, Volume 19, Issue 6, pp 605–611 | Cite as

Paradoxical and atypical responses to pasireotide in aggressive ACTH-secreting pituitary tumors

  • Yona Greenman
  • Naftali Stern



Pasireotide is the only pituitary targeted medication registered for the treatment of Cushing’s disease. Drug efficacy data are largely based on a major prospective study in which the vast majority of patients had microadenomas. The purpose of this study was to summarize results of pasireotide treatment of ACTH secreting macroadenomas from our center.


Retrospective review of data extracted from clinical files.


Three patients presented with large and invasive macroadenomas that required several surgical interventions and radiotherapy treatments. Patient 1 is a 57 year-old male who developed an extreme (27-fold) paradoxical response of urinary free cortisol (UFC) levels as measured 2 weeks after pasireotide institution, which increased further (71-fold) in response to dose increment but decreased to baseline levels after treatment interruption. Patient 2 is a 44 year old woman with a long standing (26 years) ACTH-secreting carcinoma metastatic to bone and after bilateral adrenalectomy. After an initial excellent response to pasireotide treatment, ACTH levels escaped suppression and a further rebound was noted 6 weeks after treatment interruption. Patient 3 is a 53 year old man that after escape from temozolomide therapy was started on pasireotide and rapidly responded by almost normalizing UFC excretion after 4 weeks, but returned to baseline UFC levels after four additional weeks of treatment.


We describe as yet unreported atypical responses to pasireotide treatment in patients with aggressive ACTH-secreting tumors. Increased vigilance is recommended during pasireotide treatment of such patients.


Cushing’s disease Atypical tumor Pasireotide Paradoxical response Pituitary carcinoma 



No specific funding was provided for this work.

Compliance with ethical standards


YG has received research grants from Novartis, speaker honorarium from Novartis and Medison, and has participated in advisory boards for Novartis and Pfizer. NS has nothing to disclose.


