Article information
Los tumores neuroendocrinos gastroenteropancreáticos (TEGEP) son una entidad clínica poco frecuente. Dado que el único tratamiento curativo es la resección quirúrgica completa, es necesario realizar un diagnóstico temprano. La medición de marcadores neuroendocrinos específicos y la expresión de receptores para la somatostatina por estos tumores ayudan a confirmar la sospecha clínica. Aun en los casos en los que la cirugía no es curativa, puede disminuir el volumen tumoral y la hipersecreción hormonal, resolver las complicaciones mecánicas, facilitar la respuesta posterior al tratamiento médico y disminuir sus complicaciones, mejorar la calidad de vida y la supervivencia y, por último, identificar marcadores histológicos de mal pronóstico. La expresión en los TEGEP de diversos subtipos de receptores para la somatostatina permite el tratamiento con análogos de somatostatina de acción prolongada como el octreótida LAR y el lanreótido Autogel. Ambos fármacos tienen efecto antisecretor, antiproliferativo (citostático) y citotóxico (apoptosis), producen una mejoría clínica y bioquímica, una estabilización tumoral e incluso, en algunos casos, una regresión tumoral. Además, pueden actuar como vehículo de isótopos radiactivos y permiten una radioterapia específica y eficaz. El interferón-α está indicado en pacientes con resistencia a análogos de somatostatina, especialmente en carcinoides. La quimioterapia debe considerarse bien en TEGEP poco diferenciados o en casos de enfermedad progresiva sin respuesta a otros tratamientos. Siempre debe considerarse el riesgo-beneficio de utilizar tratamientos agresivos en pacientes que, a pesar de tener enfermedad diseminada, suelen tener supervivencias prolongadas.
Palabras clave:
Tumores neuroendocrinos gastroenteropancreáticos
Tratamiento farmacológico
Análogos de somatostatina
Digestive neuroendocrine tumors are a rare clinical entity. Because surgery is the only curative therapy, early diagnosis is required. Clinical suspicion is usually confirmed by specific serological neuroendocrine markers and tissue expression of somatostatin receptors. Even when surgery is not curative, it can reduce tumor volume and hormone hypersecretion, resolve mechanical complications and help subsequent response to medical treatment, improve quality of life and survival, and identify histological markers of poor prognosis.
Expression of different subtypes of somatostatin receptors in digestive neuroendocrine tumors allows treatment with somatostatin analogs such as Octreotide LAR and Lanreotide Autogel. Both treatments are anti-secretory, anti-proliferative (cytostatic) and cytotoxic (apoptosis), induce clinical and biochemical remission, stabilize the tumor, and can even produce tumor regression in some cases. These agents can also play a role as isotope carriers, allowing specific and effective radiotherapy.
Interferon-alpha is indicated in patientswith somatostatin analog resistance, especially in carcinoids. Chemotherapy should be considered in poorly differentiated tumors or in patients with progressive disease and no response to somatostatin analogs and/or interferon. The risk-benefit ratio of using aggressive therapy should always be considered in patients who, despite having disseminated disease, usually have prolonged survival.
Key words:
Gastroenteropancreatic neuroendocrine tumors
Pharmacological treatment
Somatostatin analogs
Full text is only aviable in PDF
Bibliografía
[1.]
G. Rindi, C. Bordi.
Highlights of the biology of endocrine tumours of the gut and pancreas.
Endocr Relat Cancer, 10 (2003), pp. 427-436
[2.]
P.D. Leotlela, A. Jauch, H. Holtgreve-Grez, R.V. Thakker.
Genetics of neuroendocrine and carcinoid tumours.
Endocr Relat Cancer, 10 (2003), pp. 437-450
[3.]
I.M. Modlin, M. Kidd, I. Latich, M.N. Zikusoka, M.D. Shapiro.
Current status of gastrointestinal carcinoids.
Gastroenterology, 128 (2005), pp. 1717-1751
[4.]
W.W. De Herder, E.P. Krenning, C.H.J. Van Eijck, S.W.J. Lamberts.
Considerations concerning a tailored, individualizad therapeutic management of patients with neuroendocrine tumours of the gastrointestinal tract and pancreas.
Endocr Relat Cancer, 11 (2004), pp. 19-34
[5.]
K. Öberg, L. Kvols, M. Caplin, G. Delle Fave, W. De Herder, G. Rindi, et al.
Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumours of the gastroenteropancreatic system.
Ann Oncol, 15 (2004), pp. 966-973
[6.]
