Abstract
Digestive neuroendocrine neoplasms (DNENs) have an incidence of 2.39 per 100,000 inhabitants per year, and a prevalence of 35 cases per 100,000; the gap between these rates is to be referred to the relatively long survival that characterizes the majority of these tumors, which can be thus considered as chronic oncological diseases. Up to 80% of patients are stage IV since the first diagnosis, presenting a 5-yr overall survival rate of 35%–55% and a twice higher mortality than limited disease. DNENs express somatostatin receptors in more than 80% of cases, detected through immunohistochemistry or functional imaging tests (FITs). This feature identifies patients who may benefit from “cold” somatostatin analogs (SSAs) or peptide receptors radionuclide therapy, although SSAs are sometimes used also with a negative uptake at FITs. The therapeutic options have been recently increased after the identification of molecular pathways involved in DNENs pathogenesis, and the subsequent use of targeted therapies (i.e., Everolimus and Sunitinib) for these neoplasms.
This review offers an overview about pancreatic and small bowel NENs, critically underlining the issues that still need to be clarified and the future perspectives to be investigated.
Keywords
1. Introduction
Digestive neuroendocrine neoplasms (DNENs) are usually considered as “rare” cancers, characterized by a gap between the low incidence and the prevalence. They are in fact frequently slowly growing, and behave as chronic oncological diseases with a relatively long survival [
1
, 2
, 3
]. Up to 80% of cases present as stage IV since diagnosis, with a 5-yr overall survival (OS) of 35%–55% and a mortality rate twice higher than patients without distant metastases [4
, 5
, 6
]. As they are often occasionally found at the age of fifty or even earlier, it is easy to imagine the impact on quality of life that these conditions may cause.DNENs express somatostatin receptors (SSTRs) in more than 80% of cases; this feature can be detected through immunohistochemistry or functional imaging tests (FITs), such as Somatostatin Receptor Scintigraphy (SRS), (also called Octreoscan®) or 68Ga-DOTA-peptide Positron Emission Tomography (PET)/Computed Tomography (CT) (68Ga-DOTA-PET/CT). These diagnostic tools have a pivotal role at diagnosis, completing disease staging and selecting cases eligible for peptide receptors radionuclide therapy (PRRT) or “cold” somatostatin analogs (SSAs); the latter treatment is however used also for patients with negative uptake at FIT [
7
, 8
]. After the identification of molecular pathways involved in DNENs pathogenesis (i.e., mTOR, VEGF signaling and TK inhibitors), the available options have been enriched by the introduction of targeted therapies (Everolimus, Sunitinib) [9
, 10
, 11
, 12
, 13
]. However studies focusing on the mechanisms underlying the resistance to these drugs, the strategies to escape it and how to potentiate their efficacy, are still ongoing [14
, - François R.A.
- Maeng K.
- Nawab A.
- et al.
Targeting focal adhesion kinase and resistance to mTOR inhibition in pancreatic neuroendocrine tumors.
Journal of the National Cancer Institute. 2015; 107https://doi.org/10.1093/jnci/djv123
15
, 16
, 17
].This review offers an overview about pancreatic (PNENs) and small bowel (SbNENs) NENs, critically underlining the issues that still need to be validated or optimized.
2. Epidemiology
The prevalence amounts for 35 cases per 100,000 inhabitants, and incidence has substantially increased over the past two decades, due to diagnostic techniques improvement [
1
, 18
]. In details, European age-adjusted rate raised from 13.3 to 21.3 per 100,000 person years. The estimated annual increase was of 5.1% in women and 2.1% in men, and it was more pronounced for tumors with intermediate aggressiveness.Epidemiological data mostly derive from retrospective analysis, such as national registries. The only prospective study remains the paper by Niederle et al., collecting all newly diagnosed DNENs during one year in Austria according to the “World Health Organization” (WHO) classification and the “European Neuroendocrine Tumor Society” (ENETS) [
19
, 20
, 21
, 22
]. Among its results, overall incidence of tumors with benign, uncertain and malignant behavior was described as 1.15, 0.43 and 0.81 per 100,000 inhabitants, respectively. The tumor primary site was small bowel in 15% of cases, and pancreas in only 9%.Up-to-date:
- •Prevalence rate higher than incidence (chronic oncological disease)
- •Increasing incidence over the last 20 years
Future perspectives:
- •To promote European registries collecting NENs patients’ information, with regular updating and data sharing, in order to produce papers with larger populations
- •To develop prospective studies enrolling new NENs diagnosis in several countries, in order to define their incidence rate in Europe
3. Molecular pathogenesis
Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of sporadic DNENs, identifying several pivotal pathways and providing new options in terms of therapy [
[23]
]. The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine kinase regulating cell survival, proliferation and motility; its expression increases (without mutations) in PNENs and is correlated with a higher proliferation index (evaluated by ki67) and a worse prognosis. The antagonist of PI3K (PTEN) is instead mutated or lost in about 10%–29% of sporadic PNENs, correlated with a better clinical outcome. EGFR (ErbB-1), a member of the ErbB family of tyrosine kinase receptors, is also involved in the mTOR pathway, and its activation is a negative prognostic factor for patients, upregulating downstream effectors such as Akt and ERK. Src Family of Kinases (SFK) is implicated in EGFR transactivation, cell adhesion and spreading of tumoral cells [- Capurso G.