  1. 1.
    Pivonello R, De Leo M, Cozzolino A, Colao A (2015) The treatment of Cushing’s disease. Endocr Rev 36:385–486CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BMK (2012) A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 366:914–924CrossRefPubMedGoogle Scholar
  3. 3.
    Shimon I, Rot L, Inbar E (2012) Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review. Pituitary 15:608–613CrossRefPubMedGoogle Scholar
  4. 4.
    Lu L, Duan L, Jin Z, Lu Z, Gu F (2013) Effective long-term treatment of Cushing’s disease with pasireotide: a case report. Endocr Pract 19:e92–e96CrossRefPubMedGoogle Scholar
  5. 5.
    Simeoli C, Auriemma RS, Tortora F, De Leo M, Iacuaniello D, Cozzolino A, De Martino MC, Pivonello C, Mainolfi CG, Rossi R, Cirillo S, Colao A, Pivonello R (2015) The treatment with pasireotide in Cushing’s disease: effects of long-term treatment on tumor mass in the experience of a single center. Endocrine 50:725–740CrossRefPubMedGoogle Scholar
  6. 6.
    Grossrubatscher E, Zampetti B, Dalino Ciaramella P, Doneda P, Loli P (2015) Effectiveness of low-dose pasireotide in a patient with Cushing’s disease: antiproliferative effect and predictivity of a short pasireotide suppression test. Clin Case Rep 3:718–722CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kakade HR, Kasaliwal R, Khadilkar KS, Jadhav S, Bukan A, Khare S, Budyal SR, Goel A, Lila AR, Bandgar T, Shah NS (2014) Clinical, biochemical and imaging characteristics of Cushing’s macroadenomas and their long-term treatment outcome. Clin Endocrinol 81:336–342CrossRefGoogle Scholar
  8. 8.
    Trementino L, Michetti G, Angeletti A, Marcelli G, Concettoni C, Cardinaletti C, Polenta B, Boscaro M, Arnaldi G (2016) A single-center 10-year experience with pasireotide in Cushing’s disease: patients’ characteristics and outcome. Horm Metab Res 48:290–298CrossRefPubMedGoogle Scholar
  9. 9.
    Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP, Thomé C (2010) SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp Clin Endocrinol Diabet 118:760–763CrossRefGoogle Scholar
  10. 10.
    Cannavo S, Messina E, Albani A, Ferrau F, Barresi V, Priola S, Esposito F, Angileri F (2016) Clinical management of critically ill patients with Cushing’s disease due to ACTH-secreting pituitary macroadenomas: effectiveness of presurgical treatment with pasireotide. Endocrine 52:481–487CrossRefPubMedGoogle Scholar
  11. 11.
    Katznelson L (2013) Sustained improvements in plasma ACTH and clinical status in a patient with Nelson’s syndrome treated with pasireotide LAR, a multireceptor somatostatin analog. J Clin Endocrinol Metab 98:1803–1807CrossRefPubMedGoogle Scholar
  12. 12.
    Rajendran R, Naik S, Sandeman DD, Nasruddin AB (2013) Pasireotide therapy in a rare and unusual case of plurihormonal pituitary macroadenoma. Endocrinol Diabet Metab Case Rep 2013:130026Google Scholar
  13. 13.
    Modlin IM, Pavel M, Kidd M, Gustafsson BI (2010) Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 31:169–188PubMedGoogle Scholar
  14. 14.
    Hofland LJ, Lamberts SW (2003) The pathophysiological consequences of somatostatin receptor internalization and resistance. Endoc Rev 24:28–47CrossRefGoogle Scholar
  15. 15.
    Ben-Shlomo A, Schmid H, Wawrowsky K, Pichurin O, Hubina E, Chesnokova V, Liu NA, Culler M, Melmed S (2009) Differential ligand-mediated pituitary somatostatin receptor subtype signaling: implications for corticotroph tumor therapy. J Clin Endocrinol Metab 94:4342–4350CrossRefPubMedGoogle Scholar
  16. 16.
    Lesche S, Lehmann D, Nagel F, Schmid HA, Schulz S (2009) Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J Clin Endocrinol Metab 94:654–661CrossRefPubMedGoogle Scholar
  17. 17.
    Mohamed A, Blanchard MP, Albertelli M, Barbieri F, Brue T, Niccoli P, Delpero JR, Monges G, Garcia S, Ferone D, Florio T, Enjalbert A, Moutardier V, Schonbrunn A, Gerard C, Barlier A, Saveanu A (2014) Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. Endocr Relat Cancer 21:691–704CrossRefPubMedGoogle Scholar
  18. 18.
    Petrich A, Mann A, Kliewer A, Nagel F, Strigli A, Märtens JC, Pöll F, Schulz S (2013) Phosphorylation of threonine 333 regulates trafficking of the human sst5 somatostatin receptor. Mol Endocrinol 27:671–682CrossRefPubMedGoogle Scholar
  19. 19.
    Duquenne M, Dousset B, Weryha G, Fade-Schneller O, Duriez T, Anthoine D, Leclere J, Hartemann P (1991) Paradoxical effect of octreotide in neoplastic inappropriate corticotropin secretion. Lancet 338:1407–1408CrossRefPubMedGoogle Scholar
  20. 20.
    Rieu M, Rosilio M, Richard A, Vannetzel JM, Kuhn JM (1993) Paradoxical effect of somatostatin analogues on the ectopic secretion of corticotropin in two cases of small cell lung carcinoma. Horm Res 39:207–212CrossRefPubMedGoogle Scholar
  21. 21.
    Cescato R, Loesch KA, Waser B, Mäcke HR, Rivier JE, Reubi JC, Schonbrunn A (2010) Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways. Mol Endocrinol 24:240–249CrossRefPubMedGoogle Scholar
  22. 22.
    Pecori Giraldi F, Pagliardini L, Cassarino MF, Martucci F, Sesta A, Castelli L, Montanari E, Schmid HA, Cavagnini F (2012) Stimulatory effect of SOM230 on human and rat adrenal corticosteroid secretion in vitro. Gen Comp Endocrinol 178:436–439CrossRefPubMedGoogle Scholar
  23. 23.
    Meinardi JR, Wolffenbuttel BH, Dullaart RP (2007) Cyclic Cushing’s syndrome: a clinical challenge. Eur J Endocrinol 157:245–254CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center and Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

Personalised recommendations