Skip to main content
SpringerLink
Log in

Somatostatin analogs in patients with Zollinger Ellison syndrome (ZES): an observational study

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Zollinger Ellison syndrome (ZES) is a rare syndrome caused by gastrin hypersecretion from a gastrinoma. Gastrinoma treatment has two goals: the control of acid hypersecretion and the control of tumor growth. While therapy for the syndrome is univocally based on proton pump inhibitors, the one for disease control is still debated. We here aimed at evaluating the role of somatostatin analogs (SSAs) in the control of tumor progression in a series of ZES patients.

Methods

A retrospective analysis of a prospectively collected database of ZES patients, followed and managed from 1990 to 2019, was performed. The patients’ clinical, pathological, treatment, and follow-up data were analyzed. Data regarding SSAs therapy start, dosage, duration, and side effects were collected.

Results

33 patients with ZES were diagnosed. Fourteen patients (42%) had a grade 1 (G1) neuroendocrine neoplasm (NEN), five had G2 (15%), none had G3. Fifteen patients (45%) had metastatic disease. Overall, 12 (36%) underwent SSAs therapy. The median treatment duration was 36 months. Eight patients (67%) had a sustained response to SSAs, four (33%) showed an early progression, with a significant difference in terms of PFS between the patients with early and late progression (84 vs 2 months, p = 0.004). No differences in terms of OS and PFS were observed between the treated and non-treated patients, despite the proportion of metastatic patients was greater in the SSAs-treated group (75% vs 29% in the non-treated group, p = 0.01).

Conclusion

Present data support the use of SSAs in ZES, considering that gastrinoma is mainly a well-differentiated low-grade tumor (G1 or G2), with a high expression of somatostatin receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. V. Zimmer, M. Glanemann, F. Lammert, Zollinger-Ellison syndrome. CMAJ 191, 1358 (2019)

    Article  Google Scholar 

  2. M. Béhé, M. Gotthardt, T.M. Behr, Imaging of gastrinomas by nuclear medicine methods. Wien Klin. Wochenschr. 119, 593–596 (2007)

    Article  Google Scholar 

  3. J.A. Norton et al. Surgery to cure the Zollinger-Ellison syndrome. N. Engl. J. Med. 341, 635–644 (1999)

    Article  CAS  Google Scholar 

  4. M. Quatrini, L. Castoldi, G. Rossi, B.M. Cesana, M. Peracchi, M.T. Bardella, A follow-up study of patients with Zollinger-Ellison syndrome in the period 1966-2002: effects of surgical and medical treatments on long-term survival. J. Clin. Gastroenterol 39, 376–380 (2005)

    Article  Google Scholar 

  5. G. Rumenapf, P.O. Schwille, R.G. Erben, M. Schreiber, B. Berge, W. Fries, A. Schmiedl, S. Koroma, W. Hohenberger, Gastric fundectomy in the rat: effects on mineral and bone metabolism, with emphasis on the gastrin-calcitonin-parathyroid hormone-vitamin D axis. Calcif. Tissue. Int. 63, 433–441 (1998)

    Article  CAS  Google Scholar 

  6. G. Kaltsas, A.B. Grossman, The expanding role of somatostatin analogues in the treatment of neuroendocrine tumours: the CLARINET study. Clin. Endocrinol. (Oxf). 83, 759–761 (2015)

    Article  Google Scholar 

  7. A. Rinke, H.H. Müller, C. Schade-Brittinger, K.J. Klose, P. Barth, M. Wied, C. Mayer, B. Aminossadati, U.F. Pape, M. Bläker, J. Harder, C. Arnold, T. Gress, R. Arnold, P.S. Group, 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. 27, 4656–4663 (2009)

    Article  CAS  Google Scholar 

  8. M.E. Caplin, M. Pavel, P. Ruszniewski, Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N. Engl. J. Med 371, 1556–1557 (2014)

    Article  Google Scholar 

  9. F. Saijo, H. Naito, Y. Funayama, K. Fukushima, C. Shibata, A. Hashimoto, T. Kitayama, M. Nagao, S. Matsuno, I. Sasaki, Octreotide in control of multiple liver metastases from gastrinoma. J. Gastroenterol. 38, 905–908 (2003)

    Article  Google Scholar 

  10. D. Granberg, H. Jacobsson, K. Oberg, J. Gustavsson, M. Lehtihet, Regression of a large malignant gastrinoma on treatment with Sandostatin LAR: a case report. Digestion. 77, 92–95 (2008)