- Archibugi L.
- Delle Fave G.
Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.
Journal of Hepato-Biliary-Pancreatic Surgery. 2015; https://doi.org/10.1002/jhbp.210
24
, 25
, 26
].Angiogenesis also seems to have a pivotal role in DNENs pathogenesis, as the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are expressed in these neoplasms and in the surrounding endothelia. Data evaluating their correlation with prognosis are controversial: some studies have proportionally related them to an aggressive tumor biology, others have paradoxically shown malignant forms as characterized by a lower VEGF expression. A possible explanation for this disparity might be that VEGF is somehow a marker of “well-differentiated” neoplasms; thus, when NENs are less differentiated and their rapid growth causes hypoxia, the hypoxia-inducible factors-1α (HIF-1α) pathway is activated, leading to an increase of endothelial proliferation. However, neoangiogenesis inhibition is the basis of a treatment choice for DNENs, using either tyrosine kinase inhibitors targeting the VEGFR and/or other related receptors [
27
, 28
].Besides these pathways that have already provided a therapeutic approach, new mechanisms are being investigated. For example, mutations of the alpha-thalasemia/mental retardation syndrome, X-linked (ATRX), and death domain-associated protein (DAXX) genes have been identified in DNENs. Data suggest them to be correlated with a worse prognosis, based on telomerase activity and chromosomal instability; however larger studies are needed to validate these results [
29
, 30
].Up-to-date:
- •PI3K/Akt/mTOR pathway and angiogenesis markers are the protagonists of the currently available targeted therapies
Future perspectives:
- •To better define the mechanisms underlining tumor escape from targeted therapies control, and defeat them by combining treatments acting on different pathway levels
- •To identify new molecular pathways, opening new horizons in terms of targeted therapies
4. Clinical presentation
DNENs are defined as “functioning” (25%–35% of patients) when associated with a syndrome due to hypersecretion of hormones or amines. For SbNENs, a typical “carcinoid syndrome” may be present and really impair quality of life. It is characterized by release of serotonin determining diarrhea, cutaneous flushing (especially on the face and neck skin) and in 20% of cases a carcinoid heart disease (with cardiac valve disfunction) [
31
, 32
]. The conventional treatment is the use of SSAs, which have been proved to be very effective in symptoms control; however, as not responding patients may occur, telotristat etiprate has been recently proposed to treat severe cases [33
, 34
, 35
, 36
]. This is an oral, systemically available drug, able to inhibit tryptophan hydroxylase, the rate limiting enzyme in the conversion of tryptophan to serotonin. The results of a Randomized Controlled Trial (RCT) (www.clinicaltrials.gov, NCT01677910) have been presented at the last European Cancer Congress (ECC; Vienna, September 2015); 135 patients with metastatic disease and uncontrolled carcinoid syndrome were randomly assigned to receive telotristat 250 mg (n = 45), telotristat 500 mg (n = 45), or placebo (n = 45). A significant clinical (improvement in diarrhea) and biochemical response was observed in the treatment arms; in details, both treatment groups met a reduced mean of bowel movements frequency than the placebo arm (P < 0.001), and the rate of cases with a durable response after the 12-week double-blind period was 44%, 42% and 20%, respectively. The therapy was continued at a dosage of 500 mg in an open-label regimen by 87% of patients.- Kulke M.H.
- Hörsch D.
- Caplin M.
- et al.
37LBA – Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial).
in: Late Breaking Abstract (37LBA) at the 2015 European Cancer Congress (ECC), Vienna, Austria2015
In PNENs, syndrome can be due to release of: gastrin in “gastrinomas”, vasoactive intestinal peptide in “VIPomas”, insulin in “insulinomas” and somatostatin in “somatostatinomas”. Clinical presentation is related to the different hormone released: gastrinoma diagnosis may follow the occurrence of diarrhea and gastric ulcers, not responding to high dose proton pump inhibitors; insulinoma patients may suffer from symptomatic hypoglycaemia, with sweating, confusion and even loss of consciousness [
[37]
].“Non-functioning” tumors, instead, can be silent for years even though 75% of these patients already have an advanced disease at the beginning of their clinical history. Thus, diagnosis is often incidentally made at surgery or during radiological follow-up for other malignancies. They are for example found at imaging tests performed for non-specific symptoms such as nausea, vomiting, anaemia, or pain due to tumor local invasion, bowel obstruction or mesenteric ischaemia. In addition, they can also present with mass effect of the primary tumor or metastases on the adjacent structures (i.e., jaundice due to primary site in the pancreatic head).
Being “rare” diseases, with a genetic background still to be defined, screening programs are not available.
