Treatment Strategies for Metastatic Neuroendocrine Tumors of the Gastrointestinal Tract

Abstract

The therapeutic landscape of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) has evolved significantly in recent years. Current and emerging treatment options include somatostatin analogs, radiolabeled somatostatin analogs, the mTOR inhibitor everolimus, and the tyrosine kinase inhibitor sunitinib. Although high-quality data from phase III trials are lacking, cytotoxic agents are commonly used for the treatment of poorly differentiated neuroendocrine carcinomas and well-differentiated NETs originating in the pancreas. Hepatic-directed therapies are recommended for patients with slow-growing, liver-predominant disease but have never been compared to systemic agents. Telotristat ethyl, a novel serotonin synthesis inhibitor, has recently demonstrated efficacy in palliating diarrhea in patients with poorly controlled carcinoid syndrome. In the absence of definite predictive biomarkers, therapeutic decisions in most cases rely on clinical and pathological criteria. However, navigating the current therapeutic algorithm may be challenging, and future trials need to address several important questions: what is the best sequence of treatment? Is there a role for combination therapies in GEP-NETs? Are neoadjuvant, adjuvant, or maintenance strategies safe and effective? Do all NET patients require active treatment? What new molecular targets can be clinically exploited? A tight integration between basic and clinical research is needed to further advance the field of NETs.

Extremely Long Survival under Combined Immunotherapy in a Metastatic Functional Neuroendocrine Neoplasia Patient

“…Treatment and prognosis depends on the size, stage, grade, resectability, and distant metastasis. In most cases, a multimodality approach is the mainstay of care in advanced disease [18-22]. …”

Diagnosis, Assessment, and Therapeutic Strategy for Colorectal Mixed Adenoneuroendocrine Carcinoma

“…In addition to these cytotoxic regimens, everolimus, an oral inhibitor of mechanistic target of rapamycin (mTOR) is a candidate for treating unresectable neuroendocrine tumors. Although mutations of mTOR pathway genes are infrequently detected in gastrointestinal neuroendocrine tumors, mTOR overexpression and its downstream activity are implicated in adverse clinical outcomes [62,63] . In RADIANT-4, a phase III trial, everolimus was demonstrated to be superior to placebo for improving the median progression-free survival with gastrointestinal or lung neuroendocrine tumors (11.0 and 3.9 months, respectively) [64,65] .…”

Pathophysiology of Gastric NETs: Role of Gastrin and Menin

“…More recently, targeted therapies have evolved such as gastrin receptor antagonist YM022 (netazepide) to treat the gastrin-dependent ECL-based tumors GC type 1 and GC type 2 (73, 74). Telotristat etiprate blocks serotonin production by inhibiting tryptophan hydroxylase 1 and could be used to palliate symptoms from the carcinoid syndrome (71, 75). For widely metastatic, poorly-differentiated and local unresectable disease, platinum-based regimens remain therapy of choice while the newer target therapies inhibiting specific signaling molecules such as everolimus for mTOR and sunitinib to block tyrosine kinases are currently being tested in clinical trials (71, 76, 77).…”