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. 2016 Oct 25;10(1):132–141. doi: 10.1177/1756283X16674660

Everolimus in the management of metastatic neuroendocrine tumours

David L Chan 1, Eva Segelov 2, Simron Singh 3,✉
PMCID: PMC5330615  PMID: 28286565

Abstract

Neuroendocrine tumours are increasing in incidence and cause a variety of symptoms. The mammalian target of rapamycin (mTOR) pathway plays a key role in neuroendocrine tumour (NET) pathogenesis, leading to increased lipid synthesis, protein synthesis and cellular growth. Upregulation of this pathway is noted in both hereditary and sporadic NETs. This understanding has led to investigations of mTOR inhibitors as therapy for metastatic NETs. After promising preclinical findings, everolimus, an mTOR inhibitor, was trialled in the RADIANT-1−4 studies on patients with advanced, well differentiated NETs. RADIANT-3 and RADIANT-4 established the efficacy of everolimus in improving progression-free survival (PFS) for metastatic NET of pancreatic, lung and gastrointestinal origin, leading to the US Food and Drug Administration (FDA) approval for its use in tumour control in those settings. Everolimus treatment is generally well tolerated; common adverse events include stomatitis, diarrhoea, rash and hyperglycaemia. Although discontinuation rates are low, many patients may require dose modification to successfully continue therapy. The combination of everolimus with somatostatin analogues (SSAs) (such as octreotide or pasireotide) or other targeted agents such as bevacizumab has not produced additional incremental benefit, and dual biologic therapy is not used widely. Ongoing trials are investigating everolimus compared with chemotherapy, optimal sequencing of therapy and combination of everolimus with radiotherapy. Future research should concentrate on identification of predictive biomarkers for benefit from mTOR therapy and include quality of life as a measure.

Keywords: everolimus, neuroendocrine tumors, RADIANT, review

Introduction

Neuroendocrine tumours (NETs) are a heterogeneous group of malignancies arising from neuroendocrine cells that are scattered throughout the body. NETs most commonly arise from the gastrointestinal tract (particularly pancreas and small bowel), followed by lung, unknown primary, liver and thymus [Yao et al. 2008]. Previously considered as a rare tumour, their incidence has increased markedly over the last 15 years [Hallet et al. 2015]. Increased incidence can be attributed to greater utilization of gastrointestinal (GI) investigations for vague or often unrelated symptoms (endoscopy and various modalities of greatly improved GI imaging), as well as greater clinician and patient awareness of the disease; increasing prevalence is due to the extended prognosis of many of these tumours, even with widespread metastatic disease.

NETs are challenging malignancies to diagnose and treat because of the marked variability in clinical presentation and course. Much progress has been made in the last 10 years in understanding the heterogeneity of NETs and developing appropriate clinical pathways for diagnosis, monitoring and therapy. NETs are usually classified by anatomical origin as well as histological grade based on the European Neuroendocrine Tumour Society (ENETS)/World Health Organization (WHO) 2010 classification (Table 1) [Klimstra et al. 2010]. The term gastroenteropancreatic NET (GEPNET) encompasses all tumours from the foregut, midgut and hindgut. However, certain subtypes of NET [particularly pancreatic NETs (pNET)] vary in terms of genetic mutations, clinical course and response to therapies, which is the basis for clinical trials being restricted to various predefined subgroups.

Table 1.

World Health Organization (WHO) 2010 classification of neuroendocrine tumours.

Grade Mitotic count (mitoses/ 10 high power fields) Ki-67 index WHO/ENETS nomenclature
Grade 1 <2 mit/10 HPF <3% Neuroendocrine tumour
Grade 2 2–20 mit/10 HPF 3–20% Neuroendocrine tumour
Grade 3 >20 mit/10 HPF >20% Neuroendocrine carcinoma (large cell or small cell type)
Mixed adenoneuroendocrine carcinoma
Hyperplastic and preneoplastic lesions
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Mit, mitoses; HPF, high power fields; WHO, World Health Organization; ENETS, European Neuroendocrine Tumour Society.