Up-to-date:
- •DNENs may be an incidental diagnosis in case of “non functioning” tumors
Future perspectives:
- •To identify biomarkers, effective in early diagnosing non-functioning DNENs, allowing early treatments and influencing prognosis
5. Prognostic factors and classifications
Due to their biological and clinical heterogeneity, DNENs may show different prognosis; in fact, some tumors have a very malignant behavior, whereas in other patients disease may be stable for a long time even without any treatment. Several prognostic factors have been identified until now.Tumor primary site has been proved to affect OS by different papers, with pancreas showing a worse outcome than small bowel (5-yr survival rates: 62% vs. 89.9%, respectively) [
38
, 39
].Ki67 indicates neoplastic replicative index as the rate (expressed in percentage) of tumoral cells being in replicative phase, identified by positivity at a specific immunohistochemical staining. It represents the major, independent risk factor for disease progression (DP) in DNENs, with a hazard ratio (HR) of 1.02 for each increasing unit (P < 0.001) [
[6]
]. The G Grading classification has been proposed by the ENETS, identifying 3 categories of patients: G1 when ki67 is ≤2%, G2 when 3%–20%, and G3 if >20% [20
, 21
]. Although several papers have shown how the G Grading affects clinical outcome and response to therapy, the cut-off values are currently debated, in order to distinguish homogeneous groups. For example, G3 cases are affected by more active and aggressive neoplasms than G1/G2, but this group is represented by the major range of ki67 (from 21% to 100%); furthermore, the 55% cut-off has been proved to be associated with a different tumor response to chemotherapy (CHT). G1–G2 definition is being discussed as well, and an alternative value of 5% instead of 2% has been applied in retrospective series, testing its prognostic meaning in DNENs [5
, 6
, 38
, 39
, 40
, 41
].In parallel, the WHO classification has been introduced in 1980, revised in 2000 and then in 2010 (Table 1). This last version adopted the term “neuroendocrine” instead of “endocrine”, and beyond the histological differentiation it considered also G Grading to describe the tumoral subgroups [
[20]
]. For what concerns the third category (NEC G3), a subclassification distinguishing “well” vs. “poorly-differentiated” cases is currently discussed (NET G3 vs. NEC G3), as data in literature prove them to represent different populations; however larger series and prospective studies are needed to validate this suggestion [[42]
].Table 1World Health Organization (WHO) classification versions (1980, 2000, 2010).
| WHO 1980 | WHO 2000 | WHO 2010 |
|---|---|---|
| I. Carcinoid | 1. Well-differentiated endocrine tumor (WDET) 2. Well-differentiated endocrine carcinoma (WDEC) 3. Poorly-differentiated endocrine carcinoma/small-cell carcinoma (PDEC) | 1. NET G1 (carcinoid) 2. NET G2 3. NEC G3 large-cell or small-cell type |
| II. Mucocarcinoid III. Mixed forms carcinoid-adenocarcinoma | 4. Mixed exocrine-endocrine carcinoma (MEEC) | 4. Mixed adenoneuroendocrine carcinoma (MANEC) |
| IV. Pseudotumor lesions | 5. Tumor-like lesions (TLL) | 5. Hyperplastic and preneoplastic lesions |
For what concerns the disease staging, in 2006–2007 the ENETS TNM system was published, with T indicating tumor size and regional extent, N indicating the presence of lymph nodal involvement and M representing the distant metastases [
21
, 22
]. The “American Joint Committee on Cancer” (AJCC) has proposed another TNM in 2010; Table 2 directly compares the AJCC and the ENETS systems [[43]
].Table 2TNM staging systems for pancreatic neuroendocrine neoplasms according to the American Joint Committee on Cancer (AJCC) and the European Neuroendocrine Tumor Society (ENETS).
