Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome.
alpha-interferon
carcinoid syndrome
medical therapy
neuroendocrine tumors
somatostatin analogues
Journal
Journal of neuroendocrinology
ISSN: 1365-2826
Titre abrégé: J Neuroendocrinol
Pays: United States
ID NLM: 8913461
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
06
04
2022
received:
18
02
2022
accepted:
31
05
2022
pubmed:
8
7
2022
medline:
30
7
2022
entrez:
7
7
2022
Statut:
ppublish
Résumé
This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.
Substances chimiques
Somatostatin
51110-01-1
Tryptophan Hydroxylase
EC 1.14.16.4
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13174Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022 British Society for Neuroendocrinology.
Références
Dimitriadis GK, Weickert MO, Randeva HS, Kaltsas G, Grossman A. Medical management of secretory syndromes related to gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2016;23(9):R423-R436.
Ransom W. A case of primary carcinoma of the ileum. The Lancet. 1890;136(3507):1020-1023.
Koumarianou A, Alexandraki KI, Wallin G, Kaltsas G, Daskalakis K. Pathogenesis and clinical Management of Mesenteric Fibrosis in small intestinal Neuroendocine neoplasms: a systematic review. J Clin Med. 2020;9(6): [PMC7357094].
Koffas A, Toumpanakis C. Managing carcinoid heart disease in patients with neuroendocrine tumors. Ann Endocrinol (Paris). 2020.
Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the Management of Patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153-171. [PMC4849884].
Feldman JM, Jones RS. Carcinoid syndrome from gastrointestinal carcinoids without liver metastasis. Ann Surg. 1982;196(1):33-37. [PMC1352493].
Preda VA, Chitoni M, Talbot D, Reed N, Grossman AB. Primary ovarian carcinoid: extensive clinical experience with an Underrecognized uncommon entity. Int J Gynecol Cancer. 2018;28(3):466-471.
Halperin DM, Shen C, Dasari A, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017;18:525-534.
Maroun J, Kocha W, Kvols L, et al. Guidelines for the diagnosis and management of carcinoid tumours. Part 1: the gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group. Curr Oncol. 2006;13(2):67-76. [PMC1891174].
de Mestier L, Savagner F, Brixi H, et al. Plasmatic and urinary 5-hydroxyindolacetic acid measurements in patients with midgut neuroendocrine tumors: a GTE study. J Clin Endocrinol Metab. 2020;106:1673-1682.
Wedin M, Mehta S, Angeras-Kraftling J, Wallin G, Daskalakis K. The role of serum 5-HIAA as a predictor of progression and an alternative to 24-h urine 5-HIAA in well-differentiated neuroendocrine neoplasms. Biology (Basel). 2021;10(2): [PMC7909826].
O'Toole D, Grossman A, Gross D, et al. ENETS consensus guidelines for the standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology. 2009;90(2):194-202.
Pavel M, Oberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860.
Reichlin S. Somatostatin. N Engl J Med. 1983;309(24):1495-1501.
Kvols LK, Reubi JC, Horisberger U, Moertel CG, Rubin J, Charboneau JW. The presence of somatostatin receptors in malignant neuroendocrine tumor tissue predicts responsiveness to octreotide. Yale J Biol Med. 1992;65(5):505-518. discussion 531-506.[PMC2589749].
Bauer W, Briner U, Doepfner W, et al. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 1982;31(11):1133-1140.
Kvols LK, Reubi JC. Metastatic carcinoid tumors and the malignant carcinoid syndrome. Acta Oncol. 1993;32(2):197-201.
Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986;315(11):663-666.
Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17(2):600-606.
Murphy WA, Lance VA, Moreau S, Moreau JP, Coy DH. Inhibition of rat prostate tumor growth by an octapeptide analog of somatostatin. Life Sci. 1987;40(26):2515-2522.
Ruszniewski P, Ducreux M, Chayvialle JA, et al. Treatment of the carcinoid syndrome with the longacting somatostatin analogue lanreotide: a prospective study in 39 patients. Gut. 1996;39(2):279-283. [PMC1383312].
Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA. * ESG. Evaluation of Lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment (Elect): a randomized, double-blind, placebo-controlled trial. Endocr Pract. 2016;22(9):1068-1080.