Metastatic NETs can cause symptoms from secretion of hormones (flushing, diarrhoea, hypoglycaemia, gastric ulcers from excess production of serotonin or specific hormones relating to cell of origin, for example, insulin from insulinoma, gastrin from gastrinoma) or from mass effect (pain, anorexia, weight loss, nausea, bowel obstruction). Until recently, treatment options in NETs were limited and consisted of somatostatin analogues (SSAs), which are highly effective in controlling hormonal secretory symptoms. Long-acting formulations of SSA were subsequently shown to have an antiproliferative effect even in nonsecretory tumours [Caplin et al. 2014; Rinke et al. 2009]. Two other classes of therapy have been used for more than 20 years: interferon [di Bartolomeo et al. 1996; Faiss et al. 2003] and chemotherapy [Moertel et al. 1992]; however, these have limited efficacy and a dearth of high-quality evidence for use.

Understanding the molecular pathways underlying NET tumourogenesis and proliferation has been facilitated by the advent of highly sensitive deep sequencing and other molecular techniques. The identification of intracellular pathways amenable to targeting by specific ‘biological agents’ has been particularly successful. Targeting of the ubiquitous mammalian rapamycin (mTOR) pathway has been a story of rapid success in translational cancer therapeutics; NETs being a prime example of the successful implementation of this ‘bench to bedside’ approach.

The role of the mTOR pathway: the biological rationale for everolimus in treatment of neuroendocrine tumours

mTOR is an intracellular protein kinase with critical functions related to cell-cycle control [Hashemolhosseini et al. 1998] and cell growth [Dufner and Thomas, 1999]. It is a serine/threonine kinase belonging to the phosphoinositide-3 kinase (PI3K) family that forms two complexes – mTOR complexes 1 and 2 (mTORC1, mTORC2). It receives much of its upstream inputs from tuberous sclerosis (TSC1/2) that transmits inputs from diverse pathways such as insulin-like growth factor 1 (IGF1), protein kinase B (Akt/PKB), extracellular-signal-regulated kinases 1 and 2 (ERK1/2), ribosomal s6 kinase 1 (RSK1) and the Wnt pathway (Figure 1). It also receives inputs from TSC1/2-independent mechanisms such as Akt (via pras40) and AMPK. Downstream, mTORC1 upregulates protein synthesis, lipid synthesis and cellular metabolism, as well as downregulating autophagy. The role of mTORC2 is less well defined and the subject of ongoing research. For an extensive review of the mTOR pathway, readers are referred to Laplante and Sabatini [Laplante and Sabatini, 2012].

Figure 1.

Figure 1.

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Upstream activation (Figure 1A) and downstream effects (Figure 1B) of mTORC1. Reproduced with permission from Laplante and Sabatini [2012].

As the name suggests, rapamycin has inhibitory effects on the mTOR pathway, and biosimilar drugs such as the oral agent everolimus (formerly known as RAD001) and the intravenous drug temsirolimus have been used for many years as a key component of the immunosuppressive regimen in organ-transplant recipients [Eisen et al. 2003; Webster et al. 2006]. Everolimus binds to the intracellular receptor FKBP-12 and inhibits the mTOR pathway. In significantly higher doses than its immunosuppressive effect, everolimus has shown anticancer activity in renal cell carcinoma [Motzer et al. 2008] and as a reverser of acquired resistance to aromatase inhibition in hormone-positive metastatic breast cancer [Baselga et al. 2012].

Several key observations led to the investigation of mTOR inhibitors in NETs. Patients with TSC1/2 and neurofibromatosis (NF1), mediated by the TSC1/2 pathway, have an increased risk of NETs. TSC1/2 is intimately related to mTOR regulation and mTOR is constitutively activated in NF-1-deficient cells [Johannessen et al. 2005]. Whole-exome sequencing of initially 10 and then a further 58 pNETs demonstrated mutations in genes in the mTOR pathway in 14% of cases [Jiao et al. 2011]. A series of 99 GEPNETs reported a 70% rate of mutation in foregut NET and 53% in midgut NETs. Additionally, downregulation of the TSC2 gene was shown in 90 of 137 pNETs (67%), where pNET downregulation was seen in 56 of 137 (41%) [Missiaglia et al. 2010].

Treatment with both rapamcyin and RAD001 inhibited cell proliferation in various NET cell-culture models [Missiaglia et al. 2010; Moreno et al. 2008; Zatelli et al. 2010]. Upregulation of mTOR and its downstream components (p-RPS6KB1, p-RPS6, or p-EIF4EBP1) in tissue from unexposed patients with resected/biopsied gastrointestinal and lung NETs was associated with shorter overall and progression-free survival (PFS) [Qian et al. 2013; Righi et al. 2010].

