Opportunities to Improve Symptom Control with Somatostatin Congeners in GEP-NETs: A Review of Key Issues

Abstract

Octreotide acetate (octreotide) is the most prescribed and most studied somatostatin congener, or analog, for gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) and carcinoid syndrome, the latter of which may be characterized by debilitating diarrhea and flushing. Approved in the U.S. more than 30 years ago, octreotide is widely used to control the symptoms of carcinoid syndrome and has been shown to demonstrate antiproliferative activity. The two formulations available in the U.S. include a subcutaneous immediate‐release (IR) injection introduced in 1989 and a long‐acting repeatable (LAR) intramuscular injection approved in 1999. Lanreotide depot (lanreotide), a more recent somatostatin congener, has been available in the U.S. since 2014. Despite widespread use of octreotide LAR, several key challenges exist with the current depot‐based treatment paradigm. Studies indicate that LAR formulations are associated with continued unmet patient needs, owing in part to a loss of bioactivity over time that may necessitate progressive supplemental treatment with IR octreotide to adequately control symptoms. Clinicians should understand the key differences in the pharmacokinetic profiles of the LAR and IR formulations that may contribute to bioactivity loss and somatostatin receptor desensitization. In addition, there is a need to re‐evaluate the role of IR octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms. The purpose of this review is to explore all these issues and to re‐establish a rationale for the IR formulation, particularly with respect to novel use cases and its use during the COVID‐19 pandemic. Implications for Practice There is a need to re‐evaluate the role of immediate‐release octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms.

Prescribing Characteristics of Octreotide Immediate-Release and Long-Acting Release in Patients with Neuroendocrine Tumors

“…Consequently, IR had unique advantage in combination with LAR to provide consistent bioavailability and better control CS symptoms. 1 …”

“…Neuroendocrine tumors (NETs) are rare and slow-growing neoplasms originating from widely diffused neuroendocrine cells throughout the body, most frequently occurring in the gastrointestinal tract, pancreas, and lungs. 1 Histologically well-differentiated NETs, previously called carcinoid tumors, are the most common NETs. 1 The incidence of NETs increased from 1.09 to 6.98 per 100,000 in the US from 1973 to 2012.…”

“… 1 Histologically well-differentiated NETs, previously called carcinoid tumors, are the most common NETs. 1 The incidence of NETs increased from 1.09 to 6.98 per 100,000 in the US from 1973 to 2012. 2 The primary clinical symptoms in patients with advanced, functional NETs is called carcinoid syndrome (CS), 3 which includes flushing, diarrhea, cardiac valvular fibrosis, mesenteric fibrosis, abdominal pain, and decreased health-related quality of life.…”

“… 14 Supplemental IR can control symptoms beyond the dose escalation of LAR to provide more comprehensive management when a sudden increase of serotonin may cause breakthrough symptoms in certain situations for patients using LAR. 1 …”

The Role of Receptor–Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

“…Tachyphylaxis, on the other hand, is the rapid decline in cellular response to repeated doses of the drug. The mechanisms of somatostatin receptor expression play a crucial role in these phenomena [ 218 , 230 ]. Receptor–ligand interactions, involving the interplay between the ligand and SSRT receptor, are essential for initiating cellular signaling.…”