Neuroendocrine tumors: recent progress in diagnosis and treatment

in Endocrine-Related Cancer
Author:
Kjell Oberg Department of Endocrine Oncology, Department of Medical Sciences, University Hospital, Entrance 78, SE-751 85 Uppsala, Sweden
Department of Endocrine Oncology, Department of Medical Sciences, University Hospital, Entrance 78, SE-751 85 Uppsala, Sweden

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Neuroendocrine tumors (NETs) present a diverse group of malignancies considered to be rare, but recent data are indicating a significant increase in both incidence and prevalence during the last few decades. Current figures indicate an incidence of 5.1/100 000 per year and a prevalence of 35/100 000 (Yao et al. 2008a; Fig. 1). The exact reason for this increase is not known, but it might be related to increased awareness among physicians as well as better diagnosis and treatment. A new WHO classification system has emerged that distinguished between well-differentiated and poorly differentiated neoplasms in order to prognostically stratify the NETs that are further classified according to a TNM grading system that was recently proposed by European Neuroendocrine Tumor Society (ENETS) and the AJCC/UICC (Capella et al. 2000, Rindi et al. 2007, Kloppel et al. 2010). The grading system is based on the proliferative activity (Ki-67 index, mitoses) of the tumor. The classification and the pathology of gastro-entero-pancreatic neuroendocrine neoplasms is discussed by Prof. Günter Klöppel (Klöppel 2011). A number of biomarkers has been developed during the last decades based on development of the immunoassays for various gut hormones and amines. The most applied general tumor marker is chromogranin A (CgA) with high sensitivity and specificity but must be evaluated in relation to other diseases and therapeutic agents that can increase circulating levels without any tumor (Nobels et al. 1997, Tomassetti et al. 2001). Plasma CgA also gives prognostic information, where high levels indicate a worse prognosis (Janson et al. 1997). Other general markers include pancreatic polypeptide, neuron-specific enolase, and HCG-subunits. Depending on the type of clinical syndrome, specific markers such as gastrin, glucagon, insulin, and so forth may be used. For patients with carcinoid syndrome, urinary-5HIAA is still an important biomarker. The majority of patients with NETs (>60%) present with metastatic disease, and therefore, there is a need for more sensitive and specific biomarkers in the future. It might also be of interest to see whether analysis of circulating tumor cells can be of value for the selection of specific treatments. Biomarkers are discussed by myself (Oberg 2011).

Figure 1
Figure 1

Incidence of neuroendocrine tumors in the western world. Reprinted from The Lancet Oncology 9, Irvin M Modlin et al., Gastroenteropancreatic neuroendocrine tumours, pages 61–72, Copyright (2008), with permission from Elsevier.

Citation: Endocrine-Related Cancer 18, S1; 10.1530/ERC-10-0288

Nuclear medicine plays a pivotal role in the imaging and treatment of NETs. Somatostatin receptor scintigraphy (SRS) with Indium-111-DPA-octreotide has proven its role in the diagnosis and staging of NETs (Krenning et al. 1993). Positron emission tomography (PET) using short-lived isotopes that are specifically accumulated in NETs has increased in importance during the last years. The latter imaging modality especially in combination with computed tomography (CT) is of interest because of encouraging results in terms of improved imaging quality and detection capabilities but also prognostic information (Orlefors et al. 2005, Binderup et al. 2010). One such tracer might be Gallium-68-DOTA-octreotate that might, in the future, replace SRS as the gold standard. This PET/CT show higher sensitive and specificity and is also easily applied in the clinic because it is a one-stop procedure and the patient does not have to come back for repeated scanning (Gabriel et al. 2005). The tracer is also generated by a generator that makes it cheaper than traditional PET tracers developed by a cyclotron. Peptide receptors radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasized NETs as it can induce symptomatic improvement and prolong survival. In the largest series of patients receiving PRRT with Lutetium-177-DOTA-octreotate, a survival benefit of several years compared to historical controls has been reported (Kwekkeboom et al. 2008). In this supplement, Doctors Teunissen, Kwekkeboom, Valkema, and Krenning discuss imaging and the PRRT treatment of NETs (Teunissen et al. 2011).