Based on the data above, a number of randomized phase II and III studies have been conducted to examine the clinical effect of everolimus in metastatic, inoperable GEPNETs. The major trials have been summarized in Table 2.

Table 2.

Randomized trials of everolimus in neuroendocrine tumours.

Trial (phase) Intervention Population Progression-free survival
HR, p value,
median		 Overall survival
HR, p value or 95% CI		 Objective response rate
RADIANT-2 (III) Everolimus + octreotide LAR versus octreotide LAR Mixed functioning NET HR 0.77, p = 0.026, 16.4 versus 11.3 months HR 1.22; 95% CI, 0.91–1.62 2.4% versus 2%
RADIANT-3 (III) Everolimus versus placebo pNET HR 0.35; p < 0.001; 11 versus 4.6 months HR 1.05, p = 0.59; 95% CI, 0.71–1.55 5% versus 2%
RADIANT-4 (III) Everolimus versus placebo Gastrointestinal and lung nonfunctioning NET HR 0.48; p < 0.00001; 11.0 versus 3.9 months Median not reached 2% versus 1%
COOPERATE-2 (II) Everolimus + pasireotide versus everolimus PNET HR 0.99; p = 0.488; 16.82 versus 16.59 months Median not reached 20.3% versus 6.2%
CALGB 80701 (II) Everolimus + octreotide LAR + bevacizumab versus everolimus + octreotide LAR pNET HR 0.80; p = 0.12; 16.7 versus 14 months HR 0.75; p = 0.16; 95% CI, 0.42–1.33; 36.7 versus 35 months 31% versus 12%
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LAR, long-acting release; CI, confidence interval; HR, hazard ratio; NET, neuroendocrine tumour; pNET, pancreatic neuroendocrine tumour.

The RADIANT trials

The RADIANT trials are a series of studies that have firmly embedded everolimus in the management of patients with metastatic NETs. The RADIANT-1 trial [Yao et al. 2010] was a single-arm phase II study of everolimus 10 mg daily in 160 patients with metastatic pNETs who had progressed after prior chemotherapy. The primary endpoint, response rate (RR), was reported at 9.6% in the stratum of 115 patients not being treated with octreotide with acceptable toxicity profiles. The median PFS was 9.7 months and overall survival (OS) was 24.9 months. A smaller cohort of 45 patients (Stratum 2) received everolimus and continued octreotide long-acting release (LAR) at the prestudy dose, with RR 4.4%, PFS 16.7 months and OS not reached at time of data cutoff.

RADIANT-1 formed the basis for proceeding to phase III randomized controlled trials to explore efficacy of everolimus in NET with carcinoid syndrome (RADIANT-2), pNET (RADIANT-3) and both lung and gastrointestinal NET (RADIANT-4). RADIANT-3 [Yao et al. 2011] was a pivotal multicentre, double blind, randomized phase III study of 410 patients with low-to-intermediate grade advanced pNET who were randomized 1:1 to everolimus 10 mg daily or placebo plus best supportive care. Crossover was allowed on RECIST-confirmed disease progression. The primary endpoint of PFS was significantly prolonged from 4.6 months in the placebo arm to 11 months in the everolimus arm [hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.27–0.45; p < 0.0001]. Subgroup analyses revealed benefit regardless of age, performance status, use of prior SSA or tumour grade. With regard to secondary endpoints, RR was 2% in the placebo arm compared with 5% in the everolimus arm, underscoring the main benefit of everolimus in maintaining stable disease rather than radiological shrinkage of tumour, although it is recognized that the RECIST criteria may be particularly inadequate for assessing response to biological therapies. OS was not significantly different (HR, 1.05; p = 0.59), likely due to the 73% of patients in the placebo arm who crossed over to active treatment on progression. Everolimus was generally well tolerated, with 13% of patients discontinuing therapy due to side effects. The most common side effects were stomatitis (all grades, 64%; grade 3−4, 7%), rash (all grades, 49%; grade 3−4, <1%), diarrhoea (all grades, 34%; grade 3−4, 3%) and fatigue (all grades, 31%; grade 3−4, 2%). Hyperglycaemia was seen in 13% of patients on everolimus, with 5% being grade 3–4. One patient died from pneumonitis likely related to treatment.

