Skip to main content

Advertisement

Log in

Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE as a promising treatment of malignant insulinoma: a series of case reports and literature review

  • Short Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Introduction

Insulinomas are a rare type of pancreatic neuroendocrine tumours characterized by insulin hypersecretion. They are considered malignant when metastases are present. Traditional therapies often promote only temporarily symptomatic relief and may be associated with severe adverse effects. There is scarce experience in treating malignant insulinomas with peptide receptors radionuclide therapy (PRRNT).

Patients and methods

We describe PRRNT results in four patients with inoperable malignant insulinomas with poorly controllable hypoglycaemia. All patients received therapy with 177Lu-DOTA-TATE after conventional therapies failed in controlling disease progression and symptoms. The activity administered per cycle was 4.8–7.4 GBq. The interval between cycles was 10–16 weeks. Haematology, liver and kidney function tests were performed before treatment initiation and 5 and 10 weeks after each cycle.

Results

Patient 1 presented significant clinical benefit for 13 months after PRRNT, with imaging improvement. Patient 2 obtained reduction of the number and severity of hypoglycaemic episodes during 15 months after therapy. Patient 3 is asymptomatic since PRRNT first cycle performed 23 months ago and revealed significant imaging improvement. Patient 4 had resolution of hypoglycaemia only 3 days after PRRNT first cycle and today, 16 months after therapy, the disease seems to be in remission and the patient maintains euglycaemic state. PRRNT was well tolerated, with only hematologic grade 2 toxicity in patient 1 and mild kidney toxicity in patient 3.

Conclusions

After the start of 177Lu-DOTA-TATE all patients achieved hypoglycaemia symptomatic control and had evident improvement of their quality of life. Three patients showed imagiological improvement suggesting reduced tumour load.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

NETs:

Neuroendocrine tumours

WHO:

World Health Organization

SSTRs:

Somatostatin receptors

LAR:

Long-acting repeatable

PRRNT:

Peptide receptors radionuclide therapy

SSAs:

Somatostatin analogues

mTOR:

Mammalian target of rapamycin

177Lu-DOTA-TATE:

Lutetium-177-tetraazacyclododecane-tetra-acetic acid-Octreotate

IAEA:

International Atomic Energy Agency

EANM:

European Association of Nuclear Medicine

SNMMI:

Society of Nuclear Medicine and Molecular Imaging

68Ga-DOTA-SSA-PET/CT:

68Ga-DOTA-Somatostatin Analogue Positron Emission Tomography/Computed Tomography

18F-FDG-PET/CT:

18-Fluorodeoxyglucose positron emission tomography/computed tomography

SRS:

Somatostatin receptor scintigraphy

GFR:

Glomerular filtration rate

51Cr-EDTA:

Chromium-51 labeled ethylenediamine tetraacetic acid

pNET:

Pancreatic neuroendocrine tumor

QoL:

Quality of life

GEP-NETs:

Gastroenteropancreatic neuroendocrine tumours

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

IFN:

Interferon alpha

90Y:

Yttrium-90

DTPA:

Diethylenetriamine penta-acetic acid

References

  1. Albu A, Zirnea A, Georgescu O, Terzea D, Jinga D, Fica S (2008) Malignant insulinoma with hepatic and pulmonary metastases associated with primary hyperparathyroidism. Case report and review of the literature. J Med Life 1(2):210–217

    PubMed  CAS  Google Scholar 

  2. van Schaik E, van Vliet EI, Feelders RA, Krenning EP, Khan S, Kamp K, Valkema R, van Nederveen FH, Teunissen JJ, Kwekkeboom DJ, de Herder WW (2011) Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy. J Clin Endocrinol Metab 96(11):3381–3389. https://doi.org/10.1210/jc.2011-1563

    Article  PubMed  CAS  Google Scholar 

  3. Brabander T, Teunissen JJ, Van Eijck CH, Franssen GJ, Feelders RA, de Herder WW, Kwekkeboom DJ (2016) Peptide receptor radionuclide therapy of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 30(1):103–114. https://doi.org/10.1016/j.beem.2015.10.005

    Article  PubMed  CAS  Google Scholar 

  4. Cives M, Strosberg J (2017) Treatment strategies for metastatic neuroendocrine tumors of the gastrointestinal tract. Curr Treat Options Oncol 18(3):14. https://doi.org/10.1007/s11864-017-0461-5

