MATERIALS AND METHODS

Identification

A comprehensive literature search was designed and conducted by an experienced medical librarian with input from the study investigators. We searched the electronic databases Ovid MEDLINE, Embase and Scopus. Various combinations of database-specific controlled vocabulary (subject headings) were used, supplemented by keywords, title and abstract terms for the concepts and synonyms relating to neuroendocrine tumor, neuroendocrine tumors, neuroendocrine tumor, neuroendocrine tumors, neuroendocrine neoplasm, neuroendocrine neoplasms, carcinoid tumor or carcinoid tumors and lung, pulmonary, bronchopulmonary, broncho-pulmonary or bronchial and everolimus, rad001, m-tor inhibitor, m-tor inhibitors, mammalian target of rapamycin inhibitor or mammalian target of rapamycin inhibitors. Last updated literature search was performed on December 30th, 2019.

Screening


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Literature search results in records. Record screening was performed in order to include patients with advanced well-differentiated pulmonary NETs treated with EVE. Review articles, preclinical studies and book chapters were excluded. English language restriction was applied.

Eligibility

Eligible studies were selected by reviewing the full-text articles.

Studies including advanced pulmonary NETs receiving EVE with palliative intent were eligible.

Studies exploring the role of EVE in combination with other therapies such as with PRRT, chemotherapy, SSA, interferon (IFN) or local therapies were considered eligible.

Studies exploring the role of other therapies such as PRRT, chemotherapy or SSA or IFN without EVE were considered ineligible.

Studies were required to report tumor response and survival data.

Length of follow-up should be more than 3 months.

Prospective clinical trials and retrospective analysis of prospective trials were eligible; clinical trials or case series with less than 10 patients were excluded. If results were given for a population of mixed poorly and well-differentiated NETs, these studies were excluded. Patients treated with adjuvant intent were not included in the qualitative synthesis.

Qualitative Description

Clinical and methodological data were extracted from the eligible studies.

Details of the study design, therapy regimen, prior therapies, histological typing, patient characteristics, side effects ad length of follow-up were collected.

THE BIOLOGICAL LANDSCAPE OF NEUROENDOCRINE TUMOR OF THE LUNG

Pathologic and Phenotypic Features

Lung NETs show the neuroendocrine (NE) morphology and derive from the mature cells of the pulmonary diffuse NE system.4,5

Mitoses and necrosis are essential for classifying TC and AC.1 Immunohistochemistry can be very helpful considering its constant positive staining for cytokeratin, neuroendocrine markers as chromogranin A (CgA), synaptophysin (SYN) and neuron-specific enolase (NSE).6

The Ki-67 is not necessary to classify lung NETs but its level can be useful in distinguishing between WD and PD forms, especially in limited diagnostic material,1,7,8 and it could have a prognostic role.9–13

The functional expression of somatostatin receptors (SSTRs) is usually detected through a positron emission tomography/computed tomography (PET/CT) with68 Ga-DOTA-peptide or, if not available, a somatostatin receptor scintigraphy (SRS).14 These nuclear medicine techniques play an important role in the staging,15,16 detection of recurrence,17 prediction of the response to PRRT,18 prediction of positive prognosis,19 therefore lead to a better clinical management.20,21

By contrast, the value of PET/CT with 18F-fluorodeoxyglucose (FDG) is still controversial. Some studies reported that the standardized uptake value is generally higher in AC, demonstrating that FDG PET is helpful in predicting the behaviour of lung NETs.22–25

Evidence about the clinical utility of circulating biomarkers in lung NET is lacking. Despite the low specificity and the very poor level of evidence, plasma chromogranin A (CgA) in lung NET is the most used marker at baseline and in the follow-up.2,26 Elevated level of plasma CgA is usually associated with an advanced disease and with indolent disease.27,28 Novel markers, such as circulating tumor DNA, circulating tumor cells, circulating miRNAs and measurements of multianalyte transcript analysis appear to represent the most promising strategy in lung NET.26

Epidemiologic and Clinical Features

Compared with lung NECs lung NETs occur predominantly in female, younger and non-smoker patients and they have a better prognosis.2,29

Typical carcinoid is ten times more common than AC and develops metastatic lesions in up to 15% of cases with a median time to recurrence of 4 years. Atypical carcinoid is metastatic in up to one half of cases with a median time to recurrence of 1.8 years.2

