Progress in the Evaluation and Treatment of Small Bowel Neuroendocrine Tumors

The incidence of well-differentiated neuroendocrine tumors (NETs) has been climbing since at least the 1970s.1 This feature, coupled with a typically indolent disease course, has translated into a relatively high prevalence of NETs.1 With a median survival of 8.5 years in the setting of metastatic disease for small bowel NETs,1 a thoughtful approach to care is necessary, balancing the desire to treat symptoms and/or tumor growth with quality of life. The accompanying review by Scott and Howe2 provides a comprehensive overview of recent changes to the work-up and pathologic classification of small bowel NETs, along with an update on current strategies for symptom control and inhibition of tumor growth. The review outlines a practical framework for a multidisciplinary approach to the management of these malignancies. Small bowel NETs pose several unique challenges for diagnosis and treatment. Much of the small bowel is difficult to visualize endoscopically, and anatomic cross-sectional imaging has historically fallen short for detection of small bowel primary tumors.3 Our ability to localize and stage small bowel NETs has improved with the availability of positron emission tomography (PET) imaging with 68Ga-labeled somatostatin analogs.4 In addition, the pathologic staging system for NETs has recently been refined. Updates to the WHO classification in 2017 clarified that tumors with a Ki 67 proliferation index < 3% are considered grade 1. Use of the newly identified well-differentiated grade 3 NET category is currently restricted to tumors arising in the pancreas.5 For more than two decades, US Food and Drug Administration–approved systemic treatment of small bowel NETs was limited to the somatostatin analog octreotide, but several important advances have been made in the last few years. Technically approved for symptom relief only, the cytostatic activity of octreotide in midgut NETs was demonstrated in the PROMID study in 2009.6 Lanreotide (another somatostatin analog) was approved for tumor control in gastroenteropancreatic NETs on the basis of the results of the CLARINET study in 2014.7 The mTOR inhibitor everolimus also delays tumor progression, and was approved for pancreatic NETs in 20118 and gastrointestinal and pulmonary NETs in 2016.9 Most recently, peptide receptor radionuclide therapy with 177Lu-DOTATATE was approved on the basis of a significant prolongation of progression-free survival in the NETTER-1 study.10 Finally, telotristat (an oral tryptophan hydroxylase inhibitor which inhibits serotonin biosynthesis) is now approved for symptom