    Article  PubMed  Google Scholar 

  5. Cives M, Strosberg J (2017) Radionuclide therapy for neuroendocrine tumors. Current Oncol Rep 19(2):9. https://doi.org/10.1007/s11912-017-0567-8

    Article  CAS  Google Scholar 

  6. Kim SJ, Pak K, Koo PJ, Kwak JJ, Chang S (2015) The efficacy of (177)Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumours: a meta-analysis. Eur J Nuclear Med Mol Imaging 42(13):1964–1970. https://doi.org/10.1007/s00259-015-3155-x

    Article  CAS  Google Scholar 

  7. Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A (2008) Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9(1):61–72. https://doi.org/10.1016/s1470-2045(07)70410-2

    Article  PubMed  CAS  Google Scholar 

  8. Oberg KE (2012) The management of neuroendocrine tumours: current and future medical therapy options. Clin Oncol (R Coll Radiol (G B)) 24(4):282–293. https://doi.org/10.1016/j.clon.2011.08.006

    Article  CAS  Google Scholar 

  9. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26(18):3063–3072. https://doi.org/10.1200/jco.2007.15.4377

    Article  PubMed  Google Scholar 

  10. Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, Knigge U, Salazar R, Pape UF, Oberg K (2016) ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 103(2):172–185. https://doi.org/10.1159/000443167

    Article  PubMed  CAS  Google Scholar 

  11. Merola E, Rinzivillo M, Cicchese N, Capurso G, Panzuto F, Delle Fave G (2016) Digestive neuroendocrine neoplasms: a 2016 overview. Dig Liver Dis 48(8):829–835. https://doi.org/10.1016/j.dld.2016.04.008

    Article  PubMed  CAS  Google Scholar 

  12. Cives M, Strosberg J (2015) The expanding role of somatostatin analogs in gastroenteropancreatic and lung neuroendocrine tumors. Drugs 75(8):847–858. https://doi.org/10.1007/s40265-015-0397-7

    Article  PubMed  CAS  Google Scholar 

  13. Kunz PL (2015) Carcinoid and neuroendocrine tumors: building on success. J Clin Oncol 33(16):1855–1863. https://doi.org/10.1200/jco.2014.60.2532

    Article  PubMed  CAS  Google Scholar 

  14. Usukura M, Yoneda T, Oda N, Yamamoto Y, Takata H, Hasatani K, Takeda Y (2007) Medical treatment of benign insulinoma using octreotide LAR: a case report. Endocr J 54(1):95–101

    Article  PubMed  CAS  Google Scholar 

  15. Barrons RW (1997) Octreotide in hyperinsulinism. Ann Pharmacother 31(2):239–241

    Article  PubMed  CAS  Google Scholar 

  16. Stehouwer CD, Lems WF, Fischer HR, Hackeng WH, Naafs MA (1989) Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (Sandostatin). Acta Endocrinol 121(1):34–40

    Article  PubMed  CAS  Google Scholar 

  17. Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Horsch D, O’Dorisio MS, O’Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ (2013) The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nuclear Med Mol Imaging 40(5):800–816. https://doi.org/10.1007/s00259-012-2330-6

    Article  CAS  Google Scholar 

  18. Fajans SS, Floyd JC Jr, Knopf RF, Rull J, Guntsche EM, Conn JW (1966) Benzothiadiazine suppression of insulin release from normal and abnormal islet tissue in man. J Clin Investig 45(4):481–492. https://doi.org/10.1172/jci105362

    Article  PubMed  CAS  Google Scholar 

  19. Goode PN, Farndon JR, Anderson J, Johnston ID, Morte JA (1986) Diazoxide in the management of patients with insulinoma. World J Surg 10(4):586–592

    Article  PubMed  CAS  Google Scholar 

  20. Portela-Gomes GM, Stridsberg M, Grimelius L, Rorstad O, Janson ET (2007) Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas—predominance of receptor subtype 4. Endocr Pathol 18(2):79–85

    Article  PubMed  CAS  Google Scholar 

  21. Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22(23):4762–4771. https://doi.org/10.1200/jco.2004.04.024

    Article  PubMed  CAS  Google Scholar 

  22. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Horsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513. https://doi.org/10.1056/NEJMoa1003825

    Article  PubMed  CAS  Google Scholar 

  23. Komori Y, Yada K, Ohta M, Uchida H, Iwashita Y, Fukuzawa K, Kashima K, Yokoyama S, Inomata M, Kitano S (2014) Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors. J Hepato Biliary Pancreat Sci 21(4):288–295. https://doi.org/10.1002/jhbp.26