Synchronous metastases are present in 28% of lung NET patients,30 and metachronous metastases may develop even many years after surgical removal of the primary tumor and regional nodes,30–34 hence justifying a long-term surveillance even up to 15 years.2,35,36

Metastases usually occur in regional lymph nodes but also distantly to the liver, bones, lung, distant lymph node and subcutis.27,32,37

Although lung NETs are usually slow-growing malignancies, the prognosis of distant metastases disease is relatively poor. However metastatic survival data are lacking and have been mainly extracted from SEER database analysis30,36 and retrospective analyses.32,38,39

Moreover most of survival data have been collected considering the whole stage population (localized, regional, and distant metastatic) or have been extracted from surgical databases.40–44

The latest ESMO guidelines summarize these data reporting that TC patients have a 5-year survival rate of 87–90%, much higher than that of AC, that is 44–78%.35

Median survival from diagnosis of advanced lung NET patients is 6–7 years, as reported in three retrospective studies.27,32,45

Several prognostic factors have been associated with poor survival in the metastatic setting, however more efforts should be made to identify univocal results and consequently improve patient selection. To date several independent clinical prognostic factors were described, such as age, poor ECOG PS, histotype, tumor size, symptoms, high CgA levels, negative SRS, presence of bone metastasis, liver metastasis, Ki-67 as a continuous variable and lower time to relapse.27,32,41,44,46

Rationale of mTOR Inhibitors in Lung NETs

Lung NETs present a few genetic abnormalities compared with NECs, especially regarding chromatin-remodelling genes and DNA repair pathways.47–49 The most frequently mutated somatic genes are reported in Table 1.

Publishers Alliance 081420 Table 1

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase and is the catalytic subunit of two functionally distinct multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2).

The mTOR is activated via phosphorylation, following activation of an upstream signaling cascade, the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, that is important in regulating the cell cycle.

Everolimus, also known as RAD001, is an oral derivative of rapamycin, which has shown a potent inhibitory activity of the mTORC1 in primary cultures of human NET50 and proven efficacy in lung NETs. Lung NETs exhibit genetic abnormalities located in the PI3K/AKT/mTOR pathway causing the upregulation of mTOR signaling components or downregulation of its upstream negative regulators.48,51-53

Furthermore, deregulation of PI3K and loss of function of PTEN can predict response to mTOR inhibitors54–56 and lower level of mTOR, p70S6K and Akt were described as potential predictive markers of resistance.51,57

Considering the overexpression of pro-angiogenic molecules and of tyrosine kinase receptors (TKRs), the rationale of EVE in lung NET is also based on its involvement in angiogenesis process (regulating the activity of hypoxia-inducible factor alpha, HIF-α, and the expression of VEGF and PDGF-b)58 and in tyrosine kinase activation (EGFR, IGFR and FGFR-3).

CLINICAL EVALUATION OF EVEROLIMUS TREATMENT IN NEUROENDOCRINE TUMOR OF THE LUNG

Results of Literature Review

Records identified through literature search were 610:123 from MEDLINE searching, 357 from Embase and 130 from Scopus.

The total number of manuscripts screened was 97.

On the basis of the aforementioned criteria of selection, eligible studies included in the final analysis were 6 (Table 2, Supplementary Figure 1).59–65

Publishers Alliance 081420 Table 2

All but one included thoracic and extra-thoracic populations. Three were randomised controlled trials (RCTs), two Phase III and one Phase II. The LUNA trial was the only one specifically designed for patients with advanced lung/thymic NETs. It was a three-arm randomised Phase II trial comparing Pasireotide (PAS) with everolimus (EVE) with both. The other two randomised trials were double-arm placebo-controlled phase III randomised trials: the RADIANT-2 for patients with carcinoid syndrome-associated NETs from any origin and RADIANT-4 for non-functioning non-pancreatic gastrointestinal and lung NETs.

Finally, the ITMO study was a prospective single-arm phase II and two studies were post hoc retrospective analyses from the RADIANT-2 and RADIANT-4.

Overall, 185 patients with lung NET received EVE within prospective trials (Table 3)

Publishers Alliance 081420 Table 3

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