Comparative safety review of the current therapies for gastroenteropancreatic neuroendocrine tumors

ABSTRACT

Introduction: Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of neoplasms, whose management requires complex and individualized clinical decisions. Over the last decades the advent of novel medications and advanced diagnostic and therapeutic modalities, alongside our deeper understanding of the disease, revolutionized the landscape of their management, significantly improving both prognosis and quality of life of patients.

Area covered: Treatment-related adverse events and safety concerns as demonstrated in clinical trials, as well as in real-world clinical practice.

Expert opinion: The only true curative option for NENs remains surgery, whereas high-grade advanced neuroendocrine carcinomas should be primarily managed with platinum-based chemotherapy. For the remaining cases, that comprise the vast majority, the current armamentarium includes somatostatin analogs, interferon, telotristat ethyl, molecular targeted therapies, chemotherapy, peptide receptor radionuclide therapy, and locoregional treatment. The use of the aforementioned therapeutic options is associated with several and not uncommonly severe treatment-related adverse events. However, the benefits offered inclusive of improved prognosis, amelioration of symptoms, and better quality of life amidst others, by far outweighs any adverse event.

KEYWORDS:

• Neuroendocrine neoplasms
• somatostatin analogs
• telotristat ehtyl
• everolimus
• sunitinib
• peptide receptor radionuclide therapy
• temozolomide/capecitabine

Author contributions

Apostolos Koffas: Preparation of the manuscript, Drafting the article, Final approval of the version to be submitted; Christos Toumpanakis: Conception and design of the study, Drafting the article, Critical Revision, Final approval of the version to be submitted.

Article highlights

• The only true curative option for neuroendocrine neoplasms (NENs) remains surgery, primarily indicated for small grade 1 tumors without evidence of metastatic disease.

• High-grade advanced neuroendocrine carcinomas (NECs) should be primarily managed with platinum-based chemotherapy, although it is associated with severe AEs and impaired quality of life.

• Somatostatin analogs represent the first-line therapeutic option for carcinoid syndrome and functionally active neuroendocrine tumors (NETs). They exhibit a favorable safety profile and excellent tolerability and have been mainly associated with GI disturbances, hypo- or hyper-glycemia, arrhythmia, pancreatic enzyme insufficiency, gallstone disease and vitamin deficiencies, albeit rarely severe.

• Telotristat ethyl is registered as an adjunct to SSAs in the treatment of refractory carcinoid syndrome diarrhea. It represents a safe and well-tolerated agent.

• Molecular targeted therapy, i.e., everolimus or sunitinib, are registered as second-line options, for the treatment of progressive metastatic pNETs. Everolimus is also registered for the treatment of progressive metastatic SB-NETs. Both drugs have been associated with severe treatment-related AEs and treatment discontinuation or dose adjustment in not uncommon. Nevertheless, despite the unfavorable adverse-events profile, they contribute to preserved quality of life.

• Peptide receptor radionuclide therapy and in particular treatment with ¹⁷⁷Lu-Dotatate is currently recommended for progressive NETs with SSRT-positive lesions. It is associated with both immediate and long-term treatment-related adverse events, but is overall a highly effective and relative safe treatment modality.

• NEN management should be relied upon decision-making in an MDT setting.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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