patient care perspectives

Somatostatin Analogues: Optimizing the Use of Long-Acting Repeatable Depot and Immediate-Release Formulations

by Lowell B. Anthony, MD, FACP

Overview

While some patients with carcinoid syndrome are well controlled on long-acting repeatable (LAR) depot somatostatin analogues (SSAs), others may benefit from rescue therapy with immediate-release (IR) SSAs to control clinically significant secretory diarrhea.

Expert Commentary

Lowell B. Anthony, MD, FACP

Professor and Chief

Division of Medical Oncology

Department of Medicine

Member, UK Markey Cancer Center

University of Kentucky

Lexington, KY

“A better control of breakthrough symptoms is obtained when patients have the IR formulation on hand to combine with the depot formulation when needed.”

Lowell B. Anthony, MD, FACP

In addition to controlling debilitating diarrhea and flushing, SSAs are helpful in the management of other aspects of carcinoid syndrome, such as carcinoid heart disease and mesenteric fibrosis. There are 2 SSAs that are available in the United States: octreotide and lanreotide. Octreotide is available in a subcutaneous IR injection and in an LAR depot formulation for intramuscular injection. Additionally, lanreotide depot was introduced in 2014. 

Despite their utility, data suggest that LAR formulations may be associated with a loss of bioactivity over time that may necessitate progressive supplemental treatment with octreotide IR to adequately control the patient's symptoms. The need to supplement the LAR formulation with the IR formulation occurs in a considerable number of individuals. A typical scenario would be a patient with carcinoid syndrome who develops more diarrhea that could eventually become clinically significant approximately 1 week before the next SSA depot is due. 

The LAR formulation is designed to release the drug over a 28‐day period, which provides dosing convenience over the IR formulation; however, not all patients are 100% controlled symptomatically, despite relatively stable blood levels of SSA. A better control of breakthrough symptoms is obtained when patients have the IR formulation on hand to combine with the depot formulation when needed. Breakthrough diarrhea could be due to a number of factors, including normal life stressors, such as getting a tooth pulled, undergoing a procedure with anesthetics containing epinephrine, or, perhaps, other events related to catecholamines. Not enough receptors are occupied by the SSAs, and the cells are releasing serotonin, resulting in patients becoming symptomatic. 

Many patients with carcinoid syndrome become quite familiar with the different types and causes of diarrhea, and this is very much a part of our patient education. Some individuals with carcinoid syndrome have their intestines shortened with surgery, and their bowels will have a tendency to move within approximately 30 minutes to 1 hour of eating. If the patient has steatorrhea, their stools float. With the syndromic diarrhea of carcinoid syndrome, patients have watery diarrhea that is thought to be due to serotonin receptors in the gut increasing motility and electrolyte secretion into the gut lumen. And, if patients are going to use the IR SSA formulation as a rescue medication, we want it to be that watery diarrhea, not diarrhea due to some other cause.

We need to be proactive and use the rescue SSA before the watery diarrhea leads to dehydration. If a patient is dehydrated, that needs to be reversed; some individuals may need intravenous fluids. To help control our patients' watery diarrhea, we often use an electrolyte beverage that is a mixture of 5 amino acids and has antidiarrheal effects (Enterade; Entrinsic Bioscience, LLC). This is followed by octreotide IR 3 times per day until we establish good control, at which point the dosage is reduced.

In conclusion, the depot formulation is, in a sense, the backbone of treatment for carcinoid syndrome, and we add additional treatment(s) as needed. If a patient with carcinoid syndrome is experiencing significant diarrhea on the LAR formulation, we consider it to be a breakthrough day rather than a breakthrough event within a given day. And I would say that, if a patient has more than 5 breakthrough days in 1 month, a consideration of another treatment plan is warranted.

References

Anthony LB, O'Dorisio TM. Opportunities to improve symptom control with somatostatin congeners in GEP-NETs: a review of key issues. Oncologist. 2021;26(7):e1171-e1178. doi:10.1002/onco.13847

Chauhan A, Das S, Miller R, et al. Can an amino acid mixture alleviate gastrointestinal symptoms in neuroendocrine tumor patients? BMC Cancer. 2021;21(1):580. doi:10.1186/s12885-021-08315-4

Lamberts SWJ, Hofland LJ. Anniversary review: octreotide, 40 years later. Eur J Endocrinol. 2019;181(5):R173-R183. doi:10.1530/EJE-19-0074

Naraev BG, Halland M, Halperin DM, Purvis AJ, OʼDorisio TM, Halfdanarson TR. Management of diarrhea in patients with carcinoid syndrome. Pancreas. 2019;48(8):961-972. doi:10.1097/MPA.0000000000001384

Randall R, Bennett B, Valone T, Blue K. Optimizing the management of carcinoid syndrome to reduce the impact of diarrhea. J Adv Pract Oncol. 2019;10(8):862-872. doi:10.6004/jadpro.2019.10.8.7

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