Endocrinol Metab.  2019 Mar;34(1):53-62. 10.3803/EnM.2019.34.1.53.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement

• Chin SO
• Ku CR
• Kim BJ
• Kim SW
• Park KH
• Song KH
• Oh S
• Yoon HK
• Lee EJ
• Lee JM
• Lim JS
• Kim JH
• Kim KJ
• Jin HY
• Kim DJ
• Lee KA
• Moon SS
• Lim DJ
• Shin DY
• Kim SH
• Kwon MJ
• Kim HY
• Kim JH
• Kim DS
• Kim CH

• KMID: 2441679
• DOI: http://doi.org/10.3803/EnM.2019.34.1.53

Abstract

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

Keyword

Acromegaly; Somatostatin analogues; Octreotide; Lanreotide; Pasireotide

MeSH Terms

Acromegaly*
Consensus
Expert Testimony
Insurance Coverage
Insurance, Health
Octreotide
Somatostatin*
Octreotide
Somatostatin

Figure

• 

  Fig. 1 Initial dose and up-/down-titration of octreotide long-acting release (LAR) and lanreotide autogel (ATG) in patients with acromegaly. SSA, somatostatin analogues; OCT, octreotide; LAN, lanreotide; GH, growth hormone.

• 

  Fig. 2 Switching between octreotide long-acting release (LAR) and lanreotide autogel (ATG) during the medical treatment of acromegaly.

Reference

1. Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009; 119:3189–3202.

2. Reid TJ, Post KD, Bruce JN, Nabi Kanibir M, Reyes-Vidal CM, Freda PU. Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed. Clin Endocrinol (Oxf). 2010; 72:203–208.

3. Kwon O, Song YD, Kim SY, Lee EJ. Rare Disease Study Group. Science and Research Committee. Korean Endocrine Society. Nationwide survey of acromegaly in South Korea. Clin Endocrinol (Oxf). 2013; 78:577–585.

4. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014; 99:3933–3951.

5. Wass JA, Turner HE, Adams CB. The importance of locating a good pituitary surgeon. Pituitary. 1999; 2:51–54.

6. Ahmed S, Elsheikh M, Stratton IM, Page RC, Adams CB, Wass JA. Outcome of transphenoidal surgery for acromegaly and its relationship to surgical experience. Clin Endocrinol (Oxf). 1999; 50:561–567.

7. Shimon I, Cohen ZR, Ram Z, Hadani M. Transsphenoidal surgery for acromegaly: endocrinological follow-up of 98 patients. Neurosurgery. 2001; 48:1239–1243.

8. McLaughlin N, Laws ER, Oyesiku NM, Katznelson L, Kelly DF. Pituitary centers of excellence. Neurosurgery. 2012; 71:916–924.

9. Kreutzer J, Vance ML, Lopes MB, Laws ER Jr. Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria. J Clin Endocrinol Metab. 2001; 86:4072–4077.

10. Choe JH, Lee KS, Jeun SS, Cho JH, Hong YK. Endocrine outcome of endoscopic endonasal transsphenoidal surgery in functioning pituitary adenomas. J Korean Neurosurg Soc. 2008; 44:151–155.

11. Reichlin S. Somatostatin. N Engl J Med. 1983; 309:1495–1501.

12. Cuevas-Ramos D, Fleseriu M. Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol. 2014; 52:R223–R240.

13. Fleseriu M, Petersenn S. Medical management of Cushing's disease: what is the future? Pituitary. 2012; 15:330–341.

14. Reubi JC, Schaer JC, Waser B, Mengod G. Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Cancer Res. 1994; 54:3455–3459.

15. Krantic S, Goddard I, Saveanu A, Giannetti N, Fombonne J, Cardoso A, et al. Novel modalities of somatostatin actions. Eur J Endocrinol. 2004; 151:643–655.

16. Maffezzoni F, Formenti AM, Mazziotti G, Frara S, Giustina A. Current and future medical treatments for patients with acromegaly. Expert Opin Pharmacother. 2016; 17:1631–1642.

17. Bauer W, Briner U, Doepfner W, Haller R, Huguenin R, Marbach P, et al. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 1982; 31:1133–1140.