The treatment landscape has significantly changed over the last years with the introduction of not only PRRT but also new biological therapies such as targeted treatments with tyrosine kinase and mTOR inhibitors but also the introduction of a new cytotoxic treatment with temozolomide alone or in combination with capecitabine or bevacizumab (Kulke 2006, Kulke et al. 2008, Yao et al. 2008b, 2010).

In the last paper of this supplement, the overall management of patients with NETs is discussed. It is obvious that these patients with very complicated clinical symptomatology need to be treated in specialized centers as part of a multi-disciplinary team comprising gastroenterologist, oncologist, endocrinologist, gastrointestinal hepatopancreaticobiliary surgeons, pathologist, nuclear medicine physicians, technicians, and radiologist. Although the number of medical treatments and clinical trials has increased in the last decade, there is still a lack of prospective randomized trials. Thus, management is mainly based on limited and often single-center studies, although there are now formal guidelines based on consensus expert opinions (ENETS, NANETS guidelines; Ramage et al. 2005, 2008, Steinmuller et al. 2008). In the last paper, Dr Khan and Caplin discuss the current optimal management of patients with NETs (Khan & Caplin 2011).

There is still an unmet need for randomized trials in patients with various subtypes of NETs. Moreover, the new classification systems should be introduced in the daily management of these patients but also in the clinical trials. We need more sensitive and specific markers to diagnose and follow up these patients. Many of the new treatments are expensive, and therefore, it is necessary to develop specific markers and imaging modalities that can detect and present early clinical responses to the introduced treatment. It is also important to emphasize the need for further education of doctors in the field of NETs and also establish center of expertise or excellence worldwide to give these patients the best possible treatment. In the future, we will aim at personalized treatment based on tumor biology, genetics, localization, and performance status to give the patients a good quality of life even in those patients that cannot be cured by surgery, PRRT, or medical treatment. In general, many of these patients are living with the disease for 10–15 years, and therefore, future management of these patients must include quality of life aspects.

Declaration of interest

K Oberg is on advisory boards for Novartis, Ipsen and Pfizer, and has received lecture honoraria from Novartis, Ipsen and Pfizer.

Funding

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

References

  • Binderup T, Knigge U, Loft A, Federspiel B & Kjaer A 2010 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clinical Cancer Research 16 978985. doi:10.1158/1078-0432.CCR-09-1759.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Capella C, Solcia E, Sobin LH & Arnold R 2000 Endocrine tumours of the oesophagus. In Pathology and Genetics. Tumours of the Digestive System. WHO Classification of Tumours, Hamilton SR, Aaltonen LA. Lyon: IARC Press.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gabriel M, Hausler F, Bale R, Moncayo R, Decristoforo C, Kovacs P & Virgolini I 2005 Image fusion analysis of (99m)Tc-HYNIC-Tyr(3)-octreotide SPECT and diagnostic CT using an immobilisation device with external markers in patients with endocrine tumours. European Journal of Nuclear Medicine and Molecular Imaging 32 14401451. doi:10.1007/s00259-005-1875-z.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Janson ET, Holmberg L, Stridsberg M, Eriksson B, Theodorsson E, Wilander E & Oberg K 1997 Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Annals of Oncology 8 685690. doi:10.1023/A:1008215730767.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khan MS & Caplin ME 2011 Therapeutic management of patients with gastroenteropancreatic neuroendocrine tumours. Endocrine-Related Cancer 18 (Supplement) S57S78.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G 2011 Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocrine-Related Cancer 18 (Supplement) S5S20.

  • Kloppel G, Rindi G, Perren A, Komminoth P & Klimstra DS 2010 The ENETS AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Archiv 456 595597. doi:10.1007/s00428-010-0924-6.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M & Reubi JC et al. 1993 Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. European Journal of Nuclear Medicine 20 716731. doi:10.1007/BF00181765.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kulke MH 2006 A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. ASCO Annual Meeting. Abstract No. 4044..