G. Rindi, C. Bordi, S. Rappel, S. La Rosa, M. Stolte, E. Solcia.
Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior.
World J Surg, 20 (1996), pp. 168-172
[7.]
R. Sutton, H.E. Doran, E.M. Williams, J. Vora, S. Vinjamuri, J. Evans, et al.
Surgery for midgut carcinoid.
Endocr Relat Cancer, 10 (2003), pp. 469-481
[8.]
R. Sutcliffe, D. Maguire, J. Ramage, M. Rela, N. Heaton.
Management of neuroendocrine liver metastases.
Am J Surg, 187 (2004), pp. 39-46
[9.]
W.W. De Herder, S.W.J. Lamberts.
Gut endocrine tumours.
Best Pract Res Clin Endocrinol Metab, 18 (2004), pp. 477-495
[10.]
J.M. Sarmiento, G. Heywood, J. Rubin, D.M. Ilstrup, D.M. Nagorney, F.G. Que, et al.
Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival.
J Am Coll Surg, 197 (2003), pp. 29-37
[11.]
G.A. Kaltsas, D. Papadogias, P. Makras, A.B. Grossman.
Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues.
Endocr Relat Cancer, 12 (2005), pp. 683-699
[12.]
G.A. Kaltsas, G.M. Besser, A.B. Grossmasn.
The diagnosis and medical management of advanced neuroendocrine tumors.
Endocr Rev, 25 (2004), pp. 458-511
[13.]
G. Kaltsas, J.J. Mukherjee, P.N. Plowman, A.B. Grossman.
The role of chemotherapy in the nonsurgical management of malignant neuroendocrine tumours.
Clin Endocrinol (Oxf), 55 (2001), pp. 575-587
[14.]
P. Brazeau, W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, et al.
Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone.
Science, 179 (1973), pp. 77-79
[15.]
Y.C. Patel.
Somatostatin and its receptor family.
Front Neuroendocrinol, 20 (1999), pp. 157-198
[16.]
L.K. Kvols, J.C. Reubi, U. Horisberger, C.G. Moertel, J. Rubin, J.W. Charboneau.
The presence of somatostatin receptors in malignant neuroendocrine tumors tissue predicts responsiveness to octreotide.
Yale J Biol Med, 65 (1992), pp. 505-518
[17.]
S. Krantic, I. Goddard, A. Saveanu, N. Giannetti, J. Fombonne, A. Cardoso, et al.
Novel modalities of somatostatin actions.
Eur J Endocrinol, 151 (2004), pp. 643-655
[18.]
M. Rocheville, D.C. Lange, U. Kumar, R. Sasi, R.C. Patel, Y.C. Patel.
Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers.
J Biol Chem, 275 (2000), pp. 7862-7869
[19.]
V.M. Macaulay.
Insulin-like growth factors and cancer.
Br J Cancer, 65 (1992), pp. 311-320
[20.]
N. García de la Torre, J.A. Wass, H.E. Turner.
Antiangiogenic effects of somatostatin analogues.
Clin Endocrinol (Oxf), 57 (2002), pp. 425-441
[21.]
K. Sharma, Y.C. Patel, C.B. Srikant.
C-terminal region of human somatostatin receptor required for induction G1.
Cell Cycle Arrest Mol Endocrinol, 13 (1999), pp. 82-90
[22.]
V.A. Dalm, P.M. Van Hagen, P.M. Van Koetsveld, A.W. Langerak, A.J. Van der Lely, S.W. Lamberts, et al.
Cortistatin rather than somatostatin as a potential endogenous ligand for somatostatin receptors in the human immune system.
J Clin Endocrinol Metab, 88 (2003), pp. 270-276
[23.]
S.W.J. Lamberts, A.J. Van der Lely, L.J. Hofland.
New somatostatin analogs: will they fulfill old promises?.
Eur J Endocrinol, 146 (2002), pp. 701-705
[24.]
A. Saveanu, G. Gunz, H. Dufour, P. Caron, F. Fina, L. Ouafik, et al.
BIM-23244, a somatostatin receptor subtype 2-and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas.
J Clin Endocrinol Metab, 86 (2001), pp. 140-145
[25.]
P. Jaquet, G. Gunz, A. Saveanu, A. Barlier, H. Dufour, J. Taylor, et al.
BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide.
J Endocrinol Invest., 28 (2005), pp. 21-27
[26.]
J.P. Hannon, C. Nunn, B. Stolz, C. Bruns, G. Weckbecker, I. Lewis, et al.