RADIANT-2, [Pavel et al. 2011] commenced at the same time as RADIANT-3, was a phase III double-blinded randomized trial which investigated the use of everolimus in addition to SSA in 429 patients with advanced low-to-intermediate grade functional NETs originating in the small intestine (52%), lung (10%) and other GI primary sites (colon 6%, pancreas 6%, liver 4%, other 21%). Patients were randomized 1:1 to the combination of everolimus 10 mg daily plus octreotide LAR 30 mg every 28 days versus placebo plus octreotide LAR. PFS by central radiology review, the primary endpoint, was 16.4 versus 11.3 months respectively, with HR 0.77 (95% CI, 0.59–1.00; p = 0.026). As the significance boundary for the p value had been set at 0.0246 due to adjustment for two interim analyses, this result did not reach prespecified significance. On retrospective analysis, however, there was imbalance in the arms based on known prognostic indicators (the high proportion of patients with lung primary, performance status 1−2 and moderately differentiated disease in the everolimus group), as well as discrepancy between the central and local radiological review, reflecting a common issue of response assessment in NETs. Rates of toxicity were comparable with those noted in RADIANT-3.

RADIANT-4 [Yao et al. 2016] followed from the somewhat inconclusive RADIANT-2 results. The trial was designed to restrict enrolment to patients with either gastrointestinal or lung NETs without evidence of carcinoid syndrome. A total of 302 patients were randomized on a 2:1 basis to everolimus or placebo. Prior SSA treatment was allowed, but SSAs were not continued on study except to treat symptoms of carcinoid syndrome that emerged on trial. Crossover was not permitted until trial results were available. A total of 67% of patients had pathological grade 1 disease with the remainder having grade 2 disease according to the WHO 2010 classification. The most common primary tumour sites were lung (30%), ileum (24%) and rectum (13%). Patients were stratified by tumour site, prior SSA use and WHO performance status; baseline characteristics were well balanced. The primary endpoint, centrally assessed PFS, was met with a median of 11 months in the everolimus arm versus 3.9 months in the placebo arm; HR of 0.48 (0.35–0.67; p < 0.00001). Preliminary OS analyses indicated a trend toward improved OS (HR, 0.64; p = 0.037); formal data awaits maturation of the trial cohort. Objective RR was 2% in the everolimus arm and 1% in placebo arm; disease stabilization was achieved in 81% of the everolimus arm compared with 64% with placebo. The adverse event profile was similar to RADIANT-2 and RADIANT-3, with treatment discontinuation rate 12% in the everolimus arm and a 16% incidence of pneumonitis (1% Grade 3; no Grade 4). An a priori analysis by primary tumour origin suggested consistent PFS benefit in patients with gastrointestinal primaries (HR, 0.56; 95% CI, 0.37–0.84) [Singh et al. 2016a] and those with lung primary (HR, 0.50; 95% CI, 0.28–0.88) [Fazio et al. 2016].

Based on this data, everolimus has recently received US Food and Drug Administration (FDA) approval for the treatment of adult patients with progressive, well differentiated, nonfunctional, advanced NET of GI or lung origin. The abovementioned trials have caused much debate as to the optimal role of everolimus in the treatment paradigm, particularly in combination with SSA. In functional NETs, the use of SSA can ameliorate symptoms. However, the RADIANT-3 and -4 trials, as above, did not allow SSAs on enrolment. While patients on both arms of RADIANT-2 received SSAs, the change in statistical threshold for significance due to interim analyses meant that the p value of 0.026 was not deemed significant. The combination of SSA and everolimus, therefore, is known to be well tolerated, but its antineoplastic efficacy over either of the drugs alone, in either functional or nonfunctional NETs, is yet to be fully determined.

Everolimus in combination with new somatostatin analogues

Pasireotide is an SSA with greater affinity to the somatostatin receptors 1, 3 and particularly 5, in comparison with both octreotide and lanreotide that predominantly bind to somatostatin receptor 2. COOPERATE-2 [Kulke et al. 2015a] was a phase II study in which 160 patients with advanced, progressive grade 1−2 pNET (56% with elevated chromogranin A or neuron-specific enolase (NSE)) were randomized to the combination of everolimus plus pasireotide versus everolimus alone. The results were reported in abstract form at ENETS 2015. PFS was not improved with HR 0.991 (95% CI, 0.64–1.54), although RR was significantly improved (20% versus 6%). Significantly higher rates of toxicity were noted with the combination, particularly hyperglycaemia (all grades 76% versus 27%) and diabetes mellitus (26% versus 7%). Results regarding symptom control have not yet been presented.

