Neuroendocrine tumors (NETs) are a group of rare oncologic diseases that can originate from anywhere in the body and can have a very heterogeneous natural history of disease progression (Oncology (Williston Park) 2015;29(10):755-756, 759). NETs can be either classified based on anatomic origin (e.g., bronchial NETs, pancreatic NETs, etc.). GI tract followed by lung are two of the most common sites for NETs (Visc Med 2017;33(5):324-330).
NETs can be classified into grade 1, 2, and 3 based on Ki-67 index. Ki-67 is an immunohistochemistry marker that corresponds to cell division. The higher the Ki-67 index, the greater the malignant potential of the tumor and its ability to be more aggressive. In 2010, WHO classified NETs into grade 1 (Ki-67 <2%), grade 2 (Ki-67 2-20%), and grade 3 (Ki-67 >20%).
A third important classification of NETs is based on tumor differentiation. NETs can be either well-differentiated or poorly differentiated (Visc Med 2017;33(5):324-330, Nat Rev Clin Oncol 2016;13(11):691-705). A well-differentiated NET maintains a typical neuroendocrine cell morphology under microscope and stains for chromogranin A. In contrast, a non-well differentiated neuroendocrine carcinoma can be large cell, small cell, or poorly differentiated neuroendocrine carcinoma. This subset of non-well differentiated neuroendocrine carcinomas are aggressive cancers that often stain positive for neuron specific enolase (Cancer Treat Rev 2016;50:61-67).
Lastly, NETs can be classified as functional or non-functional based on their ability to produce certain vasoactive amines (Front Horm Res 2015;44:177-192). Broadly, about 30-40 percent of all NETs are functional and produce hormones like serotonin, vasoactive intestinal peptide, insulin, gastrin, glucagon, adrenocorticotropic hormone, ghrelin, etc. Phenotypic presentation of function NETs is determined by the specific hormone that is produced. By far the commonest functional NET is carcinoid syndrome (Curr Med Res Opin 2009;25(12):2989-2999). It is a clinical constellation of symptoms produced by overproduction of serotonin by NET cells. Excessive tumor over-secretion of amines and peptides often correlates with diarrhea, wheezing, and flushing. Chronic exposure to high serotonin is associated with systemic fibrosis including cardiac valvular defects.
In the past 5 years, there has been a marked increase in therapeutic agents approved for NET patients. In 2016, the FDA approved everolimus, an mTOR inhibitor for treatment of bronchial as well as gastroenteropancreatic neuroendocrine tumor (GEP-NET) (Lancet 2016;387(10022):968-977).
In 2017, the FDA approved teletristat ethyl, a first-in-class oral tryptophan hydroxylase inhibitor that decreases the production of serotonin. FDA approval of teletristat was based on the large, multinational, randomized control, phase III TELESTAR clinical trial (J Clin Oncol 2017;35(1):14-23).
Recently, the FDA approved peptide receptor radiotherapy for the management of progressive metastatic NETs in January 2018 (N Engl J Med 2017;376(2):125-135). This recent spurt in drug development came after decades of therapeutic stagnation and was a welcome addition to current backbone of treatments (i.e., somatostatin analogs).
In this article, we will be reviewing our early pilot data on enterade, a first-in-its-class, amino acid-based oral rehydration solution (AA-ORS) for diarrheal management in the NET patients. This data was presented at the 2018 Gastrointestinal Cancers Symposium in San Francisco (Abstract 509).
Methods & Results
Medical records were retrospectively reviewed for all the GEP-NET patients who received enterade for symptomatic diarrhea. Patients were evaluated at Markey Cancer Center between July 2017 and September 2017 and managed in the multidisciplinary neuroendocrine tumor clinic. Retrospective chart review was conducted under IRB-approved protocol.
The dietitian, an integral part of our multidisciplinary team, kept detailed records about patients' diarrhea, hydration, and diet. After receiving samples, she provided enterade to patients and gave instructions to the subjects on how to use it. Based on patient feedback, there was anecdotal improvement of their diarrhea, which prompted this study.
