Skip to main content
SpringerLink
Log in

Should everolimus be stopped after radiological progression in metastatic insulinoma? A “cons” point of view

  • Viewpoint
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Insulinoma is a rare pancreatic neuroendocrine tumor (pNET) potentially associated with severe hypoglycaemic crisis. The great majority of these tumors are benign. In patients with metastatic malignant insulinoma, systemic therapies aim to control both the syndrome and tumor growth. Everolimus is a drug approved for the management of advanced pNETs that can achieve both these goals. According to international guidelines and regulatory authorities, everolimus in patients with pNET should be continued until the demonstration of disease progression with standard radiologic imaging techniques. The drug is neither recommended nor authorized beyond progression. This could not be the case of advanced insulinoma patients since the antineoplastic and the glycaemic effects of everolimus seem to follow independent mechanisms. The authors present here their point of view in favor of continuing everolimus beyond progression in symptomatic insulinoma patients on the basis of a robust rationale and describing a case.

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. M. Anlauf, N. Garbrecht, J. Bauersfeld, A. Schmitt, T. Henopp, P. Komminoth, P.U. Heitz, A. Perren, G. Klöppel, Hereditary neuroendocrine tumors of the gastroenteropancreatic system. Virchows Arch. 451(Suppl 1), S29–S38 (2007)

    Article  Google Scholar 

  2. P. Iglesias, J.J. Diaz, A clincal upted on tumor induced hypoglicemia. Eur. J. Endocrinol. 170, R147–R157 (2014)

    Article  CAS  Google Scholar 

  3. E. Baudin, P. Caron, C. Lombard-Bohas, A. Tabarin, E. Mitry, Y. Reznick, D. Taieb, F. Pattou, P. Goudet, D. Vezzosi, J. Scoazec, G. Cadiot, F. Borson-Chazot, C. Do Cao, Malignant insulinoma: recommendations for characterisation and treatment. Ann. d’Endocrinologie 74, 523–533 (2013)

    Article  Google Scholar 

  4. M.E. Pavel, J.D. Hainsworth, E. Baudin, M. Peeters, D. Hörsch, R.E. Winkler, J. Klimovsky, D. Lebwohl, V. Jehl, E.M. Wolin, K. Öberg, E. Van Cutsem, J.C. Yao, 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 378, 2005–2012 (2011)

    Article  CAS  Google Scholar 

  5. J.C. Yao, M.H. Shah, T. Ito, K. Lombard Bohas, E.M. Wolin, E. Van Cutsem, T.J. Hobday, T. Okusaka, J. Capdevila, E.G.E. de Vries, P. Tomassetti, M.E. Pavel, S. Hoosen, T. Haas, J. Lincy, D. Lebwohl, K. Öberg, Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 514–523 (2011)

    Article  CAS  Google Scholar 

  6. J.C. Yao, N. Fazio, S. Singh, R. Buzzoni, C. Carnaghi, E. Wolin, J. Tomasek, M. Raderer, H. Lahner, M. Voi, L. Bubuteishvili Pacaud, N. Rouyrre, C. Sachs, J.W. Valle, G. Delle Fave, E. Van Cutsem, M. Tesselaar, Y. Shimada, D. Oh, J. Strosberg, M.H. Kulke, M.E. Pavel, Everolimus for the treatment of advanced, nonfunctional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387(10022), 968–977 (2016)

    Article  CAS  Google Scholar 

  7. F. Panzuto, M. Rinzvillo, N. Fazio, F. De Braud, G. Luppi, M.C. Zatelli, F. Lugli, P. Tomasetti, F. Riccardi, C. Nuzzo, M.P. Brizzi, A. Faggiano, A. Zaniboni, E. Nobili, D. Pastorelli, S. Cascinu, M. Merlano, S. Chiara, L. Antonuzzo, C. Funaioli, F. Spada, S. Pusceddu, A. Fontana, M.R. Ambrosio, A. Cassano, D. Campana, G. Cartenì, M. Appetecchia, A. Berruti, A. Colao, M. Falconi, G. Delle Fave, Real-world study of everolimus in advanced progressive neuroendocrine tumors. Oncologist 19, 966–974 (2014)

    Article  CAS  Google Scholar 

  8. M. Falconi, B. Eriksson, G. Kaltsas, D.K. Bartsch, J. Capdevila, M. Caplin, B. Kos-Kudla, D. Kwekkeboom, G. Rindi, G. Klöppel, N. Reed, R. Kianmanesh, R.T. Jensen, And all other Vienna Consensus Conference participants. Consensus guidelines update for the management of functional p-NETs (F-p-NETs) and non-functional p-NETs (NF-p-NETs). Neuroendocrinology 103(2), 153–171 (2016)

    Article  CAS  Google Scholar 

  9. M. Pavel, K. Oberg, M. Falconi, E. Krenning, A. Sundin, A. Perren, A. Berruti, Gastroenteropancreartic enuroendrocine neoplasm: ESMO clinical practice guidelines for diagnosis, treatment and follow up. Ann. Oncol. S0923–7534(20), 36394–36398 (2020)

    Google Scholar 

  10. A. Barthel, D. Schmoll, Novel concepts in insulin regulation of hepatic gluconeogenesis. Am. J. Physiol. Endocrinol. Metab. 285, E685–E692 (2003)

    Article  CAS  Google Scholar 

  11. A. Veltroni, E. Cosaro, F. Spada, N. Fazio, A. Faggiano, A. Colao, S. Pusceddu, M.C. Zatelli, D. Campana, A. Piovesan, A. Pia, E.M. Grossrubatscher, A. Filice, A. Bianchi, P. Razzore, M. Toaiari, S. Cingarlini, L. Landoni, R. Micciolo, M.V. Davì, Clinico–pathological features, treatments and survival of malignant insulinomas: a multicenter study. Eur. J. Endocrinol. 182, 439–446 (2020)