Everolimus in combination with other biological agents

CALGB 80701 [Kulke et al. 2015b] was a randomized phase II trial comparing the combination of everolimus and the vascular endothelial growth factor (VEGF)-inhibitor bevacizumab (10 mg/kg twice per week) to everolimus alone in 150 patients with advanced Grade 1−2 pNET who had progressed in the prior 12 months. Patients in both arms, regardless of the functionality of the tumours, received concomitant octreotide at the standard institutional dosage. The patient population was roughly comparable with other major NET trials, with median age 59 years and 57% of patients having performance status 0. The primary endpoint, PFS, was marginally improved from 14 months to 16.7 months (HR, 0.80; p = 0.12); this was deemed statistically significant due to a predetermined p value cutoff of 0.15. The RR was also improved (31% versus 12%; p = 0.005). Grade 3–4 adverse events were reported in 81% of the combination arm and 49% of the monotherapy arm. Notably, Grade 3–4 hypertension occurred in 38% of bevacizumab arm compared with 8% of the monotherapy arm, with proteinuria (16% versus 1%), diarrhoea (11% versus 1%) and hypophosphataemia (10% versus 1%) all being more common in the combination arm; these are well known specific side effects of bevacizumab. Hyperglycaemia was not significantly different at 14% and 12%, respectively.

The results of the two trials above illustrate the amount that is still unknown about the use of everolimus. The increased RR observed in COOPERATE-2 failed to translate into an increased PFS. A study of single-agent pasireotide compared with octreotide in a phase III trial that did show improved PFS, but this was not the primary endpoint of the trial [Wolin et al. 2015]. While the full publication of COOPERATE-2 is awaited, there is currently insufficient data to recommend the combination of everolimus and pasireotide in clinical practice.

The significant improvement in PFS seen in CALGB 80701 should also be seen as a preliminary finding. The RR of 31% is quite impressive in this cohort of patients, and points to the potential biological activity of this combination. The high alpha (type I error rate) of the trial design means that further confirmatory trials will be necessary to determine the true benefit of everolimus and bevacizumab in addition to octreotide. This route of investigation is further supported by a phase II single-arm trial of temsirolimus and bevacizumab in pNETs which reported a promising RR of 41% [Hobday et al. 2015].

Quality of life

Quality of life (QOL) data were measured in RADIANT-4 using FACT-G; this was reported at two recent conferences. The time to deterioration in FACT-G was not significantly different in the two arms [Pavel et al. 2016a]; disease progression was associated with worse FACT-G [Singh et al. 2016b]. No QOL data were collected in the other RADIANT trials. The only other data published on QOL in patients on everolimus comes from an expanded access programme involving 246 patients of which 50% had pNET. Patients with pNET experienced stable QOL during treatment, while patients with midgut NET reported a −13-point change in QLQ-C30 from baseline, which was attributed mainly due to disease progression [Pavel et al. 2013]. The lack of extensive QOL data in NETS represents a gap in full understanding of best possible treatment in NET care. In an often indolent or slowly progressive disease like NETs, QOL may be an important factor in determining treatment options. It is imperative that further trials of everolimus in NETs include QOL.

Ongoing trials of everolimus

Several larger trials are currently ongoing investigating the role of everolimus in other settings. A phase II trial [ClinicalTrials.gov identifier: NCT02031536] randomizing patients with resected liver metastases from pNET to everolimus or placebo in an adjuvant fashion, was closed due to poor accrual. There is currently a phase III trial [ClinicalTrials.gov identifier: NCT02246127] randomizing patients with metastatic NET to everolimus or STZ-5FU. A phase II trial [EudraCT Number: 2014-003951-72] is randomizing patients with metastatic NEC (Ki67 <55%) and stable disease or better, on first-line platinum-based chemotherapy to everolimus or observation. SEQTOR is a trial randomizing patients to everolimus followed by STZ-5FU or the same drugs in reverse order. Results of these trials will help to further optimize the use of everolimus in this population. A phase I/II trial [ClinicalTrials.gov identifier: NCT02205515] of external-beam radiotherapy with concurrent everolimus, is due to open for accrual shortly.