18. Taylor JE, Bogden AE, Moreau JP, Coy DH. In vitro and in vivo inhibition of human small cell lung carcinoma (NCI-H69) growth by a somatostatin analogue. Biochem Biophys Res Commun. 1988; 153:81–86.

19. Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2002; 87:3013–3018.

20. Grass P, Marbach P, Bruns C, Lancranjan I. Sandostatin LAR (microencapsulated octreotide acetate) in acromegaly: pharmacokinetic and pharmacodynamic relationships. Metabolism. 1996; 45:8 Suppl 1. 27–30.

21. McKeage K, Cheer S, Wagstaff AJ. Octreotide long-acting release (LAR): a review of its use in the management of acromegaly. Drugs. 2003; 63:2473–2499.

22. Ciccarelli A, Daly A, Beckers A. Lanreotide autogel for acromegaly: a new addition to the treatment armamentarium. Treat Endocrinol. 2004; 3:77–81.

23. Taboada GF, Luque RM, Bastos W, Guimaraes RF, Marcondes JB, Chimelli LM, et al. Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol. 2007; 156:65–74.

24. Park C, Yang I, Woo J, Kim S, Kim J, Kim Y, et al. Somatostatin (SRIF) receptor subtype 2 and 5 gene expression in growth hormone-secreting pituitary adenomas: the relationship with endogenous srif activity and response to octreotide. Endocr J. 2004; 51:227–236.

25. Dietrich H, Hu K, Ruffin M, Song D, Bouillaud E, Wang Y, et al. Safety, tolerability, and pharmacokinetics of a single dose of pasireotide long-acting release in healthy volunteers: a single-center phase I study. Eur J Endocrinol. 2012; 166:821–828.

26. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002; 146:707–716.

27. Wolin EM, Hu K, Hughes G, Bouillaud E, Giannone V, Resendiz KH. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a long-acting release (LAR) formulation of pasireotide (SOM230) in patients with gastroenteropancreatic neuroendocrine tumors: results from a randomized, multicenter, open-label, phase I study. Cancer Chemother Pharmacol. 2013; 72:387–395.

28. Jorgensen JO, Feldt-Rasmussen U, Frystyk J, Chen JW, Kristensen LO, Hagen C, et al. Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist. J Clin Endocrinol Metab. 2005; 90:5627–5631.

29. Conway-Campbell BL, Brooks AJ, Robinson PJ, Perani M, Waters MJ. The extracellular domain of the growth hormone receptor interacts with coactivator activator to promote cell proliferation. Mol Endocrinol. 2008; 22:2190–2202.

30. Lamberts SW, Uitterlinden P, Verschoor L, van Dongen KJ, del Pozo E. Long-term treatment of acromegaly with the somatostatin analogue SMS 201-995. N Engl J Med. 1985; 313:1576–1580.

31. Fleseriu M. Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: a literature review. Pituitary. 2011; 14:184–193.

32. Roelfsema F, Biermasz NR, Pereira AM, Romijn JA. Therapeutic options in the management of acromegaly: focus on lanreotide autogel. Biologics. 2008; 2:463–479.

33. Mercado M, Borges F, Bouterfa H, Chang TC, Chervin A, Farrall AJ, et al. A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol (Oxf). 2007; 66:859–868.

34. Caron PJ, Bevan JS, Petersenn S, Flanagan D, Tabarin A, Prevost G, et al. Tumor shrinkage with lanreotide autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial. J Clin Endocrinol Metab. 2014; 99:1282–1290.

35. Yang SJ, Seo YJ, Eun CR, Chung HS, Choi HJ, Kim NH, et al. Therapeutic effects of a long-acting formulation of lanreotide in Korean patients with acromegaly. Korean J Med. 2007; 73:50–57.

36. Colao A, Bronstein MD, Freda P, Gu F, Shen CC, Gadelha M, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014; 99:791–799.

37. Sheppard M, Bronstein MD, Freda P, Serri O, De Marinis L, Naves L, et al. Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, phase III study. Pituitary. 2015; 18:385–394.

