biomed Res Int. 2015;2015, 917968.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Turner HE, Thornton-Jones VA, Wass JA. Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly. Clin Endocrinol. 2004;61(2):224–31.CrossRefGoogle Scholar
  57. 57.
    Lucas T, Astorga R. Efficacy of lanreotide Autogel administered every 4–8 weeks in patients with acromegaly previously responsive to lanreotide microparticles 30 mg: a phase III trial. Clin Endocrinol. 2006;65(3):320–6.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Medical OncologyRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of Pharmacy, Carolinas Healthcare SystemLevine Cancer InstituteCharlotteUSA

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