Everolimus in the current clinical setting

Based on the recent trials mentioned above, it is clear that everolimus has an influence on the mTOR pathway in metastatic GEPNETs and improving PFS (an acceptable surrogate endpoint in NETs) [Ter-Minassian et al. 2015]. The generally manageable toxicity profile and oral mode of administration make this an exciting agent for NET patients who have few treatments available traditionally.

Everolimus is currently approved by the FDA for treatment of adult patients with progressive, well differentiated (grade 1 and 2) nonfunctional NETs of gastrointestinal or lung origin, as well as progressive pNETs based on the RADIANT-4 and -3 trials, respectively. Generally, everolimus is used on most patients after progression on SSA in GI NETs largely due to the favourable safety profile of SSA. However, it should be noted that 39% of patients in RADIANT-4 had not received an SSA or chemotherapy prior to everolimus treatment. Subgroup analysis revealed significant improvement in PFS regardless of prior SSA use making everolimus an option as first-line treatment. Unfortunately, no biomarker is currently available to determine what patients may benefit from everolimus first line, which would be valuable information to help guide treatment. Everolimus may be considered in the first-line context where the evidence for SSAs does not exist (e.g. lung NET), or specific effects of everolimus are desired (e.g. in treatment of insulinoma) [Pavel et al. 2016b]. Treatment is usually initiated at 10 mg daily, with dose reduction to 5 mg daily (level 1) then 5 mg every second day (level 2), in case of unmanageable toxicities. Dose reduction is required in clinical practice in a significant proportion of patients; 67% of patients treated with everolimus in RADIANT-4 underwent dose reductions or temporary treatment interruptions. In select poor-performance patients, 5 mg daily could be used as the initial dose with uptitration to 10 mg daily if treatment is well tolerated. Regular tumour measurements, with computed tomography or magnetic resonance imaging at approximately 3-monthly intervals is recommended, as per the RADIANT trials, as well as monitoring of serum chromogranin A/urinary 5-HIAA according to institutional practice.

Future directions

Everolimus has been firmly established as a viable and effective treatment option in NETs, moving from the pNET population to now encompass patients with metastatic NET of any origin, since the recent publication of the RADIANT-4 trial. However, many questions remain, including understanding of the development of resistance to mTOR inhibition and optimal partnering with other antiproliferative agents, as well as sequencing strategies. While multiple candidate biomarkers have been explored to predict efficacy of everolimus, no effective and reproducible biomarker has been identified. A phase II trial of temsirolimus identified higher baseline plasma mTOR levels as a predictor of treatment response, but this is yet to be shown as useful in clinical monitoring.

Currently, everolimus is approved in the treatment of nonfunctional GI NETs based on the results of the RADIANT-4 clinical trial. Based on the ambiguous results of the RADIANT-2 trial, it is unclear as to the effect of everolimus in functional patients. Recent studies [Caplin et al. 2014; Rinke et al. 2009] have confirmed the antiproliferative effect of SSAs which may have muted the effect of everolimus in the RADIANT-2 trial, in addition to the problems with study design (imbalance between the arms, discrepancy in response determination in central versus local review). Although everolimus is known to be beneficial in certain specific hormonal syndromes such as insulinoma [Kulke et al. 2009], its use in functional GI NETs remains unclear. There appears to be little evidence pointing towards a clinical discrepancy between functional and nonfunctional GI NETs [Wang et al. 2011].

Conclusion

The establishment of everolimus as an oral, effective treatment option in NETs is an exemplar of translational medicine. Further research will investigate the value of combining everolimus with other therapies targeting intersecting cellular pathways and the important question of optimally sequencing NET therapies. Deeper understanding of the molecular landscape of the heterogeneous entity of NETs will drive research into diagnostic and therapeutic options and help achieve prolonged survival and improved QOL for NET patients.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: DC has received honoraria from Ipsen and travel funding from Novartis. SS has received honoraria and travel funding from Ipsen, Pfizer and Novartis.

Contributor Information

David L. Chan, Odette Cancer Centre, Toronto, ON, Canada

Eva Segelov, St Vincent’s Hospital, New South Wales, Australia.

