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Treatment Advances in Carcinoid Syndrome and Neuroendocrine Tumors


By Eileen Koutnik-Fotopoulos

Neuroendocrine tumors (NETs) are a heterogeneous group of slow-growing neoplasms that can arise from neuroendocrine cells throughout the body, characterized by their production of peptides and secretion of hormones such as serotonin. NETs often present at an advanced stage, can be aggressive, treatment resistant, and potentially life-threatening. These tumors can secrete hormones that result in carcinoid syndrome, the hallmark features of which are frequent episodes of diarrhea and flushing. 

“Among patients with metastatic or advanced NETs, those with carcinoid syndrome have a poorer prognosis than those with NETs alone,” said Eric Liu, MD, FACS, neuroendocrine tumor surgeon, Rocky Mountain Cancer Centers, during a recent Academy of Managed Care Pharmacy webinar titled “Clinical Overview and Treatment Advances in Carcinoid Treatment.” It was sponsored by Lexicon Pharmaceuticals, Inc.

Burden of Carcinoid Syndrome

The incidence of NETs continues to rise. Surveillance, Epidemiology, and End Results data found that the prevalence of NETs in United States exceeds 100,000. The most common are gastroenteropancreatic NETs, which are classified as functioning and nonfunctioning carcinoid tumors. Although carcinoid syndrome is rare with Dr Liu reporting that approximately 13,000 patients are currently living with carcinoid syndrome in the United States, it is often misunderstood, misdiagnosed, and impacts quality of life. Potentially devastating short- and long-term effects of carcinoid syndrome include life-altering diarrhea and carcinoid heart disease, respectively, according to the presentation.

Dr Liu, who is also chief medical advisor, Healing NET Foundation, shared data illustrating the impact of carcinoid syndrome diarrhea, noting that diarrhea occurs in more than 70% of patients and may occur several times daily. Additionally, fluid loss from severe diarrhea may result in dehydration and serious health consequences, with 9% developing severe, life-threatening diarrhea. Patients can also experience significant weight loss and hypoproteinemia.

Diarrhea is burdensome and expensive in patients with carcinoid syndrome, according to a study using a commercial claims database (2003-2012) and published in 2016 in World of Gastroenterology. Carcinoid syndrome diarrhea accounted for 1.5-fold higher total health care spending and almost a 2-fold higher risk of carcinoid syndrome-related hospitalizations. The adjusted mean total health care cost in the analysis was $81,610 per year among patients with carcinoid syndrome diarrhea.

“Reduction of health care expenditures attributable to diarrhea may be achievable through preventive treatment and appropriate management of diarrhea in patients with CS [carcinoid syndrome],” concluded the researchers.

Treatment Strategies and Challenges

Tumor resection surgery is considered an important treatment strategy. “If we can operate on patients and get the tumors out, they actually do much better,” said Dr Liu, noting that NETs is a very complicated multimodal disease. Somatostatin analogs (SSAs) have been the mainstay of therapy for the control of symptoms associated with carcinoid syndrome. SSAs have also been shown to inhibit the growth of well-differentiated gastrointestinal and pancreatic NETs, according to a 2016 article in Hematology/Oncology Clinics of North America. In a study published in The Oncologist in 2016, researchers reported that SSAs have demonstrated efficacy in symptomatic relief of diarrhea and flushing episodes associated with carcinoid syndrome. Furthermore, long-acting SSAs are now available and have been shown to provide sustained symptomatic benefit.

“We use SSAs all the time and it has been a great tool to have for the past 25 years. It has helped a lot of people, but it’s not perfect,” explained Dr Liu, adding that patients may become refractory to treatment and require additional management of their carcinoid syndrome diarrhea. Therefore, therapies that target the root cause of carcinoid syndrome treatment are needed.

Xermelo (telotristat ethyl; Lexicon Pharmaceuticals Inc)—tryptopham hydroxylase inhibitor—offers clinicians an alternative treatment strategy. Approved by the FDA in February 2017, Xermelo is indicated for the treatment of carcinoid syndrome diarrhea in combination with SSA therapy in adults inadequately controlled by SSA therapy. 

The 12-week, double-blind, placebo-controlled, randomized, multicenter, phase 3, TELESTAR trial found that 89% of patients receiving Xermelo plus SSA experienced improvement in bowel-movement frequency. The oral therapy demonstrated superior and significant reductions in daily bowel movements averaged over 12 weeks. Xermelo plus SSA also provided early and sustained reductions in bowel-movement frequency. It was safe and well tolerated, with nausea being the most common adverse reaction, according to the presentation.

Value of Treatment

Assigning value to therapy is an important component for stakeholders in treatment paradigms. An online survey of more than 30 managed care organizations and pharmacy benefit managers found that approximately 90% of payers surveyed incorporated both benefit and cost into their value assessments, according to a 2016 article in Pharmaceutical Executive.

Dr Liu said Xermelo is an example of a therapy that incorporates both benefit and cost. Benefits include reduction in carcinoid syndrome diarrhea symptoms and its oral route of administration. For patients who become resistant SSA therapy, it can lead to increased use of SSA recuse medication and increased incidence of carcinoid syndrome diarrhea health care related utilization (HCRU), he explained. Although there is an increased cost with Xermelo, Dr Liu said the estimated budget impact is minimal because of decreased use of SSA rescue medication and decreased incidence of carcinoid syndrome diarrhea HCRU.

A recent analysis by Market Research Future predicted that the global carcinoid syndrome management market is expected to grow an average compound annual growth rate of 7% during 2017 to 2022. The company noted that the key factor driving the global carcinoid syndrome market is incidence of carcinoid tumor. 

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