38. Bronstein MD, Fleseriu M, Neggers S, Colao A, Sheppard M, Gu F, et al. Switching patients with acromegaly from octreotide to pasireotide improves biochemical control: crossover extension to a randomized, double-blind, phase III study. BMC Endocr Disord. 2016; 16:16.

39. Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014; 2:875–884.

40. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004; 89:667–674.

41. Zeinalizadeh M, Habibi Z, Fernandez-Miranda JC, Gardner PA, Hodak SP, Challinor SM. Discordance between growth hormone and insulin-like growth factor-1 after pituitary surgery for acromegaly: a stepwise approach and management. Pituitary. 2015; 18:48–59.

42. Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab. 2004; 89:1613–1617.

43. Paragliola RM, Corsello SM, Salvatori R. Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance. Pituitary. 2017; 20:109–115.

44. Andries M, Glintborg D, Kvistborg A, Hagen C, Andersen M. A 12-month randomized crossover study on the effects of lanreotide autogel and octreotide long-acting repeatable on GH and IGF-l in patients with acromegaly. Clin Endocrinol (Oxf). 2008; 68:473–480.

45. Kim SY, Kim D. Comparison of the efficacy of octreotide long-acting repeatable and lanreotide autogel in acromegalic patients. J Korean Endocr Soc. 2010; 25:37–45.

46. Giustina A, Bonadonna S, Bugari G, Colao A, Cozzi R, Cannavo S, et al. High-dose intramuscular octreotide in patients with acromegaly inadequately controlled on conventional somatostatin analogue therapy: a randomised controlled trial. Eur J Endocrinol. 2009; 161:331–338.

47. Neggers SJ, Pronin V, Balcere I, Lee MK, Rozhinskaya L, Bronstein MD, et al. Lanreotide autogel 120 mg at extended dosing intervals in patients with acromegaly biochemically controlled with octreotide LAR: the LEAD study. Eur J Endocrinol. 2015; 173:313–323.

48. Orlewska E, Kos-Kudla B, Sowinski J, Sworczak K, Zgliczynski W;. Dosage and costs of lanreotide autogel 120 mg administered as part of routine acromegaly care in Poland: two years of data from Lanro-Study. Endokrynol Pol. 2015; 66:142–148.

49. Carlsen SM, Lund-Johansen M, Schreiner T, Aanderud S, Johannesen O, Svartberg J, et al. Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-term postoperative rates: a prospective, randomized trial. J Clin Endocrinol Metab. 2008; 93:2984–2990.

50. Fougner SL, Bollerslev J, Svartberg J, Oksnes M, Cooper J, Carlsen SM. Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial. Eur J Endocrinol. 2014; 171:229–235.

51. Strowski MZ, Parmar RM, Blake AD, Schaeffer JM. Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology. 2000; 141:111–117.

52. Correa LL, Taboada GF, Van Haute FR, Casini AF, Balarini GA, Vieira Neto L, et al. Evaluation of glucose metabolism in acromegalic patients before and after treatment with octreotide LAR. Arq Bras Endocrinol Metabol. 2008; 52:55–64.

53. Caron PJ, Petersenn S, Houchard A, Sert C, Bevan JS. Glucose and lipid levels with lanreotide autogel 120 mg in treatment-naive patients with acromegaly: data from the PRIMARYS study. Clin Endocrinol (Oxf). 2017; 86:541–551.

54. Kumar U, Sasi R, Suresh S, Patel A, Thangaraju M, Metrakos P, et al. Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. Diabetes. 1999; 48:77–85.

55. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013; 98:3446–3453.

56. Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF. Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary. 2014; 17:180–186.

57. Maffei P, Tamagno G, Nardelli GB, Videau C, Menegazzo C, Milan G, et al. Effects of octreotide exposure during pregnancy in acromegaly. Clin Endocrinol (Oxf). 2010; 72:668–677.

58. Caron P, Broussaud S, Bertherat J, Borson-Chazot F, Brue T, Cortet-Rudelli C, et al. Acromegaly and pregnancy: a retrospective multicenter study of 59 pregnancies in 46 women. J Clin Endocrinol Metab. 2010; 95:4680–4687.