Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome

Abstract

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.

Urinary 5-Hydroxyindolacetic Acid Measurements in Patients with Neuroendocrine Tumor-Related Carcinoid Syndrome: State of the Art

“…The first-line therapy for CS is represented by somatostatin analogs (SSAs) [ 28 , 29 , 30 , 31 ], which bind to somatostatin receptors (SSTRs) and inhibit tumor secretion, ultimately, improving symptoms in up to 70% of CS patients and decreasing 24u5HIAA levels in approximately 46%.…”

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis

“…Furthermore, in refractory CS, SSA administration should never be discontinued, but for symptom control, additional therapies with telotristat ethyl as an add-on and/or PRRT should be initiated. Interferon-a is another option as an add-on to refractory CS treatment for patients on SSAs but can also be administered as first-line treatment in SSTR-negative patients [ 65 ]. For PRRT treatment and other local invasive treatments, short-acting SSAs should be used on top of the established long-acting SSA therapy to avoid a carcinoid crisis [ 6 , 11 ].…”

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

“…The first approach is represented by the use of somatostatin analogues (octreotide, lanreotide and pasireotide), which provide rapid symptom relief [ 13 ]. Telotristat ethyl, a tryptophan hydroxylase (TPH) inhibitor, the rate-limiting enzyme in 5-HT biosynthesis, represents a novel treatment in patients with CS [ 14 ]. On the other hand, approaches aimed at controlling tumor growth, such as chemotherapy, type I interferons, peptide receptor radionuclide therapy, tyrosine kinase inhibitors or liver-directed therapies (radiofrequency ablation, cryoablation, transarterial embolization, chemoembolization and radioembolization), give a more delayed mode of action in symptoms control (with the exception of liver-directed therapies) [ 15 , 16 ].…”