Wolin EM, Jarzab B, Eriksson B, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug des Devel Ther. 2015;9:5075-5086. [PMC4562767].
Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31(2):169-188.
Rinke A, Muller HH, Schade-Brittinger C, et al. 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. 2009;27(28):4656-4663.
Rinke A, Wittenberg M, Schade-Brittinger C, et al. 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 (PROMID):results of long-term survival. Neuroendocrinology. 2017;104(1):26-32.
Toumpanakis C, Garland J, Marelli L, et al. Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR. Aliment Pharmacol Ther. 2009;30(7):733-740.
Pavel ME, Hainsworth JD, Baudin E, et al. 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. 2011;378(9808):2005-2012.
Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for Midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135.
Alexandraki KI, Daskalakis K, Tsoli M, Grossman AB, Kaltsas GA. Endocrinological toxicity secondary to treatment of Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Trends Endocrinol Metab. 2020;31(3):239-255.
Bornschein J, Drozdov I, Malfertheiner P. Octreotide LAR: safety and tolerability issues. Expert Opin Drug Saf. 2009;8(6):755-768.
Pavel M, Valle JW, Eriksson B, et al. ENETS consensus guidelines for the standards of Care in Neuroendocrine Neoplasms: systemic therapy - biotherapy and novel targeted agents. Neuroendocrinology. 2017;105(3):266-280.
Saif MW, Larson H, Kaley K, Shaib W. Chronic octreotide therapy can induce pancreatic insufficiency: a common but under-recognized adverse effect. Expert Opin Drug Saf. 2010;9(6):867-873.
Pavel M, Borson-Chazot F, Cailleux A, et al. Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study. Cancer Chemother Pharmacol. 2019;83(2):375-385.
Ruszniewski P, Ish-Shalom S, Wymenga M, et al. Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide. Neuroendocrinology. 2004;80(4):244-251.
Khan MS, El-Khouly F, Davies P, Toumpanakis C, Caplin ME. Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline autogel). Aliment Pharmacol Ther. 2011;34(2):235-242.
Ruszniewski P, Valle JW, Lombard-Bohas C, et al. Patient-reported outcomes with lanreotide autogel/depot for carcinoid syndrome: an international observational study. Dig Liver Dis. 2016;48(5):552-558.
Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224-233.
Alvarez-Escola C, Cardenas-Salas JJ, Pelegrina B, Sanz-Valtierra A, Lecumberri B. Severe scalp hair loss in a female patient with acromegaly treated with lanreotide autogel after unsuccessful surgery. Clin Case Rep. 2015;3(11):945-948. [PMC4641480].
Jonsson A, Manhem P. Octreotide and loss of scalp hair. Ann Intern Med. 1991;115(11):913.
O'Toole D, Ducreux M, Bommelaer G, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer. 2000;88(4):770-776.
Riechelmann RP, Pereira AA, Rego JF, Costa FP. Refractory carcinoid syndrome: a review of treatment options. Ther Adv Med Oncol. 2017;9(2):127-137. [PMC5298401].
Strosberg J, Weber J, Feldman M, Goldman J, Almhanna K, Kvols L. Above-label doses of octreotide-LAR in patients with metastatic small intestinal carcinoid tumors. Gastrointest Cancer Res. 2013;6(3):81-85. [PMC3737510].
Albertelli M, Campana D, Faggiano A, et al. Safety and efficacy of high doses Lanreotide treatment in patients with progressive neuroendocrine tumors: results from a prospective phase II trial. Meeting abstract 1929. 14th annual ENETS conference for the diagnosis and treatment of neuroendocrine tumor disease. Barcelona, Spain. Neuroendocrinology. 2017;105(S1):190-338.
Pavel M, Ćwikła JB, Lombard-Bohas C, et al. 1162MO efficacy and safety of lanreotide autogel (LAN) 120 mg every 14 days in progressive pancreatic or midgut neuroendocrine tumours (NETs): CLARINET FORTE study results. Ann Oncol. 2020;31:S773.
Gresser I, Tovey MG. Antitumor effects of interferon. Biochim Biophys Acta. 1978;516(2):231-247.
Rosewicz S, Detjen K, Scholz A, von Marschall Z. Interferon-alpha: regulatory effects on cell cycle and angiogenesis. Neuroendocrinology. 2004;80(Suppl 1):85-93.
Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983;309(3):129-133.