| AJCC | ENETS | ||
|---|---|---|---|
| T1 | Tumors limited to the pancreas, <2 cm | Tumors limited to the pancreas, <2 cm | |
| T2 | Tumor limited to the pancreas, >2 cm | Tumor limited to the pancreas, 2–4 cm | |
| T3 | Tumor extended beyond the pancreas, but not involving celiac axis or superior mesentery artery | Tumor extended beyond the pancreas, or invading duodenum or common bile duct | |
| T4 | Tumor involving celiac axis or superior mesentery artery | Tumor invading adjacent structures | |
| N0 | No regional lymph nodes metastases | No regional lymph nodes metastases | |
| N1 | Presence of regional lymph nodes metastases | Presence of regional lymph nodes metastases | |
| M0 | No distant metastases | No distant metastases | |
| M1 | Presence of distant metastases | Presence of distant metastases | |
| AJCC | ENETS | ||
| IA | T1 N0 M0 | I | T1 N0 M0 |
| IB | T2 N0 M0 | IIA | T2 N0 M0 |
| IIA | T3 N0 M0 | IIB | T3 N0 M0 |
| IIB | T1-3 N1 M0 | IIIA | T4 N0 M0 |
| III | T4 N0-1 M0 | IIIB | Any T, N1 M0 |
| IV | Any T, Any N, M1 | IV | Any T, Any N, M1 |
Stage IV (any T, any N, M1) NENs have a 5-yr OS of 35%–55% vs. 70%–100% of lower stages, and a two-fold higher mortality rate [
4
, 5
, 6
]; however, this group does not include a homogeneous series of patients. In details, a recent paper has shown how the different metastatic pattern is an independent prognostic factor from Ki67, with poorer OS and progression-free survival (PFS) rates for patients with extra-abdominal lesions than cases with only bilobar or unilobar secondaries; median PFS was 6 months, 19 months and 27 months, respectively (P = 0.0002) [[6]
].The presence of lymph nodal disease has also been proved to represent a risk factor for PNENs, with a HR of 2.75 for patients with a lymph nodal ratio >0.20 (P < 0.02) [[44]
]. For SbNENs, the role of this parameter still needs to be clarified [[45]
].Up-to-date:
- •Ki67 and the disease staging have been proved to be the major prognostic factors for DNENs, followed by the tumor primary site
- •The WHO 2010 and the ENETS TNM staging system are the mostly used classifications in Europe; they have been validated only by retrospective studies
Future perspectives:
- •To improve the current TNM, WHO and G Grading classifications by prospective studies, focusing on the definition of stage IV subgroups, and the distinction between NET G3 and NEC G3
- •To associate all the significant factors in order to define “risk scores”, useful to early describe the prognosis of each patient
6. Diagnosis
The sure diagnosis is based on histologic evaluation with immunohistochemistry, by identifying: neuroendocrine cells expressing chromogranin A (CgA) and synaptophysin, tumoral morphology (the grade of differentiation: well, moderately, poorly), and ki67 expression. Biopsy can be obtained through endoscopic procedures (esofagogastroduodenoscopy, colonoscopy, endoscopical ultrasound), liver biopsy on metastases or surgery [
46
, 47
]. Together with the pathological definition, tumor staging is also needed to assess the disease extent; this evaluation can be performed by morphological tests (contrast-enhanced CT scan and Magnetic Resonance Imaging; MRI) and FITs (SRS and 68Ga-DOTA-PET/CT) [9
, 10
].FITs identify lesions expressing SSTRs, and thus patients eligible for somatostatin-based therapies (SSAs or PRRT) [
9
, 10
, 48
, 49
]. 68Ga-DOTA-PET/CT has a higher accuracy both in detecting intra- and extra-abdominal lesions. In fact, it is CT-based and able to gather a quantitative measure of signal intensity through the Standardized Uptake Value (SUVmax) [[50]
].Besides these tests, others are being studied to understand what is their real usefulness if adopted for DNENs diagnosis. The diffusion-weighted MRI is proposed in metastatic patients to use the apparent diffusion coefficient (ADC) calculated during the exam as a potential marker of the histologic grade of PNENs, and as a predictor of response to selective internal radiotherapy (SIRT) [
51
, 52
]. The 18F-fluorodeoxyglucose PET/CT 18F-FDG-PET/CT is a FIT documenting the metabolic activity of tumoral lesions and, as many NENs present a low ki67, it has been reserved only to selected cases; in fact the positivity at 18F-FDG-PET/CT seems associated with low differentiated and high proliferating neoplasms [53
, 54
]. In details, Bahri et al. [[55]
] prospectively enrolled in a 3-year period 38 patients with metastatic DNENs, followed-up for 55.2 ± 37.9 months. They demonstrated a positive 18F-FDG-PET/CT with a SUV ratio of at least 2.5 to be a negative prognostic factor, with a 4-year survival rate of 0%; furthermore, this exam was advised also for patients expressing SSTRs, as among them PFS and OS rates were significantly shorter when the 18F-FDG-PET/CT was positive (P < 0.0001). Data available in literature are however controversial, as Partelli et al. [[56]
] have shown, in 49 PNENs, no significant impact on clinical management with the association of 18F-FDG-PET/CT and 68Ga-DOTA-PET/CT.Up-to-date:
- •Diagnosis is based on histological evaluation with calculation of ki67, and disease staging by morphological and functional exams
- •Functional imaging tests are also needed to identify patients who may benefit from somatostatin-based treatments
Future perspectives:
- •To validate in new prospective studies the role of diffusion-weighted MRI and 18F-FDG-PET/CT in DNENs, evaluating what is the adjunctive impact of their use in patients management, and to which cases they should be reserved
7. Therapy
Being characterized by a relatively long OS, multiple sequential therapies are adopted in DNENs although the best sequence for these patients has never been defined so far. The surgical treatment with radical intent is the option to prefer [
[57]
], but no data are available about adjuvant treatments.Another open issue is the management of non metastatic pancreatic nodules with a size <2 cm, as studies are needed to define the best approach between radical surgery or only follow-up according to the potential indolent behaviour of these lesions [
[58]