Simron Singh, Odette Cancer Centre, 2075 Bayview Avenue, Room T2 047, Toronto, ON, Canada M4N 3M5.

References

  1. Baselga J., Campone M., Piccart M., Burris H., Rugo H., Sahmoud T., et al. (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366: 520–529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Caplin M., Pavel M., Ćwikła J., Phan A., Raderer M., Sedláčková E., et al. (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371: 224–233. [DOI] [PubMed] [Google Scholar]
  3. Di Bartolomeo M., Bajetta E., Buzzoni R., Mariani L., Carnaghi C., Somma L., et al. (1996) Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 77: 402–408. [DOI] [PubMed] [Google Scholar]
  4. Dufner A., Thomas G. (1999) Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res 253: 100–109. [DOI] [PubMed] [Google Scholar]
  5. Duran I., Kortmansky J., Singh D., Hirte H., Kocha W., Goss G., et al. (2006) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95: 1148–1154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Eisen H., Tuzcu E., Dorent R., Kobashigawa J., Mancini D., Valantine-von Kaeppler H., et al. (2003) Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 349: 847–858. [DOI] [PubMed] [Google Scholar]
  7. Faiss S., Pape U., Bohmig M., Dorffel Y., Mansmann U., Golder W., et al. (2003) Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 21: 2689–2696. [DOI] [PubMed] [Google Scholar]
  8. Fazio N., Buzzoni R., Delle Fave G., Tesselaar M., Wolin E., Van Cutsem E., et al. (2016) Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the lung: a subgroup analysis of the phase III RADIANT-4 study. Presented at 2016 ENETS. Abstr #P1 Neuroendocrinology 103(Suppl. 1): 104. [Google Scholar]
  9. Hallet J., Law C., Cukier M., Saskin R., Liu N., Singh S., et al. (2015) Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 121: 589–597. [DOI] [PubMed] [Google Scholar]
  10. Hashemolhosseini S., Nagamine Y., Morley S., Desrivières S., Mercep L., Ferrari S., et al. (1998) Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 273: 14424–14429. [DOI] [PubMed] [Google Scholar]
  11. Hobday T., Qin R., Reidy-Lagunes D., Moore M., Strosberg J., Kaubisch A., et al. (2015) Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol 33: 1551–1556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jiao Y., Shi C., Edil B., de Wilde R., Klimstra D., Maitra A., et al. (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331: 1199–1203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Johannessen C., Reczek E., James M., Brems H., Legius E., Cichowski K., et al. (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA 102: 8573–8578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Klimstra D., Modlin I., Coppola D., Lloyd R., Suster S. (2010) The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 39: 707–712. [DOI] [PubMed] [Google Scholar]
  15. Kulke M., Bergsland E., Yao J. (2009) Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 360: 195–197. [DOI] [PubMed] [Google Scholar]
  16. Kulke M., Ruszniewski P., van Cutsem E., Valle W., de Herder W., Pavel M., et al. (2015a) A randomized open-label phase II study of Everolimus alone or in combination with Pasireotide LAR in advanced, progressive pancreatic neuroendocrine tumors (pNET): COOPERATE-2 trial. Presented at the 12th Annual ENETS conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Barcelona Neuroendocrinology 102: 131. [Google Scholar]
  17. Kulke M., Niedzwiecki D., Foster N., Fruth B., Kunz P., Kennecke H., et al. (2015b) Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance). J Clin Oncol 33(suppl.): abstract 4005. [Google Scholar]
  18. Laplante M., Sabatini D. (2012) mTOR signaling in growth control and disease. Cell 149: 274–293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Missiaglia E., Dalai I., Barbi S., Beghelli S., Falconi M., della Peruta M., et al. (2010) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR Pathway. J Clin Oncol 28: 245–255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Moertel C., Lefkopoulo M., Lipsitz S., Hahn R., Klaassen D. (1992) Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 326: 519–523. [DOI] [PubMed] [Google Scholar]
  21. Moreno A., Akcakanat A., Munsell M., Soni A., Yao J., Meric-Bernstam F., et al. (2008) Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr Relat Cancer 15: 257–266. [DOI] [PubMed] [Google Scholar]
