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Everolimus treatment for neuroendocrine tumors: clinical potential


Neuroendocrine tumors ( NETs ) are a heterogeneous class of neoplasms with increasing incidence worldwide.
Tumor behavior and patient survival largely depend upon a number of different factors such as tumor histology, primary site, staging and proliferative index.

The management of NETs is challenging, and therefore effective and safe therapeutic options for the treatment of these tumors are actively pursued in clinical research.
In particular, targeted therapies such as Sunitinib and Everolimus have shown promising results and have thus entered clinical practice.

A bulk of preclinical evidence has shown that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs.
Everolimus is a direct inhibitor of this pathway, and therefore this molecule appear to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice.

The efficacy and safety of Everolimus was demonstrated in the RADIANT trials.

Everolimus does represent a major advance in the therapy of NETs. In fact, according to the results of well-conducted clinical trials, the efficacy of Everolimus has been consistently shown in well-differentiated NETs from all origins.

With respect to safety, the tolerability profile of Everolimus has been consistent in all studies, with most adverse events being of mild or moderate severity; the onset of grade 3/4 anemia and hyperglycemia ( both with a rate of about 5% ) must however be noticed.

Types of NETs

Pancreatic NET - Everolimus undoubtedly represents one of the most effective treatments in pNET patients. However, its role within the therapeutic sequence ( e.g. in the first-line setting or at later treatment lines ) remains unclear also due to the number of effective options in these patients with confirmed efficacy or under evaluation [ Sunitinib, Somatostatin analogues, chemotherapy, peptide receptor radionuclide therapy ( PRRT ), and Pazopanib ].
Of note, the subgroup analysis of the RADIANT 3 study showed no differences in progression-free survival between pretreated and naïve patients.
The use of Everolimus in the frontline setting is also supported by a smaller study in a heterogeneous population of patients with NETs of different origin.
Given the lack of results from well-conducted head-to-head trials, Everolimus might be a particularly suitable first-line treatment for G2 pNET patients who show rapidly-evolving disease and high disease burden, given the antiproliferative efficacy and tolerability profile of this molecule.
On the other hand, Everolimus may be more useful as a second-line therapy in patients with G1 pNET, who frequently show low tumor burden and indolent disease, and as such may be effectively treated with Somatostatin analogues.

Pulmonary NET - The RADIANT 4 trial was the first randomized study to show that Everolimus is effective in patients with pulmonary NETs, a class of disease for which no treatment is established.
In this setting, Everolimus may be particularly suitable as a first-line therapy for patients who present with aggressive disease, including those with atypical carcinoids.
Moreover, data on second-line Everolimus are even stronger, also when compared with those for chemotherapy and PRRT, which were reported in small retrospective or noncontrolled, heterogeneous series of patients.

Gastrointestinal NET - The RADIANT 4 trial showed the efficacy of Everolimus in patients with well-differentiated, advanced, progressive, nonfunctional gastrointestinal NETs.
Overall, its findings suggest that worse grade of differentiation and worse prognosis might be associated with higher efficacy of Everolimus, although specific studies appear necessary to further evaluate those findings.
Therefore, the use of Everolimus may be limited in the upfront setting for better prognosis patients with appendix, caecum, jejunum, ileum, duodenum ( midgut ) NETs, also because several other treatment options are available.
On the other hand, Everolimus may become of paramount importance for the treatment of less indolent gastrointestinal carcinoids, due to the lack of effective therapeutic opportunities other than Somatostatin analogues. ( Xagena )

Pusceddu S et al, Ther Adv Med Oncol 2017; 9: 183–188

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