Moertel CG, Rubin J, Kvols LK. Therapy of metastatic carcinoid tumor and the malignant carcinoid syndrome with recombinant leukocyte a interferon. J Clin Oncol. 1989;7(7):865-868.
Oberg K, Eriksson B. The role of interferons in the management of carcinoid tumours. Br J Haematol. 1991;79(Suppl 1):74-77.
Bajetta E, Zilembo N, Di Bartolomeo M, et al. Treatment of metastatic carcinoids and other neuroendocrine tumors with recombinant interferon-alpha-2a. A study by the Italian trials in medical oncology group. Cancer. 1993;72(10):3099-3105.
Oberg K, Norheim I, Lind E, et al. Treatment of malignant carcinoid tumors with human leukocyte interferon: long-term results. Cancer Treat Rep. 1986;70(11):1297-1304.
Di Bartolomeo M, Bajetta E, Zilembo N, et al. Treatment of carcinoid syndrome with recombinant interferon alpha-2a. Acta Oncol. 1993;32(2):235-238.
Russo S, Boon JC, Kema IP, et al. Patients with carcinoid syndrome exhibit symptoms of aggressive impulse dysregulation. Psychosom Med. 2004;66(3):422-425.
Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-229.
Arnold R, Rinke A, Klose KJ, et al. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol. 2005;3(8):761-771.
Faiss S, Pape UF, Bohmig M, et al. 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. 2003;21(14):2689-2696.
Pavel ME, Baum U, Hahn EG, Schuppan D, Lohmann T. Efficacy and tolerability of pegylated IFN-alpha in patients with neuroendocrine gastroenteropancreatic carcinomas. J Interferon Cytok Res. 2006;26(1):8-13.
Yao JC, Guthrie KA, Moran C, et al. Phase III prospective randomized comparison trial of depot octreotide plus interferon Alfa-2b versus depot octreotide plus bevacizumab in patients with advanced carcinoid tumors: SWOG S0518. J Clin Oncol. 2017;35(15):1695-1703. [PMC5455764].
Dahan L, Bonnetain F, Rougier P, et al. Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC-FFCD 9710. Endocr Relat Cancer. 2009;16(4):1351-1361.
Lapuerta P, Zambrowicz B, Flemming D, Wheeler D, Sands A. Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid syndrome. Clin Investig (London). 2015;5(5):447-456.
Kulke MH, O'Dorisio T, Phan A, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014;21(5):705-714. [PMC4295770].
Pavel M, Horsch D, Caplin M, et al. Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial. J Clin Endocrinol Metab. 2015;100(4):1511-1519.
Kulke MH, Horsch D, Caplin ME, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol. 2017;35(1):14-23.
Pavel M, Gross D, Benavent M, et al. Efficacy and safety results of telotristat ethyl in patients with carcinoid syndrome during the double-blind treatment period of the TELECAST phase 3 clinical trial. NANETS; 30th Sept-1st Oct 2016, 2016; Jackson, Wyoming.
Horsch D, Anthony L, Gross DJ, et al. Long-term treatment with Telotristat ethyl in patients with carcinoid syndrome symptoms: results from the TELEPATH study. Neuroendocrinology. 2021;112:298-310.
Dillon JS, Kulke MH, Horsch D, et al. Time to sustained improvement in bowel movement frequency with Telotristat ethyl: analyses of phase III studies in carcinoid syndrome. J Gastrointest Cancer. 2021;52(1):212-221. [PMC7714089].
Morse MA, Liu E, Joish VN, et al. Antiproliferative effects of Telotristat ethyl in patients with neuroendocrine tumors: The TELEACE Real-World Chart Review Study. Cancer Manag Res. 2020;12:6607-6614.[PMC7402667].
Strosberg J, Joish VN, Giacalone S, et al. TELEPRO: patient-reported carcinoid syndrome symptom improvement following initiation of Telotristat ethyl in the real world. Oncologist. 2019;24(11):1446-1452. [PMC6853091].
Bainbridge HE, Larbi E, Middleton G. Symptomatic control of neuroendocrine tumours with everolimus. Hormones Cancer. 2015;6(5-6):254-259.
Capdevila J, Diez Miranda I, Obiols G, Tabernero J. Control of carcinoid syndrome with everolimus. Ann Oncol. 2011;22(1):237-239.