]. The European trial entitled “Follow-up Protocol of Sub-2cm Pancreatic NETs”, is quite aimed to compare these two options, and has been recently proposed at the last annual ENETS Conference (Barcelona, March 2016).In some cases (especially with functioning tumors) when a complete resection is not possible, surgery is performed in order to reduce symptoms. This approach can be based combining surgery on primary and secondary tumors with locoregional treatments (i.e., trans-arterial liver embolization, TAE; trans-arterial chemoembolization, TACE; radiofrequency ablation, RFA) [
9
, 10
]. Data about long-term prognosis after this approach are however scanty. The opportunity to resect the primary site in advanced tumors has been widely discussed; two systematic reviews of the literature suggested a possible benefit of this approach in terms of OS for both PNENs and SbNENs but, as no RCTs were available, metanalyses could not be performed and a strong conclusion not pointed out [59
, 60
]. Liver transplant is reserved to very well selected patients with a neoplasm limited to the liver, but data derive from small cohorts [61
, 62
].Another experimental approach to metastatic disease is SIRT, based on the intra-arterial deliver of Yttrium-90 microspheres to the lesions. Although results seem appealing, they derive from retrospective series, and a recent study comparing this technique to TAE and TACE over a 10-year period did not show any advantage in terms of time to DP [
[63]
].For what concerns medical treatments, especially if G1 and G2, the first-line therapy is frequently SSAs, considering their efficacy and good safety profile. Binding to the receptors on tumoral cells surface, they are mostly prescribed when tumors express SSTRs, but sometimes also to patients with a negative uptake at FIT. Beyond their effect on symptoms due to the functional syndromes, they are also able to control tumor proliferation, as shown by two RCTs. The PROMID study has described, in 42 metastatic midgut patients treated with octreotide LAR 30 mg, a median PFS of 14.3 months vs. 6 months of the 43 cases in the placebo group. The CLARINET trial has shown, in 101 DNEN patients using lanreotide 120 mg, a 24-month PFS of 65.1% vs. 33.0% of the 103 receiving no therapy [
64
, - Rinke A.
- Müller H.H.
- Schade-Brittinger C.
- et al.
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.
Journal of Clinical Oncology. 2009; 27: 4656-4660
65
, 66
, 67
].In clinical practice, in case of DP during this treatment, a higher dosage or a shorter interval of administration is a possible strategy, but it is not “evidence-based”. A new RCT (CLARINET FORTE, NCT02651987) is currently recruiting DNEN patients to be treated with lanreotide 120 mg every 2 weeks, after DP observed during lanreotide every 4 weeks.
Besides these formulations, pasireotide is a novel SSA still under investigation. “In vivo” data derive from an open-label, phase II study enrolling 29 naïve patients with metastatic NET G1 and G2 disease showed: a PFS of 11 months, a 30-month OS rate of 70%, partial response (PR) and stable disease (SD) in 1 and 17 cases, respectively. Major predictors of response were low hepatic tumor burden, normal baseline CgA and SSTR5 expression. In fact, binding affinity for SSTR2 and SSTR5 respectively are: 0.4–2.1 and 5.6–32 for octreotide; 0.5–1.8 and 0.6–14 for lanreotide; 1 and 0.16 for pasireotide. However, the high incidence of hyperglycemia (79%) due to pasireotide is against its use as a first-line approach [
68
, 69
].PRRT acts with the same molecular mechanism, but somatostatin analog is radiolabeled with Y90 or Lu177, performing an “in loco” radiotherapy; this well tolerated treatment is able to inhibit tumor growth in up to 50%–70% of DNENs [
70
, 71
]. Results of the first Phase III multicentric RCT comparing Lutathera® vs. Octreotide in patients with inoperable, progressive, SSTR-positive G1–G2 SbNENs (NETTER-1 trial) have been presented at the last ECC (Vienna, September 2015) (www.clinicaltrials.gov, NCT01578239). They have showed how, in 230 patients enrolled, the median PFS was not reached in the PRRT-treated group vs. 8.4 months obtained by SSA (HR: 0.21, P < 0.0001). These data support the benefit of this therapy in metastatic SbNENs with a good safety profile, and will pave the way to its official registration [[72]
].Another relevant option for DNENs is represented by targeted therapies. In the RADIANT-3 trial, a phase III placebo-controlled study enrolling advanced PNENs, Everolimus (RAD001, Afinitor®, Novartis Oncology) offered a significant prolongation in median PFS vs. placebo (11 and 4.6 months; 207 and 203 patients; respectively). This result led to its approval by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of locally advanced, metastatic or unresectable PNENs [
11
, 13
]. The RADIANT-4 RCT has been recently published evaluating the efficacy of Everolimus 10 mg/die compared to placebo in progressive, well-differentiated, non-functioning lung and non-pancreatic DNENs [[73]
]. This study has proved a significantly higher PFS in the 205 patients enrolled in the treatment arm than in the 97 receiving placebo (11 vs. 3.9 months, respectively; HR: 0.48; P < 0.001). Disease stabilization was reached in 81% of the treated cases vs. 64% of the placebo arm; PR was observed in 4 and 1 cases, respectively. Everolimus benefit was significant also in terms of mortality rate, with a 36% reduction in the risk of death (HR: 0.64; P = 0.037).Instead, results from COOPERATE-2 phase II study have been presented at the ENETS 2015 Conference, proving a non significant yield in terms of PFS adding Pasireotide to Everolimus in advanced G1/G2 progressing PNENs [
[74]
].Beyond its efficacy, resistance to treatment with Everolimus may occur, due to tumoral escape routes activating the upstream PI3K/Akt pathway. Possible strategies to solve this problem might be the association of other drugs, acting on the same pathway (vertical inhibition) or on another one (horizontal inhibition), but these mechanisms still need to be explored [
14
, - François R.A.