    Article  Google Scholar 

  11. P. Ruszniewski, H. Laucournet, L. Elouaer-Blanc, M. Mignon, S. Bonfils, Long-acting somatostatin (SMS 201-995) in the management of Zollinger-Ellison syndrome: evidence for sustained efficacy. Pancreas. 3, 145–152 (1988)

    Article  CAS  Google Scholar 

  12. M. Yamaguchi, Y. Yamada, Y. Hosokawa, R. Iwamoto, S. Tamba, A. Ihara, K. Yamamoto, Y. Hoshida, Y. Matsuzawa, Long-term suppressive effect of octreotide on progression of metastatic gastrinoma with multiple endocrine neoplasia type 1: seven-year follow up. Intern. Med. 49(15), 1557–1563 (2010)

    Article  CAS  Google Scholar 

  13. L.M. Daniels, M. Khalili, W.F. Morano, M. Simoncini, B.C. Mapow, A. Leaf, W.B. Bowne, Case report: optimal tumor cytoreduction and octreotide with durable disease control in a patient with MEN-1 and Zollinger-Ellison syndrome-over a decade of follow-up. World. J. Surg. Oncol. 17, 213 (2019)

    Article  Google Scholar 

  14. G. Rindi, R. Arnold, F. Bosman, C. Capella, D. Kilmstra, G. Kloppel, Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In WHO Classification of Tumours of the Digestive System, ed. by F.T. Bosman (Lyon, IARC Press, 2010), pp 13–14.

  15. G. Rindi, G. Klöppel, H. Alhman, M. Caplin, A. Couvelard, W.W. de Herder, B. Erikssson, A. Falchetti, M. Falconi, P. Komminoth, M. Körner, J.M. Lopes, A.M. McNicol, O. Nilsson, A. Perren, A. Scarpa, J.Y. Scoazec, B. Wiedenmann, all other Frascati Consensus Conference participants; European Neuroendocrine Tumor Society (ENETS), TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows. Arch. 449, 395–401 (2006).

  16. E. Bajetta, N. Zilembo, M. Di Bartolomeo, A. Di Leo, S. Pilotti, A.M. Bochicchio, R. Castellani, R. Buzzoni, L. Celio, L. Dogliotti, Treatment of metastatic carcinoids and other neuroendocrine tumors with recombinant interferon-alpha-2a. A study by the Italian Trials in Medical Oncology Group. Cancer. 72, 3099–3105 (1993)

    Article  CAS  Google Scholar 

  17. P. Therasse, S.G. Arbuck, E.A. Eisenhauer, J. Wanders, R.S. Kaplan, L. Rubinstein, J. Verweij, M. Van Glabbeke, A.T. van Oosterom, M.C. Christian, S.G. Gwyther, New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. Cancer Inst. 92, 205–216 (2000)

    Article  CAS  Google Scholar 

  18. H. Kulaksiz, R. Eissele, D. Rössler, S. Schulz, V. Höllt, Y. Cetin, R. Arnold, Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut. 50, 52–60 (2002)

    Article  CAS  Google Scholar 

  19. E. de Kerviler, G. Cadiot, R. Lebtahi, M. Faraggi, D. Le Guludec, M. Mignon, Somatostatin receptor scintigraphy in forty-eight patients with the Zollinger-Ellison syndrome. GRESZE: Groupe d’Etude du Syndrome de Zollinger-Ellison. Eur. J. Nucl. Med. 21, 1191–1197 (1994)

    Article  Google Scholar 

  20. R.T. Jensen, F. Gibril, Somatostatin receptor scintigraphy in gastrinomas. Ital. J. Gastroenterol. Hepatol. 31, 179–185 (1999)

    Google Scholar 

  21. F. Gibril, J.C. Reynolds, J.L. Doppman, C.C. Chen, D.J. Venzon, B. Termanini, H.C. Weber, C.A. Stewart, R.T. Jensen, Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann. Intern. Med. 125, 26–34 (1996)

    Article  CAS  Google Scholar 

  22. J. Hankus, R. Tomaszewska, Neuroendocrine neoplasms and somatostatin receptor subtypes expression. Nucl. Med. Rev. Cent. East. Eur. 19, 111–1117 (2016)

    Article  Google Scholar 

  23. M. Yibirin, D. De Oliveira, R. Valera, A.E. Plitt, S. Lutgen, Adverse effects associated with proton pump inhibitor use. Cureus. 13, e12759 (2021)