Drug design at peptide receptors: somatostatin receptor ligands.
J Mol Neurosci, 18 (2002), pp. 15-27
[27.]
A. Saneanu, E. Lavaque, G. Gunz, A. Barlier, S. Kim, J.E. Taylor, et al.
Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells.
J Clin Endocrinol Metab, 87 (2002), pp. 5545-5552
[28.]
L. Yang, S.C. Berk, S.P. Rohrer, R.T. Mosley, L. Guo, D.J. Underwood, et al.
Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2.
Proc Natl Acad Sci USA, 95 (1998), pp. 10836-10841
[29.]
C. Nelson-Piercy, P.J. Hammond, M.E. Gwilliam, N. Khandan-Nia, M.J. Myers, M.A. Ghatei, et al.
Effect of a new oral somatostatin analog (SDZ CO 611) on gastric emptying, mouth to cecum transit time, and pancreatic and gut hormone release in normal male subjects.
J Clin Endocrinol Metab, 78 (1994), pp. 329-336
[30.]
J.C. Reubi, J.C. Schaer, S. Wenger, C. Hoeger, J. Erchegyi, B. Waser, et al.
SST3-selective potent peptidic somatostatin receptor antagonists.
Proc Natl Acad Sci USA, 97 (2000), pp. 13973-13978
[31.]
T. Delaunoit, J. Rubin, F. Neczyporenko, C. Erlichman, T.J. Hobday.
Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors.
Mayo Clin Proc, 80 (2005), pp. 502-506
[32.]
I. Virgolini, T. Traub-Weidinger, C. Decristoforo.
Nuclear medicine in the detection and management of pancreatic islet-cell tumours.
Best Pract Res Clin Endocrinol Metab, 19 (2005), pp. 213-227
[33.]
A.G. Plöckinger, B.R. Rindi, C.B. Arnold, D.E.P. Eriksson, E. Krenning, W.W. De Herder, et al.
Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours.
Neuroendocrinology, 80 (2004), pp. 394-424
[34.]
H. Imam, B. Eriksson, A. Lukinius, E.T. Janson, P.G. Lindgren, E. Wilander, et al.
Induction of apoptosis in neuroendocrine tumors of the digestive system during treatment with somatostatin analogs.
Acta Oncol, 36 (1997), pp. 607-614
[35.]
W.W. De Herder, L.J. Hofland, A.J. Van der Lely, S.W.J. Lamberts.
Somatostatin receptors in gastroenteropancreatic neuroendocrine tumours.
Endocr Relat Cancer, 10 (2003), pp. 451-458
[36.]
L.J. Hofland, S.W.J. Lamberts.
The pathophysiological consequences of somatostatin receptor internalization and resistance.
Endocr Rev, 24 (2003), pp. 28-47
[37.]
F.R. Nobels, D.J. Kwekkeboom, W. Coopmans, C.H. Schoenmakers, J. Lindemans, W.W. De Herder, et al.
Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones.
J Clin Endocrinol Metab, 82 (1997), pp. 2622-2628
[38.]
T. Aparicio, M. Ducreux, E. Baudin, J.C. Sabourin, T. De Baere, E. Mitry, et al.
Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours.
Eur J Cancer, 37 (2001), pp. 1014-1019
[39.]
R.T. Jensen.
Carcinoid and pancreatic endocrine tumors: recent advances in molecular pathogenesis, localization, and treatment.
Curr Opin Oncol, 12 (2000), pp. 368-377
[40.]
P.F. Quaedvlieg, O. Visser, C.B. Lamers, M.L. Janssen-Heijen, B.G. Taal.
Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2,391 patients.
Ann Oncol, 12 (2001), pp. 1295-1300
[41.]
S. Ricci, A. Antonuzzo, L. Galli, C. Orlandini, M. Ferdeghini, G. Boni, et al.
Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors.
Am J Clin Oncol, 23 (2000), pp. 412-415
[42.]
S. Ricci, A. Antonuzzo, L. Galli, M. Ferdeghini, L. Bodei, C. Orlandini, et al.
Octreotide acetate long-acting release in patients with metastatic neuroendocrine tumors pretreated with lanreotide.
Ann Oncol, 11 (2000), pp. 1127-1130
[43.]
M. Raderer, A. Kurtaran, W. Scheithauer, W. Fiebiger, G. Weinlaender, G. Oberhuber.
Different response to the long-acting somatostatin analogues lanreotide and octreotide in a patient with a malignant carcinoid.