Kvols LK, Oberg KE, O'Dorisio TM, et al. Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study. Endocr Relat Cancer. 2012;19(5):657-666.
Kulke MH, Ruszniewski P, Van Cutsem E, et al. A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. Ann Oncol. 2017;28(6):1309-1315. [PMC7360140].
Baudin E, Berruti A, Giuliano M, et al. First long-term results on efficacy and safety of long-acting pasireotide in combination with everolimus in patients with advanced carcinoids (NET) of the lung/thymus: phase II LUNA trial. J Clin Oncol. 2021;39(15_suppl): 8574-8574.
Schmid HA, Brueggen J. Effects of somatostatin analogs on glucose homeostasis in rats. J Endocrinol. 2012;212(1):49-60.
Sheppard M, Bronstein MD, Freda P, et al. Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, phase III study. Pituitary. 2015;18(3):385-394. [PMC4424273].
Wan M, Ding L, Wang D, Han J, Gao P. Serotonin: a potent immune cell modulator in autoimmune diseases. Front Immunol. 2020;11:186 [PMC7026253].
Talley NJ. Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. Aliment Pharmacol Ther. 1992;6(3):273-289.
Wymenga AN, de Vries EG, Leijsma MK, Kema IP, Kleibeuker JH. Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome. Eur J Cancer. 1998;34(8):1293-1294.
Singh S, Asa SL, Dey C, et al. Diagnosis and management of gastrointestinal neuroendocrine tumors: an evidence-based Canadian consensus. Cancer Treat Rev. 2016;47:32-45.
Pavel M, Baudin E, Couvelard A, et al. ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012;95(2):157-176.
Graff-Baker AN, Sauer DA, Pommier SJ, Pommier RF. Expanded criteria for carcinoid liver debulking: maintaining survival and increasing the number of eligible patients. Surgery. 2014;156(6):1369-1376. discussion 1376-1367.
Zandee WT, Brabander T, Blazevic A, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for symptomatic control of refractory carcinoid syndrome. J Clin Endocrinol Metab. 2021;106(9):e3665-e3672. [PMC8372632].
Halperin DM, Huynh L, Beaumont JL, et al. Assessment of change in quality of life, carcinoid syndrome symptoms and healthcare resource utilization in patients with carcinoid syndrome. BMC Cancer. 2019;19(1):274 [PMC6437890].
Halperin DM, Huynh L, Beaumont JL, et al. Impact of carcinoid syndrome symptoms and long-term use of somatostatin analogs on quality of life in patients with carcinoid syndrome: a survey study. Medicine (Baltimore). 2018;97(47):e13390 [PMC6392719].
Pearman TP, Beaumont JL, Cella D, Neary MP, Yao J. Health-related quality of life in patients with neuroendocrine tumors: an investigation of treatment type, disease status, and symptom burden. Support Care Cancer. 2016;24(9):3695-3703.
Dasari A, Joish VN, Perez-Olle R, Dharba S, Balaji K, Halperin DM. Direct costs of carcinoid syndrome diarrhea among adults in the United States. World J Gastroenterol. 2019;25(47):6857-6865. [PMC6931008].
Shaunfield S, Webster KA, Kaiser K, et al. Development of the functional assessment of cancer therapy-carcinoid syndrome symptom index (FACT-CSI). Neuroendocrinology. 2020;111:850-862.
Isenberg-Grzeda E, MacGregor M, Bergel A, et al. Antidepressants appear safe in patients with carcinoid tumor: results of a retrospective review. Eur J Surg Oncol. 2018;44(6):744-749. [PMC5970966].
Shi DD, Yuppa DP, Dutton T, et al. Retrospective review of serotonergic medication tolerability in patients with neuroendocrine tumors with biochemically proven carcinoid syndrome. Cancer. 2017;123(14):2735-2742.
Artale S, Barzaghi S, Grillo N, et al. role of diet in the management of carcinoid syndrome: clinical recommendations for nutrition in patients with neuroendocrine tumors. Nutr Cancer. 2020;1-10:2-11.
Martini C, Gamper EM, Wintner L, et al. Systematic review reveals lack of quality in reporting health-related quality of life in patients with gastroenteropancreatic neuroendocrine tumours. Health Qual Life Outcomes. 2016;14(1):127 [PMC5018190].