    PubMed  PubMed Central  Google Scholar 

  24. E.J. Mozell, A.J. Cramer, T.M. O’Dorisio, E.A. Woltering, Long-term efficacy of octreotide in the treatment of Zollinger-Ellison syndrome. Arch. Surg. 127, 1019–1024 (1992)

    Article  CAS  Google Scholar 

  25. B. Wörmann, K. Kutz, R. Ottenjann, Treatment of relapsing bleeding peptic ulcers with the somatostatin analogue SMS 201 995 in a patient with Zollinger-Ellison syndrome. Hepatogastroenterology. 32, 152–153 (1985)

    PubMed  Google Scholar 

  26. S. Gaztambide, J.A. Vazquez, Short- and long-term effect of a long-acting somatostatin analogue, lanreotide (SR-L) on metastatic gastrinoma. J. Endocrinol. Invest. 22, 144–146 (1999)

    Article  CAS  Google Scholar 

  27. S. Angeletti, V.D. Corleto, O. Schillaci, A. Moretti, F. Panzuto, B. Annibale, G. Delle Fave, Single dose of octreotide stabilize metastatic gastro-entero-pancreatic endocrine tumours. Ital. J. Gastroenterol. Hepatol. 31, 23–27 (1999)

    CAS  PubMed  Google Scholar 

  28. A.N. Wymenga, B. Eriksson, P.I. Salmela, M.B. Jacobsen, E.J. Van Cutsem, R.H. Fiasse, M.J. Välimäki, J. Renstrup, E.G. de Vries, K.E. Oberg, Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms. J. Clin. Oncol. 17, 1111 (1999)

    Article  CAS  Google Scholar 

  29. P. Tomassetti, M. Migliori, R. Corinaldesi, L. Gullo, Treatment of gastroenteropancreatic neuroendocrine tumours with octreotide LAR. Aliment. Pharmacol. Ther 14, 557–560 (2000)

    Article  CAS  Google Scholar 

  30. E. Solcia, C. Bordi, W. Creutzfeldt, Y. Dayal, A.D. Dayan, S. Falkmer, L. Grimelius, N. Havu, Histopathological classification of nonantral gastric endocrine growths in man. Digestion 41, 185–200 (1988)

    Article  CAS  Google Scholar 

  31. V. Guarnotta, C. Martini, M.V. Davì, G. Pizza, A. Colao, A. Faggiano, N. group, The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma? Endocrine. 60, 15–27 (2018)

    Article  CAS  Google Scholar 

  32. H. Shojamanesh, F. Gibril, A. Louie, J.V. Ojeaburu, S. Bashir, A. Abou-Saif, R.T. Jensen, Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma. Cancer. 94(2), 331–343 (2002)

    Article  CAS  Google Scholar 

  33. A.I. Vinik, R. Lloyd, K. Cho, The use of somatostatin analog in gastroenteropancreatic tumors other than carcinoid. Metabolism. 39, 156–162 (1990)

    Article  CAS  Google Scholar 

  34. P. Tomassetti, D. Campana, L. Piscitelli, R. Casadei, F. Nori, E. Brocchi, D. Santini, R. Pezzilli, R. Corinaldesi, Endocrine tumors of the ileum: factors correlated with survival. Neuroendocrinology. 83, 380–386 (2006)

    Article  CAS  Google Scholar 

  35. F. Cavalcoli, E. Rausa, D. Conte, A.F. Nicolini, S. Massironi, Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies? World. J. Gastroenterol. 23, 2640–2650 (2017)

    Article  Google Scholar 

Download references

Author contributions

S.M. planned the work; F.C., A.E., and M.Q. performed the literature search and collected the data in a dataset; S.M. analyzed the data; F.C. and S.M. wrote the first draft of the manuscript; F.C., A.M., and A.E. edited the subsequent versions of the manuscript; S.M. and P.I. critically revised the manuscript for relevant intellectual content. Finally, all authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo School of Medicine, Monza, Italy

    Sara Massironi, Alessandra Elvevi & Pietro Invernizzi

  2. Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy

    Federica Cavalcoli

  3. Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy

    Maurizio Quatrini

Authors
  1. Sara Massironi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federica Cavalcoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandra Elvevi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maurizio Quatrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pietro Invernizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sara Massironi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

This study was approved by the institutional review board and carried out following the approved guidelines.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Massironi, S., Cavalcoli, F., Elvevi, A. et al. Somatostatin analogs in patients with Zollinger Ellison syndrome (ZES): an observational study. Endocrine 75, 942–948 (2022). https://doi.org/10.1007/s12020-021-02915-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-021-02915-7

Keywords

Search

Navigation