  22. Motzer R., Escudier B., Oudard S., Hutson T., Porta C., Bracarda S., et al. (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372: 449–456. [DOI] [PubMed] [Google Scholar]
  23. Pavel M., Hainsworth J., Baudin E., Peeters M., Hörsch D., Winkler R., et al. (2011) Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase III study. Lancet 378: 2005–2012. [DOI] [PubMed] [Google Scholar]
  24. Pavel M., Strosberg J., Bubuteishvili-Pacaud L., Degtyarev E., Neary M., Hunger M., et al. (2016a) Health-related quality of life (HRQoL) in patients with advanced, nonfunctional, well-differentiated gastrointestinal (GI) or lung neuroendocrine tumors (NET) in the phase III RADIANT-4 trial. J Clin Oncol 34(suppl.): abstract e15657. [Google Scholar]
  25. Pavel M., O’Toole D., Costa F., Capdevila J., Gross D., Kianmanesh R., et al. (2016b) ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 103: 172–185. [DOI] [PubMed] [Google Scholar]
  26. Pavel M., Unger N., Borbath I., Ricci S., Hwang T., Park Y., et al. (2013) Safety and Quality-Of-Life (QOL) assessments in the open-label, multicenter, phase IIIb, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET). Presented at 2013, NANETS. Abstr C27. [Google Scholar]
  27. Qian Z., Ter-Minassian M., Chan J., Imamura Y., Hooshmand S., Kuchiba A., et al. (2013) Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol 31: 3418–3425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Righi L., Volante M., Rapa I., Tavaglione V., Inzani F., Pelosi G., et al. (2010) Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer 17: 977–987. [DOI] [PubMed] [Google Scholar]
  29. Rinke A., Müller H., Schade-Brittinger C., Klose K., Barth P., Wied M., et al. (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27: 4656–4663. [DOI] [PubMed] [Google Scholar]
  30. Singh S., Carnaghi C., Buzzoni R., Raderer M., Lahner H., Valle J., et al. (2016a) Everolimus for Advanced, Progressive, Nonfunctional Neuroendocrine Tumors (NET) of the Gastrointestinal (GI) Tract: efficacy and safety from a RADIANT-4 subgroup analysis. Neuroendocrinology 103(suppl. 1): 85. [PubMed] [Google Scholar]
  31. Singh S., Pavel M., Strosberg J., Bubuteishvili-Pacaud L., Degtyarev E., Neary M., et al. (2016b) Association of disease progression, health-related quality of life, and utility in patients with advanced, nonfunctional, well-differentiated gastrointestinal or lung neuroendocrine tumors in the phase 3 RADIANT-4 Trial. J Clin Oncol 34(suppl.): abstract 4093. [Google Scholar]
  32. Ter-Minassian M., Brooks N., Brais L., Chan J., Christiani D., Lin X., et al. (2015) Association of progression-free survival with overall survival (OS) in patients (pts) with neuroendocrine tumor (NET) treated with somatostatin analogs. J Clin Oncol 33: 4090. [Google Scholar]
  33. Wang S., Su C., Kuo Y., Shyr Y., Li A., Chen T., et al. (2011) Comparison of functional and nonfunctional neuroendocrine tumors in the pancreas and peripancreatic region. Pancreas 40: 253–259. [DOI] [PubMed] [Google Scholar]
  34. Webster A., Lee V., Chapman J., Craig J. (2006) Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 81: 1234–1248. [DOI] [PubMed] [Google Scholar]
  35. Wolin E., Jarzab B., Eriksson B., Walter T., Toumpanakis C., Morse M., et al. (2015) Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther 9: 5075–5086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yao J., Fazio N., Singh S., Buzzoni R., Carnaghi C., Wolin E., et al. (2016) Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase III study. Lancet 387: 968–977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yao J., Hassan M., Phan A., Dagohoy C., Leary C., Mares J., et al. (2008) One hundred years after ‘carcinoid’: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26: 3063–3072. [DOI] [PubMed] [Google Scholar]
  38. Yao J., Lombard-Bohas C., Baudin E., Kvols L., Rougier P., Ruszniewski P., et al. (2010) Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 28: 69–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yao J., Shah M., Ito T., Bohas C., Wolin E., Van Cutsem E., et al. (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364: 514–523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zatelli M., Minoia M., Martini C., Tagliati F., Ambrosio M., Schiavon M., et al. (2010) Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids. Endocr Relat Cancer 17: 719–729. [DOI] [PubMed] [Google Scholar]

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