Skip to main content
SpringerLink
Log in

Therapy for Metastatic Disease with Unknown Primary Tumor

  • Chapter
  • First Online:
Neuroendocrine Tumors in Real Life

  • 579 Accesses

Abstract

Metastatic neuroendocrine neoplasms (NENs) with an unknown primary (UP) represent a specific subset that can concern both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). An appropriate diagnostic work-up is necessary to conclude for UP NEN, including complete pathological report and morphological and functional imaging. Therapeutical approach to UP NEN is controversial and nonevidence based, as only few clinical trials include UP NEN as a specific entity. While in UP NETs the identification of the primary site can have relevant therapeutic implications, it is not the case for UP NECs, where the high grade of the neoplasm usually indicates starting chemotherapy soon. In patients with a metastatic UP NENs, ENETS guidelines suggest to base treatment decisions on grading, functionality, somatostatin receptor status, tumor extent, and hepatic tumor burden.

Metastatic UP NECs are usually approached with chemotherapy, mainly platinum-based; by contrast metastatic UP, NETs are managed in a multimodal manner, and they should be discussed within a multidisciplinary NEN-dedicated team given that several different therapies can be proposed and integrated.

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

Access this chapter

Log in via an institution

Institutional subscriptions

Bibliography

  1. Kaltsas G, Rockall A, Papadogias D, Reznek R, Grossman AB (2004) Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours. Eur J Endocrinol 151:15–27

    Article  CAS  PubMed  Google Scholar 

  2. Schreiter NF, Bartels AM, Froeling V, Steffen I, Pape UF, Beck A, Hamm B, Brenner W, Röttgen R (2014) Searching for primaries in patients with neuroendocrine tumors (NET) of unknown primary and clinically suspected NET: evaluation of Ga-68 DOTATOC PET/CT and in-111 DTPA octreotide SPECT/CT. Radiol Oncol 48(4):339–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Santhanam P, Chandramahanti S, Kroiss A, Yu R, Ruszniewski P, Kumar R, Taïeb D (2015) Nuclear imaging of neuroendocrine tumors with unknown primary: why, when and how? Eur J Nucl Med Mol Imaging 42(7):1144–1155

    Article  CAS  PubMed  Google Scholar 

  4. Deroose CM, Hindié E, Kebebew E, Goichot B, Pacak K, Taïeb D, Imperiale A (2016) Molecular imaging of gastroenteropancreatic neuroendocrine tumors: current status and future directions. J Nucl Med 57(12):1949–1956

    Article  CAS  PubMed  Google Scholar 

  5. Orlefors H, Sundin A, Garske U, Juhlin C, Oberg K, Skogseid B, Langstrom B, Bergstrom M, Eriksson B (2005) Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography. J Clin Endocrinol Metab 90:3392–3400

    Article  CAS  PubMed  Google Scholar 

  6. Koopmans KP, de Vries EG, Kema IP, Elsinga PH, Neels OC, Sluiter WJ, van der Horst-Schrivers AN, Jager PL (2006) Staging of carcinoid tumours with 18F-DOPA PET: a prospective, diagnostic accuracy study. Lancet Oncol 7:728–734

    Article  CAS  PubMed  Google Scholar 

  7. Kamaoui I, De-Luca V, Ficarelli S, Mennesson N, Lombard-Bohas C, Pilleul F (2010) Value of CT enteroclysis in suspected small-bowel carcinoid tumors. AJR Am J Roentgenol 194:629–633

    Article  PubMed  Google Scholar 

  8. Masselli G, Polettini E, Casciani E, Bertini L, Vecchioli A, Gualdi G (2009) Small-bowel neoplasms: prospective evaluation of MR enteroclysis. Radiology 251:743–750

    Article  PubMed  Google Scholar 

  9. Frilling A, Smith G, Clift AK, Martin J (2014) Capsule endoscopy to detect primary tumour site in metastatic neuroendocrine tumours. Dig Liver Dis 46(11):1038–1042

    Article  PubMed  Google Scholar 

  10. Lin X, Saad RS, Luckasevic TM, Silverman JF, Liu Y (2007) Diagnostic value of CDX-2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin. Appl Immunohistochem Mol Morphol 15(4):407

    Article  CAS  PubMed  Google Scholar 

  11. Bellizzi AM (2013) Assigning site of origin in metastatic neuroendocrine neoplasms: a clinically significant application of diagnostic immunohistochemistry. Adv Anat Pathol 20(5):285–314

    Article  CAS  PubMed  Google Scholar 

  12. Wang SC, Parekh JR, Zuraek MB, Venook AP, Bergsland EK, Warren RS, Nakakura EK (2010) Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg 145(3):276–280

    Article  PubMed  Google Scholar 

  13. Begum N, Wellner U, Thorns C, Brabant G, Hoffmann M, Bürk CG, Lehnert H, Keck T (2015) CUP syndrome in neuroendocrine neoplasia: analysis of risk factors and impact of surgical intervention. World J Surg 39(6):1443–1451