    • PubMed
    • Export Citation
  • Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L & Huang X et al. 2008 Activity of sunitinib in patients with advanced neuroendocrine tumors. Journal of Clinical Oncology 26 34033410. doi:10.1200/JCO.2007.15.9020.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, Feelders RA, van Aken MO & Krenning EP 2008 Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. Journal of Clinical Oncology 26 21242130. doi:10.1200/JCO.2007.15.2553.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nobels FR, Kwekkeboom DJ, Coopmans W, Schoenmakers CH, Lindemans J, De Herder WW, Krenning EP, Bouillon R & Lamberts SW 1997 Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. Journal of Clinical Endocrinology and Metabolism 82 26222628. doi:10.1210/jc.82.8.2622.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oberg 2011 Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocrine-Related Cancer 18 (Supplement) S21S29.

  • 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. Journal of Clinical Endocrinology and Metabolism 90 33923400. doi:10.1210/jc.2004-1938.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N & Sutton R et al. 2005 Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 54 (Supplement 4) iv1iv16. doi:10.1136/gut.2004.053314.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ramage JK, Goretzki PE, Manfredi R, Komminoth P, Ferone D, Hyrdel R, Kaltsas G, Kelestimur F, Kvols L & Scoazec JY et al. 2008 Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated colon and rectum tumour/carcinoma. Neuroendocrinology 87 3139. doi:10.1159/000111036.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rindi G, Kloppel G, Couvelard A, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A & Scarpa A et al. 2007 TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Archiv 451 757762. doi:10.1007/s00428-007-0452-1.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Steinmuller T, Kianmanesh R, Falconi M, Scarpa A, Taal B, Kwekkeboom DJ, Lopes JM, Perren A, Nikou G & Yao J et al. 2008 Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 87 4762. doi:10.1159/000111037.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Teunissen JJM, Kwekkeboom DJ, Valkema R & Krenning EP 2011 Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours. Endocrine-Related Cancer 18 (Supplement) S31S55.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomassetti P, Migliori M, Simoni P, Casadei R, De Iasio R, Corinaldesi R & Gullo L 2001 Diagnostic value of plasma chromogranin A in neuroendocrine tumours. European Journal of Gastroenterology & Hepatology 13 5558. doi:10.1097/00042737-200101000-00010.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN & Rashid A et al. 2008a One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology 26 30633072. doi:10.1200/JCO.2007.15.4377.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN & Rashid A et al. 2008b Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. Journal of Clinical Oncology 26 43114318. doi:10.1200/JCO.2008.16.7858.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T & Lebwohl D et al. 2010 Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. Journal of Clinical Oncology 28 6976. doi:10.1200/JCO.2009.24.2669.

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This paper forms part of a special issue of Endocrine-Related Cancer on Neuroendocrine Tumours. Novartis Pharmaceuticals Corporation has supported the publication of this special issue. Logistical support during development and submission of this article was provided by Springer Healthcare LLC. This support was funded by Novartis.

 

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  • Incidence of neuroendocrine tumors in the western world. Reprinted from The Lancet Oncology 9, Irvin M Modlin et al., Gastroenteropancreatic neuroendocrine tumours, pages 61–72, Copyright (2008), with permission from Elsevier.

