Diagnosing and Treating NET-Related Diarrhea

Bryson Katona, MD, PhD

Determining the true nature, causes, and optimal treatment of neuroendocrine tumors (NET) is incredibly important for patients, as even though diarrhea can be a symptom of the disease, it is not always the primary cause.

During the 10^thAnnual NANETS Symposium, Bryson Katona, MD, PhD, discussed the differential diagnosis of diarrhea, whether NETs-related or not, and ways to treat this symptom in patients, including with standard therapies for patients with NETs that may provide symptom control.

“As we know, diarrhea is very common in the general population, and NETs and function NETs are probably one of the least common causes in the general population. So, in evaluating NETs, it’s important not to forget all the other causes of diarrhea that are very, very common and could also be in the picture,” said Katona, director of the Acute and Transitional Gastroenterology Program and of the Gastrointestinal Cancer Genetics Program, Hospital of the University of Pennsylvania.

Diarrhea is defined, according to the World Health Organization (WHO), as the passage of 3 or more loose or liquid stools per day. According to the Bristol Stool Chart, there are 7 different types of stool, and only fluffy or watery stools indicate diarrhea.

“From the patient perspective, there’s often misconception about what diarrhea actually is,” he said. “I find using the Bristol stool chart to be very helpful.”

Katona noted that symptoms from diarrhea are often overreported by the patients. The best way to get a true sense of patients’ bowel movements with consistency, he said, is for them to have a stool log.

NETs or Not: Determining the Cause

Diarrhea can also be defined based on the duration of the symptoms where less than 14 days accounts for acute diarrhea, 14 to 28 days as persistent diarrhea, and more than 28 days as chronic diarrhea. For patients with NETs, chronic diarrhea is the most concerning.

He added that it can also be defined by the etiology of the diarrhea: whether secretory, osmotic, inflammatory, or fatty. Secretory diarrhea, for example, is typically associated with functional NETs that will persist at night and at high volumes.

Besides NETs, additional probable causes of diarrhea could include irritable bowel syndrome (IBS) or functional diarrhea; inflammatory bowel disease (IBD); medications; chronic infections, such as immunosuppression, travel, or antibiotic use; malabsorption; hyperthyroidism; and bile acid disease following surgery. Then, among patients with NETs, diarrhea could be caused by long-term treatment with somatostatin analog or aggressive surgery.

When working up a diagnosis of chronic diarrhea, it is important to get an accurate history of the patients’ stools, even if they do not want to talk about it, Katona stressed. He suggested asking the patient questions to determine the consistency, frequency, volume, urgency, onset, duration, and appearance of their stools. A review of the patient’s diet, medications, family history, and a physical exam are also helpful.

Testing of diarrhea in patients without NETs often include inflammatory markers and testing for Celiac disease. Tests of the patients’ stool can test for fecal fat, electrolytes, and more. Endoscopic and breath tests can also help in looking for further causes.

“With all of this in terms of the history and work-up, the question that we want to ask is, ‘is the diarrhea that the patient is having actually due to a function NET, or is it due to something else?”

For patients with NETs, 5-HIAA testing of urine and serum, chromogranin A, serotonin, and gastrin are all potential options, as these can be markers of carcinoid syndromes. However, false positives are common from both 5-HIAA and chromogranin A testing.

Katona noted that the stool osmotic gap is useful in patients experiencing watery diarrhea, as this calculation can help differentiate between secretory and osmotic diarrhea.

Treating Diarrhea in Patients With NETs

“When we’re talking about carcinoid syndrome-specific diarrhea, really a big question is [whether] antitumor management will actually treat the diarrhea,” Katona said. “I will say that there’s a lot of data out there, and at least some of the data show that just about every neuroendocrine tumor treatment that’s effective does provide some control of the diarrhea symptoms.”

For example, several years ago, somatostatin with octreotide (Somatostatin) was found to be effective at decreasing carcinoid syndrome-associated diarrhea, which has been confirmed in further studies. In the study, of 25 patients treated with long-acting (LAR) somatostatin analogs (SSA), 19 experienced a decrease in the symptom by over 50%.¹Additionally, in a retrospective study of patients with NETs treated with an escalated dose of octreotide, over 30 mg led to a reduction in diarrhea symptoms after both the first (79% resolved or improved) and second dose escalation (63% resolved or improved).²

For patients with diarrhea from carcinoid syndrome, Katona suggested starting octreotide LAR at 30 mg every 4 weeks, which could be escalated if needed, though not above 60 mg every 4 weeks. He suggested that short-acting octreotide could also be helpful for patients experiencing breakthrough symptoms.

Administration of lanreotide (Somatuline Depot) led to decreased use of short-acting SSA for the control of diarrhea symptoms compared with placebo (frequency, 1.34 vs 1.55, respectively;P= .25).³

Additionally, tryptophan hydroxylase inhibitors can be beneficial, such as telotristat ethyl (Xermelo), which was approved by the FDA in February 2017 for the treatment of patients experiencing carcinoid syndrome-related diarrhea that was not adequately controlled with SSA therapy alone.

In the TELESTAR trial, telotristat led to a decrease in the number of daily bowel movements and a decrease in urine 5-HIAA levels over placebo at both the 250 mg and 500 mg twice-daily doses.⁴

Of course, some general anti-diarrheal agents can be used, including opioid receptor agents, such as loperamide (Imodium), which has minimal crossing of the blood-brain barrier to prevent abuse, and diphenoxylate, which requires atropine to prevent abuse.

More potent anti-diarrheal agents include tincture of opium, which includes morphine plus other opium alkaloids and can be highly addictive, and eluxadoline, which is also an opioid receptor agonist and has been FDA approved for IBS, although there are concerns of pancreatitis when treating patients without a gallbladder.

Finally, serotonin receptor antagonists, such as ondansetron, which is primarily used as an anti-emetic, and alosteron, as well as bile acid sequestrants can be considered. Bile acid sequestrants should be considered after distal small intestinal resection of cholecystectomy, Katona noted.

References

1. Kvols LK, Moertel CG, O’Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue.N Engl J Med. 1986;315(11):663-666. doi: 10.1056/NEJM198609113151102.
2. Strosberg JR, Benson AB, Huynh L, 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):930-936. doi: 10.1634/theoncologist.2014-0120.
3. Vinik AI, Wolin EM, Liyanage N, et al; ELECT Study Group. Evaluation of lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment (ELECT): a randomized, double-blind, placebo-controlled trial.Endocr Pract. 2016;22(9):1068-1080. doi: 10.4158/EP151172.OR.
4. Kulke MH, Hörsch D, Caplin ME, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome.J Clin Oncol. 2017;35(1):14-23. doi: 10.1200/JCO.2016.69.2780.