    Article  PubMed  Google Scholar 

  14. Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P, CLARINET Investigators (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371(3):224

    Article  PubMed  Google Scholar 

  15. Yao JC, Fazio N, Singh S et al (2016) Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387:968–977

    Google Scholar 

  16. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R, PROMID Study Group (2009) 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(28):4656

    Article  CAS  PubMed  Google Scholar 

  17. Gridelli C, Rossi A, Airoma G et al (2013) Treatment of pulmonary neuroendocrine tumours: state of the art and future developments. Cancer Treat Rev 39:466–472. 43

    Article  PubMed  Google Scholar 

  18. Sgambato A, Casaluce F, Maione P et al (2013) Medical treatment of small cell lung cancer: state of the art and new development. Expert Opin Pharmacother 14:2019–2031

    Article  CAS  PubMed  Google Scholar 

  19. Nicholson SA, Beasley MB, Brambilla E et al (2002) Small cell carcinoma (SCLC). A clinicopathological study of 100 cases with surgical specimens. Am J Surg Pathol 26:1184–1197

    Article  PubMed  Google Scholar 

  20. Yamaguchi T et al (2014) Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system. Cancer Sci 105:1176–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mitry E et al (1999) Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer 81:1351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sørbye H et al (2013) Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 24:152–160

    Article  PubMed  Google Scholar 

  23. Greco FA, Hainsworth JD (2008) Cancer of unknown primary site. In: DeVita VT Jr, Hellman S, Rosenberg S (eds) Cancer: principles and practice of oncology, 8th edn. Lippincott, Philadelphia, pp 2363–2387

    Google Scholar 

  24. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A et al (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 26:3063–3072

    Article  PubMed  Google Scholar 

  25. Spigel DR, Hainsworth JD, Greco FA (2009) Neuroendocrine carcinoma of unknown primary site. Semin Oncol 36(1):52–59

    Article  CAS  PubMed  Google Scholar 

  26. Klimstra DS, Arnold R, Capella C et al (2010) WHO classification of tumours of the digestive system. Lyon, IACR

    Google Scholar 

  27. Massimino KP, Han E, Pommier SJ et al (2012) Laparoscopic surgical exploration is an effective strategy for locating occult primary neuroendocrine tumors. Am J Surg 203:628–631

    Article  PubMed  Google Scholar 

  28. Woltering EA, Voros BA, Beyer DT, Wang YZ, Thiagarajan R, Ryan P, Wright A, Ramirez RA, Ricks MJ, Boudreaux JP (2017) Aggressive surgical approach to the management of neuroendocrine tumors: a report of 1,000 surgical cytoreductions by a single institution. J Am Coll Surg 224(4):434–447

    Google Scholar 

  29. Stoyianni A, Pentheroudakis G, Pavlidis N (2011) Neuroendocrine carcinoma of unknown primary: a systematic review of the literature and a comparative study with other neuroendocrine tumors. Cancer Treat Rev 37(5):358–365

    Article  PubMed  Google Scholar 

  30. Faggiano A, Sabourin JC, Ducreux M, Lumbroso J et al (2007) Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas: diagnostic and prognostic features. Cancer 110(2):265–274

    Article  CAS  PubMed  Google Scholar 

  31. Pavel M, O'Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, Knigge U, Salazar R, Pape UF, Öberg K, Vienna Consensus Conference participants (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

    Article  CAS  PubMed  Google Scholar 

  32. Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, Mowatt KB, Dinnen RD, Mao Y, Stevens PD, Schrope B, Allendorf J, Lee JA, Sherman WH, Chabot JA (2013) Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 71(3):663–670

    Google Scholar 

  33. Kwekkeboom DJ, Krenning EP, Lebtahi R, Komminoth P, Kos-Kudła B, de Herder WW et al (2009) ENETS consensus guidelines for the standards of care in neuroendocrine tumors: peptide receptor radionuclide therapy with radiolabeled somatostatin analogs. Neuroendocrinology 90:220–226

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy

    Nicola Fazio & Manila Rubino

Authors
  1. Nicola Fazio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manila Rubino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicola Fazio .

Editor information

Editors and Affiliations

  1. ENETs Center of Excellence for Neuroendocrine Tumours, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

    Annamaria Colao

  2. ENETs Center of Excellence for Neuroendocrine Tumours, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

    Antongiulio Faggiano

  3. Endocrine Oncology, Internal Medicine Department, Erasmus University, Rotterdam, Zuid-Holland, The Netherlands

    Wouter de Herder

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fazio, N., Rubino, M. (2018). Therapy for Metastatic Disease with Unknown Primary Tumor. In: Colao, A., Faggiano, A., de Herder, W. (eds) Neuroendocrine Tumors in Real Life. Springer, Cham. https://doi.org/10.1007/978-3-319-59024-0_24

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-59024-0_24

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-59022-6

  • Online ISBN: 978-3-319-59024-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation