Perspectives on the current pharmacotherapeutic strategies for management of functional neuroendocrine tumor syndromes

ABSTRACT

Introduction: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult because the pharmacological-armamentarium available was limited. Recently, new therapeutic strategies have increased but it also generated controversies/uncertainties.

Areas covered: The authors briefly review: established/proposed F-NENs; the rationale for treatments; the recommended initial-pharmacotherapeutic-approach to controlling F-NENs hormone-excess-state; the secondary-approaches if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN. Also discussed are controversies/uncertainties related to new treatments.

Expert opinion: Unfortunately, except for patients with insulinomas (>90-95%), gastrinomas (<20-40%), a minority with the other F-panNENs and 0-<1% with Carcinoid-syndrome is curative-surgery possible. Except for insulinomas, gastrinomas, and ACTHomas, long-acting somatostatin-analogs are the initial-pharmacological-treatments for hormone-excess-state. For insulinomas prior to surgery/malignancy, diazoxide is the initial drug-treatment; for gastrinomas, oral PPIs; and for ACTHomas, steroidogenesis inhibitors. There are now several secondary pharmacotherapeutic treatments. Surgery and liver-directed therapies also have a role in selected patients. Particularly promising is the recent results with PRRT for the hormone-excess-state, independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.

KEYWORDS:

• Pancreatic neuroendocrine neoplasms
• insulinoma
• zollinger-ellison syndrome
• glucagonoma
• vipoma
• carcinoid syndrome
• ectopic cushing’s syndrome
• somatostatin analogue
• everolimus
• prrt

Article highlights

• In the past, functional neuroendocrine tumor’s(F-NETs) main determinant of survival was controlling the hormone-excess state, but because of new pharmacotherapeutic approaches this is now easier, but these have generated some controversies, uncertainties, and confusion.

• There are 16 different F-NEN syndromes, (9 well-described) and only a few have a high surgical cure rate, so long-term control of the hormone-excess state remains a major problem.

• Except for insulinomas, gastrinomas, and ACTHomas, somatostatin analogs are the initial treatment for the hormone-excess state.

• For insulinomas prior to surgery/malignant, diazoxide is initial drug treatment; for gastrinomas, oral PPIs; and for ACTHomas steroidogenesis inhibitors.

• There are a number of secondary pharmacotherapeutic treatments for different F-NEN-syndromes. These include telotristast (carcinoid-syndrome; mTor- inhibitors(everolimus); pasireotide; everolimus, sunitinib and some newer agents in ectopic Cushing-syndrome. Also, cytoreductive surgery, and liver-directed therapies (radioembolization, embolization, chemoembolization, radiofrequency ablation) have a role in selected patients.

• Areas of controversies and confusion in the management of the F-NEN hormone-excess state included: best order of secondary treatments and particularly the place of PRRT in this order: what are the best roles for cytoreductive surgery or liver-directed therapies; are there subgroups that should be treated with PRRT as the initial treatment; and the uncertainty of how to resolve the difficulty of diagnosis of the underlying disorder if the patient is on treatment such as somatostatin analog/PPIs with hypergastrinemia.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was partially supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health [NIDDK # DK053200–26].