    Article  Google Scholar 

  24. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6):514–523. https://doi.org/10.1056/NEJMoa1009290

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Singh S, Carnaghi C, Buzzoni R, Pommier RF, Raderer M, Tomasek J, Lahner H, Valle JW, Voi M, Bubuteishvili-Pacaud L, Lincy J, Wolin E, Okita N, Libutti SK, Oh DY, Kulke M, Strosberg J, Yao JC, Pavel ME, Fazio N (2017) Everolimus in neuroendocrine tumors of the gastrointestinal tract and unknown primary. Neuroendocrinology. https://doi.org/10.1159/000477585

    Article  PubMed  Google Scholar 

  26. Janson ET, Oberg K (1993) Long-term management of the carcinoid syndrome Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol (Stockholm, Sweden) 32(2):225–229. https://doi.org/10.3109/02841869309083916

    Article  CAS  Google Scholar 

  27. Baum RP, Kluge AW, Kulkarni H, Schorr-Neufing U, Niepsch K, Bitterlich N, van Echteld CJ (2016) [(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-Octreotide ((177)Lu-DOTATOC) For peptide receptor radiotherapy in patients with advanced neuroendocrine tumours: a Phase-II Study. Theranostics 6(4):501–510. https://doi.org/10.7150/thno.13702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O’Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Oberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E (2017) Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 376(2):125–135. https://doi.org/10.1056/NEJMoa1607427

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kwekkeboom DJ, Teunissen JJ, Bakker WH, Kooij PP, de Herder WW, Feelders RA, van Eijck CH, Esser JP, Kam BL, Krenning EP (2005) Radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol 23(12):2754–2762. https://doi.org/10.1200/jco.2005.08.066

    Article  PubMed  CAS  Google Scholar 

  30. Sampaio IL, Luiz HV, Violante LS, Santos AP, Antunes L, Torres I, Sanches C, Azevedo I, Duarte H (2016) Treatment of gastroenteropancreatic neuroendocrine tumors with 177Lu-DOTA-TATE: experience of the Portuguese Institute of Oncology in Porto. Acta Med Port 29(11):726–733. https://doi.org/10.20344/amp.7306

    Article  PubMed  Google Scholar 

  31. Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ (2011) Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0, Tyr3]octreotate. J Nuclear Med 52(9):1361–1368. https://doi.org/10.2967/jnumed.111.087932

    Article  CAS  Google Scholar 

  32. Teunissen JJ, Kwekkeboom DJ, Krenning EP (2004) Quality of life in patients with gastroenteropancreatic tumors treated with [177Lu-DOTA0, Tyr3]octreotate. J Clin Oncol 22(13):2724–2729. https://doi.org/10.1200/jco.2004.10.016

    Article  PubMed  CAS  Google Scholar 

  33. Traub-Weidinger T, Raderer M, Uffmann M, Angelberger P, Kurtaran A, Leimer M, Preitfellner J, Dudczak R, Virgolini I (2011) Improved quality of life in patients treated with Peptide radionuclides. World J Nuclear Med 10(2):115–121. https://doi.org/10.4103/1450-1147.89779

    Article  CAS  Google Scholar 

  34. de Keizer B, van Aken MO, Feelders RA, de Herder WW, Kam BL, van Essen M, Krenning EP, Kwekkeboom DJ (2008) Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3]octreotate. Eur J Nucl Med Mol Imaging 35(4):749–755. https://doi.org/10.1007/s00259-007-0691-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, Lepensky C, Kwekkeboom DJ, Baum RP, Krenning EP, Modlin IM (2015) Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging 42(1):5–19. https://doi.org/10.1007/s00259-014-2893-5

    Article  PubMed  CAS  Google Scholar 

Download references

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

Authors

Contributions

DM and ILS collected and interpreted the data and wrote the manuscript. GF, PG, DMB, RS and HD participated in the medical treatment and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to D. Magalhães.

Ethics declarations

Conflict of interest

None.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Patient consent was obtained.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Magalhães, D., Sampaio, I.L., Ferreira, G. et al. Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE as a promising treatment of malignant insulinoma: a series of case reports and literature review. J Endocrinol Invest 42, 249–260 (2019). https://doi.org/10.1007/s40618-018-0911-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-018-0911-3

Keywords

Navigation