Oncology, 60 (2001), pp. 141-145
[44.]
L. Dogliotti, M. Tampellini, M. Stivanello, G. Gorzegno, L. Fabiani.
The clinical management of neuroendocrine tumors with long-acting repeatable (LAR) octreotide: comparison with standard subcutaneous octreotide therapy.
Ann Oncol, 12 (2001), pp. S105-S109
[45.]
J. Van der Hoek, W.W. De Herder, R.A. Feelders, A.J. Van der Lely, P. Uitterlinden, V. Boerlin, et al.
A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients.
J Clin Endocrinol Metab, 89 (2004), pp. 638-645
[46.]
J. Van der Hoek, A.J. Van der Lelij, R.A. Feelders, W.W. De Herder, P. Uitterlinden, K.W. Poon, et al.
The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients.
Clin Endocrinol (Oxf), 63 (2005), pp. 176-184
[47.]
T. Stroh, A.C. Jackson, P. Sarret, C. Dal Farra, J.P. Vincent, H.J. Kreienkamp, et al.
Intracellular dynamics of sst5 receptors in transfected COS-7 cells: maintenance of cell surface receptors during ligand-induced endocytosis.
Endocrinology, 141 (2000), pp. 354-365
[48.]
R. Arnold, M. Frank.
Gastrointestinal endocrine tumours: medical management.
Bail Clin Gastroenterol, 10 (1996), pp. 737-759
[49.]
S.W. Lamberts, A.J. Van der Lely, W.W. De Herder, L.J. Hofland.
Octreotide.
N Engl J Med, 334 (1996), pp. 246-254
[50.]
K. Oberg, K. Funa, G. Alm.
Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome.
N Engl J Med, 309 (1983), pp. 129-133
[51.]
K. Oberg.
State of the art and future prospects in the management of neuroendocrine tumors.
Q J Nucl Med, 44 (2000), pp. 3-12
[52.]
K. Oberg.
Interferon in the management of neuroendocrine GEP-tumors: a review.
Digestion, 62 (2000), pp. 92-97
[53.]
K. Oberg.
Chemotherapy and biotherapy in the treatment of neuroendocrine tumours.
Ann Oncol, 12 (2001), pp. S111-S114
[54.]
B. Ericsson, K. Oberg.
An update of the medical treatment of malignant endocrine pancreatic tumors.
Act Oncol, 32 (1993), pp. 203-208
[55.]
C.G. Moertel, J. Rubin, L.K. Kvols.
Therapy of metastatic carcinoid tumor and the malignant carcinoid syndrome with recombinant leukocyte A interferon.
J Clin Oncol, 7 (1989), pp. 865-868
[57.]
S. Faiss, U.F. Pape, M. Bohmig, Y. Dorffel, U. Mansmann, W. Golder, et al.
International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors–the International Lanreotide and Interferon Alfa Study Group.
J Clin Oncol, 21 (2003), pp. 2689-2696
[58.]
R. Arnold, A. Rinke, K.J. Klose, H.H. Muller, M. Wied, K. Zamzow, et al.
Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial.
Clin Gastroenterol Hepatol, 3 (2005), pp. 761-771
[59.]
C.G. Moertel, L.K. Kvols, M.J. O’Connell, J. Rubin.
Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms.
Cancer, 68 (1991), pp. 227-232
[60.]
E. Mitry, E. Baudin, M. Ducreux, J.C. Sabourin, P. Rufie, T. Aparicio, et al.
Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin.
Br J Cancer, 81 (1999), pp. 1351-1355
[61.]
G.M. Mavligit, R.E. Pollock, H.L. Evans, S. Wallace.
Durable hepatic tumor regression after arterial chemoembolization-infusion in patients with islet cell carcinoma of the pancreas metastatic to the liver.
Cancer, 72 (1993), pp. 375-380
[62.]
K. Oberg.
Advances in chemotherapy and biotherapy of endocrine tumors.
Curr Opin Oncol, 10 (1998), pp. 58-65
[63.]
K. Oberg.
Neuroendocrine gastrointestinal tumors-a condensed overview of diagnosis and treatment.
Ann Oncol, 10 (1999), pp. S3-S8
[64.]
R.J. Pelley, R.M. Bukowski.
Recent advances in systemic therapy for gastrointestinal neuroendocrine tumors.
Curr Opin Oncol, 11 (1999), pp. 32-37
Copyright © 2007. Sociedad Española de Endocrinología y Nutrición