  • Binderup T, Knigge U, Loft A, Federspiel B & Kjaer A 2010 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clinical Cancer Research 16 978985. doi:10.1158/1078-0432.CCR-09-1759.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Capella C, Solcia E, Sobin LH & Arnold R 2000 Endocrine tumours of the oesophagus. In Pathology and Genetics. Tumours of the Digestive System. WHO Classification of Tumours, Hamilton SR, Aaltonen LA. Lyon: IARC Press.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gabriel M, Hausler F, Bale R, Moncayo R, Decristoforo C, Kovacs P & Virgolini I 2005 Image fusion analysis of (99m)Tc-HYNIC-Tyr(3)-octreotide SPECT and diagnostic CT using an immobilisation device with external markers in patients with endocrine tumours. European Journal of Nuclear Medicine and Molecular Imaging 32 14401451. doi:10.1007/s00259-005-1875-z.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Janson ET, Holmberg L, Stridsberg M, Eriksson B, Theodorsson E, Wilander E & Oberg K 1997 Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Annals of Oncology 8 685690. doi:10.1023/A:1008215730767.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khan MS & Caplin ME 2011 Therapeutic management of patients with gastroenteropancreatic neuroendocrine tumours. Endocrine-Related Cancer 18 (Supplement) S57S78.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klöppel G 2011 Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocrine-Related Cancer 18 (Supplement) S5S20.

  • Kloppel G, Rindi G, Perren A, Komminoth P & Klimstra DS 2010 The ENETS AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Archiv 456 595597. doi:10.1007/s00428-010-0924-6.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M & Reubi JC et al. 1993 Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. European Journal of Nuclear Medicine 20 716731. doi:10.1007/BF00181765.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kulke MH 2006 A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. ASCO Annual Meeting. Abstract No. 4044..

    • PubMed
    • Export Citation
  • Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L & Huang X et al. 2008 Activity of sunitinib in patients with advanced neuroendocrine tumors. Journal of Clinical Oncology 26 34033410. doi:10.1200/JCO.2007.15.9020.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, Feelders RA, van Aken MO & Krenning EP 2008 Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. Journal of Clinical Oncology 26 21242130. doi:10.1200/JCO.2007.15.2553.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nobels FR, Kwekkeboom DJ, Coopmans W, Schoenmakers CH, Lindemans J, De Herder WW, Krenning EP, Bouillon R & Lamberts SW 1997 Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. Journal of Clinical Endocrinology and Metabolism 82 26222628. doi:10.1210/jc.82.8.2622.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oberg 2011 Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocrine-Related Cancer 18 (Supplement) S21S29.

  • 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. Journal of Clinical Endocrinology and Metabolism 90 33923400. doi:10.1210/jc.2004-1938.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N & Sutton R et al. 2005 Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 54 (Supplement 4) iv1iv16. doi:10.1136/gut.2004.053314.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ramage JK, Goretzki PE, Manfredi R, Komminoth P, Ferone D, Hyrdel R, Kaltsas G, Kelestimur F, Kvols L & Scoazec JY et al. 2008 Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated colon and rectum tumour/carcinoma. Neuroendocrinology 87 3139. doi:10.1159/000111036.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rindi G, Kloppel G, Couvelard A, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A & Scarpa A et al. 2007 TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Archiv 451 757762. doi:10.1007/s00428-007-0452-1.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Steinmuller T, Kianmanesh R, Falconi M, Scarpa A, Taal B, Kwekkeboom DJ, Lopes JM, Perren A, Nikou G & Yao J et al. 2008 Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 87 4762. doi:10.1159/000111037.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Teunissen JJM, Kwekkeboom DJ, Valkema R & Krenning EP 2011 Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours. Endocrine-Related Cancer 18 (Supplement) S31S55.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomassetti P, Migliori M, Simoni P, Casadei R, De Iasio R, Corinaldesi R & Gullo L 2001 Diagnostic value of plasma chromogranin A in neuroendocrine tumours. European Journal of Gastroenterology & Hepatology 13 5558. doi:10.1097/00042737-200101000-00010.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN & Rashid A et al. 2008a One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology 26 30633072. doi:10.1200/JCO.2007.15.4377.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN & Rashid A et al. 2008b Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. Journal of Clinical Oncology 26 43114318. doi:10.1200/JCO.2008.16.7858.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T & Lebwohl D et al. 2010 Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. Journal of Clinical Oncology 28 6976. doi:10.1200/JCO.2009.24.2669.

    • PubMed
    • Search Google Scholar
    • Export Citation