Carcinoid Syndrome: Updates and Review of Current Therapy
Carcinoid syndrome (CS) is a complex disorder caused by functional neuroendocrine tumors (NETs). This debilitating disease is characterized by hyper-secretion of biologically active substances eliciting major hormonal symptoms burden and fibrotic changes that are often challenging for management. There have been a number of insights that have substantially advanced treatments since the introduction of somatostatin analogs (SSAs). Second-line treatments are needed in a substantial proportion of patients with advanced disease that have uncontrolled hormone secretion on the highest labeled doses of SSAs. International guidelines suggest several available options including dose escalation of SSAs, interferon alpha, everolimus, radionuclide therapy, liver-directed therapies, and the novel tryptophan hydroxylase 1 inhibitor, telotristat ethyl. The clear preference of one second-line therapy over the other is not stated since their relative and long-term efficacy are largely unknown, and standardized approach of hormonal response assessment is lacking in the literature. In the clinical setting, the treatment of CS is guided in conjunction with patients’ performance status, tumor origin, grade, stage, and growth rate, with regard to both anti-hormonal, as well as anti-proliferative effect. There is an unmet need for further well-designed randomized placebo-controlled and head-to-head studies that systematically assess CS symptom control and biochemical response following a specific intervention.
KeywordsTreatment Neuroendocrine Carcinoid syndrome
Compliance with Ethical Standards
Conflict of Interest
Kira Oleinikov, Shani Avniel-Polak, David J. Gross, and Simona Grozinsky-Glasberg declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
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- 1.Jensen RT, Norton JA, Oberg K. In: Feldman M, Friedman LS, Brandt LJ, editors. Neuroendocrine tumors in Sleisenger and Fordtran’s gastrointestinal and liver diseases, edn tenth. Philadelphia: Elsevier Saunders; 2016. p. 501–41.Google Scholar
- 4.• Halperin DM, Shen C, Dasari A, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017;18:525–34. Recent extensive study on the frequency and epidiomology of carcinoid syndrome. A population-based analysis focusing on epidemiology, clinical characteristics and survival of carcinoid syndrome patients.PubMedPubMedCentralCrossRefGoogle Scholar
- 5.Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017.Google Scholar
- 15.Laval VR, Pavel M, Steffen IG, Baur AD, Dilz LM, Fischer C, et al. Mesenteric fibrosis in midgut neuroendocrine tumors: functionality and radiological features. Neuroendocrinology. 2018;106(2):139–47.Google Scholar
- 18.•• Davar J, Connolly HM, Caplin ME, Pavel M, Zacks J, Bhattacharyya S, et al. Diagnosing and managing carcinoid heart disease in patients with neuroendocrine tumors: an expert statement. J Am Coll Cardiol. 2017;69(10):1288–304. A multidisciplinary consensus statement on management of carcinoid heart disease based on an evidence-based review of the published data and on the expert opinion.Google Scholar
- 20.Pavel M, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, et al. 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. 2016;103(2):172–85.PubMedCrossRefGoogle Scholar
- 25.Jin XF, Spampatti MP, Spitzweg C, Auernhammer CJ. Supportive therapy in gastroenteropancreatic neuroendocrine tumors: often forgotten but important. Rev Endocr Metab Disord. 2018;1:1–4.Google Scholar
- 34.Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, 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):4656–63.PubMedCrossRefGoogle Scholar
- 35.Arnold R, Wittenberg M, Rinke A, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, Mueller HH, PROMID Study Group. 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 on long-term survival.Google Scholar
- 37.• Hofland J, Martínez AD, Zandee WT, de Herder WW. Management of carcinoid syndrome: a systematic review and meta-analysis. Endocr Relat Cancer. 2019;1 A literature review and meta-analysis regarding pharmacological therapies in CS, focusing on treatment efficacy in terms of symptomatic and biochemical response.Google Scholar
- 38.Strosberg JR, Benson AB, Huynh L, Duh MS, Goldman J, Sahai V, et al. Clinical benefits of above-standard dose of octreotide LAR in patients with neuroendocrine tumors for control of carcinoid syndrome symptoms: a multicenter retrospective chart review study. Oncologist. 2014;19(9):930–6.PubMedPubMedCentralCrossRefGoogle Scholar
- 40.Ferolla P, Faggiano A, Grimaldi F, Ferone D, Scarpelli G, Ramundo V, et al. Shortened interval of long-acting octreotide administration is effective in patients with well-differentiated neuroendocrine carcinomas in progression on standard doses. J Endocrinol Investig. 2012;35(3):326–31.Google Scholar
- 41.O’Toole D, Ducreux M, Bommelaer G, Wemeau JL, Bouché O, Catus F, 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):770–6.Google Scholar
- 42.Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, 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 Dev Ther. 2015;9:5075.Google Scholar
- 53.European Medicines Agency. Xermelo, INN-Telotristat. Summary of product characteristics. Available from: https://www.ema.europa.eu/docs/en_GB/document./WC500237107.pdf. Accessed January, 2019.
- 56.•• Pavel M, Gross DJ, Benavent M, Perros P, Srirajaskanthan R, Warner RR, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocr Relat Cancer. 2018;25(3):309–22 A randomized, controlled phase 3 study, assessing safety and efficacy of telotristat ethyl in CS symptomatic patients.PubMedPubMedCentralCrossRefGoogle Scholar
- 60.Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, 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):2005–12.CrossRefGoogle Scholar
- 64.•• Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35 A randomized, controlled trial, evaluating the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced midgut NETs, who progressed under SSA treatment.Google Scholar
- 74.Nazario J, Gupta S. Transarterial liver-directed therapies of neuroendocrine hepatic metastases. Semin Oncol. 2010;37(2):118–26 WB Saunders.Google Scholar
- 78.Keskin O, Yalcin S. Carcinoid crisis in the intensive care unit. Oncol Crit Care. 2019:1–7.Google Scholar