- Maeng K.
- Nawab A.
- et al.
Targeting focal adhesion kinase and resistance to mTOR inhibition in pancreatic neuroendocrine tumors.
Journal of the National Cancer Institute. 2015; 107https://doi.org/10.1093/jnci/djv123
15
, 16
, 17
, 23
].- Capurso G.
- Archibugi L.
- Delle Fave G.
Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.
Journal of Hepato-Biliary-Pancreatic Surgery. 2015; https://doi.org/10.1002/jhbp.210
Sunitinib (Sutent®, Pfizer) is another targeted therapy, with antiangiogenetic action against VEGFR, PDGFR, c-KIT, Flt-3 and RET. Trials published on PNENs have shown its ability to determine a PFS of 10.2 months vs. 5.4 with placebo, together with improvement of OS rate [
12
, 13
]. Pazopanib also (Votrient®, Glaxo Group, London, UK) has an antiangiogenetic activity; it has been investigated as a monotherapy in phase II studies enrolling metastatic DNENs pre-treated with other therapies (including targeted drugs) [75
, 76
]. A recent trial has also evaluated its efficacy in controlling tumor proliferation in 52 patients affected by advanced well-differentiated NETs treated with pazopanib and octreotide, reporting an objective response rate of 21.9% in PNETs, and null response in carcinoid patients [[77]
]. Bevacizumab is another antiangiogenetic option; in the American Society of Clinical Oncology (ASCO) 2015 Conference, results from a phase III prospective trial (www.clinicaltrials.gov, NCT00569127) were presented. The study included 402 advanced G1/G2 progressive carcinoid patients, randomized to be treated with depot octreotide plus interferon alpha-2b (IFN), or with depot octreotide plus bevacizumab (BEV). No significant difference in PFS was observed among the two arms, suggesting that BEV and IFN have a similar antitumor activity in this population [[78]
].- Yao J.C.
- Guthrie K.
- Moran C.
- et al.
SWOG S0518: Phase III prospective randomized comparison of depot octreotide plus interferon alpha-2b versus depot octreotide plus bevacizumab (NSC #704865) in advanced, poor prognosis carcinoid patients.
Journal of Clinical Oncology. 2015; 33 (abstract 4004 [NCT00569127])
Treatment of G3 NENs is not well defined, as most of the RCTs so far published include G1–G2 patients. CHT is widely adopted, especially for poorly-differentiated neoplasms, but data comparing the different regimens and deriving from large series are still lacking. There are only few trials published, and mostly not randomized, enrolling well-differentiated cases and focusing on streptozotocin, temozolomide and capecitabin [
79
, 80
, 81
]. Results are controversial, as previous studies have suggested patients to benefit from CHT (especially with Ki67 >55%) in terms of objective response, although changes in OS rates are not impressive [NET01: A randomised phase II study comparing capecitabine plus streptozocin with or without cisplatin chemotherapy as treatment for unresectable or metastatic neuroendocrine tumours. http://www.ukinets.org/clinical/docs/NET1-Trial.pdf.
[47]
]; on the other side, the German experience proposes to use this approach also as a first-line choice in locally advanced G1–G2 PNENs, with an unexpected worse outcome with ki67 <15% [[82]
].If patients with well-differentiated G3 tumors might benefit from Everolimus is unknown, as the previous RCTs on this drug excluded these patients from recruitment. The ongoing EVINEC trial (www.clinicaltrials.gov, NCT02113800) is enrolling cases with G3 NENs to receive Everolimus as a second-line treatment after a first-line platinum-based regimen; endpoints will be PFS, OS and safety/tolerability.
Up-to-date:
- •SSAs are safe and effective as a first-line approach for well differentiated-DNENs
- •Targeted therapies (Everolimus and Sunitinib) have been approved for advanced G1–G2 PNENs, and proved to be effective also in the other DNENs
- •PRRTs has been proved to be indicated for advanced midgut NENs
Future perspectives:
- •To identify categories of patients at risk for recurrence after radical surgery, and then define the therapeutic option to adopt (CHT? SSAs?)