    Article  CAS  Google Scholar 

  12. A. Giustina, G. Mazziotti, F. Maffezzoni, V. Amoroso, A. Berruti, Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors. Expert Opin. Investig. Drugs 23(12), 1619–1635 (2014)

    Article  CAS  Google Scholar 

  13. E. Raymond, L. Dahan, J.L. Raoul, Y.J. Bang, I. Borbath, C. Lombard-Bohas, J. Valle, P. Metrakos, D. Smith, A. Vinik, J.S. Chen, D. Hörsch, P. Hammel, B. Wiedenmann, E. Van Cutsem, S. Patyna, D.R. Lu, C. Blanckmeister, R. Chao, P. Ruszniewski, Sunitinib malate for the treatment of pancreatic neuroendocrinetumors. N. Engl. J. Med. 364(6), 501–513 (2011)

    Article  CAS  Google Scholar 

  14. A. Demirci, O. Bal, A. Durnali, A. S. Ekinci, O. Esbah, N. Alkis, B. Okszoglu, Sunitinib-induced severe hypoglycemia in a diabetic patient. Oncol. Pharm. Pract. 20(6), 469–472 (2014)

  15. A. Fountas, S. Tigas, Z. Giotaki, D. Petrakis, G. Pentheroudakis, A. Tsatsoulis, Severe resistant hypoglycemia in a patient with a pancreatic neuroendocrine tumor on sunitinib treatment. Hormones 14(3), 438–441 (2015)

    PubMed  Google Scholar 

  16. A. Berruti, A. Pia, M. Terzolo, Advances in pancreatic neuroendocrine tumor treatment. N. Engl. J. Med. 364, 19 (2011)

    Article  Google Scholar 

  17. B. Verges, B. Cariou, mTOR inhibitors and diabetes. Diabetes Res. Clin. Pract. 110, 101–108 (2015)

    Article  CAS  Google Scholar 

  18. M. Asayama, T. Yamada-Murano, H. Hara, A. Ooki, M. Kurosumi, K. Yamaguchi, Everolimus dramatically improves glycemic control in unresectable metastatic insulinoma: a case report. Jpn. J. Clin. Oncol. 44(2), 186–190 (2014)

    Article  Google Scholar 

  19. V. Bernard, C. Lombard-Bohas, M. Taquet, F. Caroli-Bosc, P. Ruszniewski, P. Niccoli, R. Guimbaud, C.N. Chougnet, B. Goichot, V. Rohmer, F. Borson-Chazot, E. Baudin, Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia. Eur. J. Endocrinol. 168, 665–674 (2013)

    Article  CAS  Google Scholar 

  20. S. Di Paolo, A. Teutonico, D. Leogrande, C. Capobianco, P.F. Schena, Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: a crossroad between cancer and diabetes? J. Am. Soc. Nephrol. 17, 2236–2244 (2006)

    Article  Google Scholar 

  21. H. Fiebrich, E.J.M. Siemerink, A.H. Bouuwers, T.P. Links, W.S. Remkes, G.A.P. Hospers, E.G.E. de Vries, Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues. Oncologist 16, 783–787 (2011)

    Article  CAS  Google Scholar 

  22. L. Suzuki, T. Miyatsuka, M. Himuro, R. Nishio, H. Goto, T. Uchida, Y. Nishida, A. Kanazawa, H. Watada, Everolimus directly suppresses insulin secretion independently of cell growth inhibition. J. Endocr. Soc. 2, 589–596 (2018)

    Article  CAS  Google Scholar 

  23. M. Kulke, E. Bergsland, J. Yao, Glycemic control in patients with insulinoma treated with everolimus. N. Engl. J. Med. 360, 2 (2009)

    Article  Google Scholar 

  24. C. Baratelli, M.P. Brizzi, M. Tampellini, G.V. Scagliotti, A. Priola, M. Terzolo, A. Pia, A. Berruti, Intermittent everolimus administration for malignant insulinoma. Endocrinol. Diabetes Metab. Case Rep. 2014, 140047 (2014)

    PubMed  PubMed Central  Google Scholar 

  25. H.S. Kim, W.L. Shaib, C. Zhang, G.P. Nagaraju, C. Wu, O.B. Alese, Z. Chen, E. Brutcher, M. Renfroe, B.F. El-Rayes, Phase 1b study of pasireotide, everolimus, and selective internal radioembolization therapy for unresectable neuroendocrine tumors with hepatic metastases. Cancer 124(9), 1992–2000 (2018)

    Article  CAS  Google Scholar 

  26. P.G. Claringbold, J.H. Turner, NeuroEndocrine tumor therapy with lutetium-177-octreotate and everolimus (NETTLE): a phase I study. Cancer Biother. Radiopharm. 30(6), 261–269 (2015)

    Article  CAS  Google Scholar 

Download references

Author contributions

All authors contributed to the study conception and design. The first draft of the manuscript was written by VT and all authors commented on previous version of the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, Italy

    Valeria Tovazzi, Vittorio D. Ferrari, Alberto Dalla Volta, Francesca Consoli, Vito Amoroso & Alfredo Berruti

Authors
  1. Valeria Tovazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vittorio D. Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Dalla Volta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesca Consoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vito Amoroso
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alfredo Berruti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alfredo Berruti.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Tovazzi, V., Ferrari, V.D., Dalla Volta, A. et al. Should everolimus be stopped after radiological progression in metastatic insulinoma? A “cons” point of view. Endocrine 69, 481–484 (2020). https://doi.org/10.1007/s12020-020-02368-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-020-02368-4

Keywords

Search

Navigation