AA-ORS is available over the counter and is considered a medical food. It was prescribed as 8 oz. twice daily 30 minutes before or 1 hour after meals. Patients were instructed to take enterade for 1-2 weeks, but could extend the duration if they continued to benefit. Data regarding compliance with enterade, daily stool frequency, side effects, duration of treatment, and pertinent medical history were captured for analysis.
A total of eight patients received enterade. Five patients were diagnosed with small bowel NETs and three had pancreatic NETs. Five patients had history of prior bowel resections for removal of the primary tumor. Five patients were on long-acting somatostatin analogs at the time of initiation of enterade. Five of eight (62%) patients reported improvement in diarrhea within 6 days of initiating enterade. The responders had 50-percent reduction in their stool output. Mean stools dropped from six per day to three per day in responder population.
Since January 2018, our group has expanded the analysis to a larger cohort of NET patients who received enterade (n=33) and our preliminary data continues to show promising results. The updated data will be available at the upcoming 2018 ASCO Annual Meeting in June 2018.
Discussion
AA-ORS is an amino acid based oral rehydration solution that consists of five amino acids (valine, aspartic acid, serine, threonine, tyrosine) and electrolytes (potassium and sodium). It is classified as a medical food and is first in its class since it is devoid of glucose and instead uses amino acid molecules to transport electrolytes across the gut membrane.
In 2014, researchers confirmed the efficacy of amino acid based oral rehydration solution in a preclinical mouse model. In their experiment, mice were irradiated to mimic radiation-induced enteropathy. Radiation toxicity causes gut villi to shorten and leads to decreased absorption of electrolytes. Mice, which received AA-ORS, showed increased electrolyte absorption, increased weight gain, and better survival as compared to placebo (Health Physics 2014;106(6):734-744).
AA-ORS is currently being studied in a large phase II, multi-center, placebo, controlled, randomized clinical trial. Investigators are evaluating anti-diarrheal efficacy of AA-ORS in multiple myeloma patients who have received high-dose melphalan and autologous hematopoietic stem cell transplantation. The trial is currently accruing (NCT02919670).
Our pilot data is suggestive of anti-diarrheal efficacy of AA-ORS in NET patients. The majority of study patients had improvement in the frequency of diarrhea and none of the patients reported adverse effects. Our updated dataset evaluating 33 NET patients has been submitted to the 2018 ASCO Annual Meeting and it continues to show promising anti-diarrheal efficacy.
A follow-up phase II, prospective, multicenter clinical trial evaluating anti-diarrheal efficacy of enterade in NET patients is currently being developed at Markey Cancer Center. We are also planning to study the mechanism of action of AA-ORS in alleviating diarrhea symptoms in carcinoid pre-clinical model in collaboration with University of Cincinnati and University of Florida.
AMAN CHAUHAN, MD, is in the Division of Medical Oncology at the University of Kentucky in Lexington.
Research contributors to this article include the following: Aman Chauhan, MD, University of Kentucky, Division of Medical Oncology; Rachel C. Miller, MS, LD, RD, Dietitian Consultant, Markey Cancer Center; Qian Yu, BS, University of Kentucky, School of Medicine; Laura L. Luque, MD, Entrinsic Health Solutions; Hala Elnakat Thomas, PhD, University of Cincinnati, Division of Medical Oncology; Bilal Ahmed, University of Kentucky, Division of Gastroenterology; Heidi Weiss, PhD, Department of Biostatistics, University of Kentucky and Markey Cancer Center; Jill Kolesar, PharmD, Department of Pharmacy Practice and Science, College of Pharmacy, Department of Internal Medicine, College of Medicine, University of Kentucky and Markey Cancer Center; Val Adams, PharmD, Department of Pharmacy Practice and Science, College of Pharmacy, Department of Internal Medicine, College of Medicine, University of Kentucky and Markey Cancer Center; Susanne Arnold, MD, University of Kentucky, Division of Medical Oncology; Mark Evers, MD, FACS, University of Kentucky, Division of Surgical Oncology and Markey Cancer Center; and Lowell Brian Anthony, MD, FACP, University of Kentucky, Division of Medical Oncology