- •To define the management of small non metastatic PNENs (surgery vs. follow-up)
- •To develop RCTs aimed to directly compare the efficacy of targeted therapies and PRRT in advanced well-differentiated DNENs
- •To evaluate in RCTs the efficacy of chemotherapies, comparing the available regimens and their use in different lines approach
8. Tumor response assessment
Tumor response (SD or down-staging vs. PD) is usually assessed by CT scan and MRI according to the RECIST criteria [
9
, 10
, 83
]. However, the validity of these criteria is under revision, as after the introduction of targeted therapies and PRRT the feeling of clinicians is that morphological exams might fail to offer all the needed information. In clinical practice, FITs or diffusion-weighted MRI are adopted to respectively evaluate change in metabolic activity/SSTRs expression, or vascular pattern; however no prospective studies supporting this strategy have ever been performed, and this approach is based on medical experts opinions. The open debate is focusing on the cost/benefit ratio of follow-up programs, as for some patients too many procedures are repeated without any clear advantage, while for others conventional imaging tests are not enough. The correct timing to repeat each of them has not been defined yet, not even in the current Guidelines where the suggestion to repeat FITs every 12–24 months is present, but for which patients and with which time frame is not indicated [9
, 10
, 84
].Circulating CgA is a specific biomarker for DNENs. Several cut-off values have been proposed to evaluate its accuracy in detecting DP, but studies are mostly retrospective and based on small case series [
85
, 86
, 87
].Up-to-date:
- •CT scan and MRI are the tests usually adopted to follow DNENs up, and the RECIST criteria are the tools available to evaluate response to treatments and disease status
Future perspectives:
- •To evaluate the clinical usefulness of FITs, including 18F-FDG-PET/CT, and diffusion-weighted MRI during DNENs follow-up, especially in patients facing targeted therapies or PRRT
- •To define the correct timing to repeat these imaging tests after DNENs diagnosis
- •To assess the clinical usefulness of circulating CgA in prospective trials, and to identify alternative biomarkers for these patients
9. Conclusions
DNENs can be considered as chronic oncological diseases, in which patients face several sequential treatments. Moreover, being “rare” neoplasms, it is hard to develop RCTs and most of the studies published focus on PFS to evaluate response to therapies. According to DNENs heterogeneity in terms of prognosis, a specific tailored treatment is needed for each patient. Current Guidelines offer useful tools for clinicians, but future perspectives should focus on several critical issues, such as to reevaluate available classifications, to optimize DNENs follow-up (without useless diagnostic tests for low risk patients, and with a more complete program for high risk cases), and to promote new trials directly comparing targeted therapies with PRRT.
Conflict of interest
None declared.
References
- One hundred years after carcinoids: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States.Journal of Clinical Oncology. 2008; 26: 3063-3072
- Gastroenteropancreatic neuroendocrine tumors.Lancet Oncology. 2008; 9: 61-72
- The epidemiology of gastroenteropancreatic neuroendocrine tumors.Endocrinology and Metabolism Clinics of North America. 2011; 40 (vii): 1-18
- Prognostic factors influencing survival from metastatic (stage IV) gastroenteropancreatic well-differentiated endocrine carcinoma.Endocrine-Related Cancer. 2009; 16: 585-597
- Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients.Modern Pathology. 2010; 23: 824-833
- Advanced digestive neuroendocrine tumors metastatic pattern is an independent factor affecting clinical outcome.Pancreas. 2014; 43: 212-218
- Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients.European Journal of Nuclear Medicine. 1993; 20: 716-731
- Comparison between 68Ga-DOTA-NOC and 18F-DOPA PET for the detection of gastro-entero-pancreatic and lung neuroendocrine tumours.European Journal of Nuclear Medicine and Molecular Imaging. 2008; 35: 1431-1438
- ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors.Neuroendocrinology. 2016; 103: 153-171
- ENETS consensus guidelines update for neuroendocrine neoplasms of the jejunum and ileum.Neuroendocrinology. 2016; 103: 125-138
- Everolimus for advanced pancreatic neuroendocrine tumors.New England Journal of Medicine. 2011; 364: 514-523
- Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.New England Journal of Medicine. 2011; 364: 501-513
- Promising advances in the treatment of malignant pancreatic endocrine tumors.New England Journal of Medicine. 2011; 364: 564-565
- Targeting focal adhesion kinase and resistance to mTOR inhibition in pancreatic neuroendocrine tumors.Journal of the National Cancer Institute. 2015; 107https://doi.org/10.1093/jnci/djv123
- Resistance to targeted therapies in pancreatic neuroendocrine tumors (PNETs): molecular basis, preclinical data, and counteracting strategies.Targeted Oncology. 2012; 7: 173-181
- Combined therapy with RAD001 and BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition.Oncotarget. 2014; 5: 5381-5391
- Mechanisms of mTOR inhibitor resistance in cancer therapy.Targeted Oncology. 2011; 6: 17-27
- Trends in incidence of neuroendocrine neoplasms in Norway: a report of 16,075 cases from 1993 through 2010.Neuroendocrinology. 2015;
- Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters.Endocrine-Related Cancer. 2010; 17: 909-918
- WHO classification of tumours of the digestive system.IARC Press, Lyon, France2010
- TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system.Virchows Archiv. 2007; 451: 757-762
- TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.Virchows Archiv. 2006; 449: 395-401
- Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.Journal of Hepato-Biliary-Pancreatic Surgery. 2015; https://doi.org/10.1002/jhbp.210
- Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumours.Journal of Hepato-Biliary-Pancreatic Surgery. 2014; 21: 288-295
- Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumours compared to normal islet cells.American Journal of Pathology. 2000; 157: 1097-1103
- Pancreatic endocrine tumours: expression profiling evidences a role for AKT-mTOR pathway.Journal of Clinical Oncology. 2009; 28: 245-255
- Micro-vascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression.British Journal of Cancer. 2005; 92: 94-101
- Angiogenesis in neuroendocrine tumours: therapeutic applications.Neuroendocrinology. 2013; 97: 45-56
- DAXX/ATRX, MEN1 and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumours.Science. 2011; 331: 1199-1203
- Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumours.Gastroenterology. 2014; 146: 453-60.e5
- Pathophysiological causes and clinical significance of flushing.British Journal of Hospital Medicine. 1993; 50: 594-598
- Carcinoid heart disease: from pathophysiology to treatment – ‘Something in the Way It Moves’.Neuroendocrinology. 2015; 101: 263-273
- Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours.Alimentary Pharmacology and Therapeutics. 2010; 31: 169-188
- Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide.Endocrine-Related Cancer. 2014; 21: 705-714
- Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial.Journal of Clinical Endocrinology and Metabolism. 2015; 100: 1511-1519
- 37LBA – Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial).in: Late Breaking Abstract (37LBA) at the 2015 European Cancer Congress (ECC), Vienna, Austria2015
- Clinical features of pancreatic neuroendocrine tumors.Journal of Hepato-Biliary-Pancreatic Surgery. 2015; 22: 578-585
- Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression.Journal of Clinical Oncology. 2011; 29: 2372-2380
- Risk factors for disease progression in advanced jejunoileal neuroendocrine tumors.Neuroendocrinology. 2012; 96: 32-40
- Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.Annals of Oncology. 2013; 24: 152-160
- TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study.Journal of the National Cancer Institute. 2012; 104: 764-777
- Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms.Endocrine-Related Cancer. 2015; 22: 657-664
- Neuroendocrine Tumors.in: Edge S.B. AJCC Cancer Staging Manual. 7th ed. Springer, New York2010
- Malignant pancreatic neuronendocrine tumour: lymph node ratio and Ki67 are predictors of recurrence after curative resection.European Journal of Cancer. 2012; 48: 1608-1615
- Surgical treatment of NEN of small bowel: a retrospective analysis.World Journal of Surgery. 2016; 40: 749-758
- Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set.American Journal of Surgical Pathology. 2010; 34: 300-313
- Ki-67 grading of nonfunctioning pancreatic neuroendocrine tumors on histologic samples obtained by EUS-guided fine-needle tissue acquisition: a prospective study.Gastrointestinal Endoscopy. 2012; 76 (Erratum in Gastrointest Endosc 2012;76:1085): 570-577
- Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation.Radiographics. 2015; 35: 500-516
- Clinical value of (68)Ga-DOTATATE-PET/CT compared to stand-alone contrast enhanced CT for the detection of extra-hepatic metastases in patients with neuroendocrine tumours (NET).European Journal of Radiology. 2015; 84: 1866-1872
- Prognostic value of 68Ga-DOTA-NOC PET/CT SUVmax in patients with neuroendocrine tumours of the pancreas.Journal of Nuclear Medicine. 2015; 56: 1843-1848
- Intravoxel incoherent motion diffusion-weighted imaging of pancreatic neuroendocrine tumors: prediction of the histologic grade using pure diffusion coefficient and tumor size.Investigative Radiology. 2014; 49: 396-402
- Diffusion-weighted imaging with acquisition of three b-values for response evaluation of neuroendocrine liver metastases undergoing selective internal radiotherapy.European Radiology. 2014; 24: 267-276
- Octreoscan versus FDG-PET for neuroendocrine tumor staging: a biological approach.Annals of Surgical Oncology. 2015; 22: 2295-2301
- The supporting role of (18)FDG-PET in patients with neuroendocrine tumors.Annals of Surgical Oncology. 2015; 22: 2107-2109
- High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation.Journal of Nuclear Medicine. 2014; 55: 1786-1790
- The role of combined Ga-DOTANOC and (18)FDG PET/CT in the management of patients with pancreatic neuroendocrine tumors.Neuroendocrinology. 2014; 100: 293-299
- Surgical treatment of pancreatic endocrine tumours in Italy: results of a prospective multicentre study of 262 cases.Langenbeck's Archives of Surgery. 2011; 396: 313-321
- Observational study of natural history of small sporadic nonfunctioning pancreatic neuroendocrine tumors.Journal of Clinical Endocrinology and Metabolism. 2013; 98: 4784-4789
- Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease: a systematic review.Neuroendocrinology. 2011; 93: 223-229
- Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases.British Journal of Surgery. 2012; 99: 1480-1486
- Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors.Endocrine. 2014; 47: 177-182
- Liver transplantation for unresectable neuroendocrine tumor liver metastases.Annals of Surgical Oncology. 2014; 21: 2398-2405
- Comparison of transarterial liver-directed therapies for low-grade metastatic neuroendocrine tumors in a single institution.Pancreas. 2014; 43: 219-225
- 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.Journal of Clinical Oncology. 2009; 27: 4656-4660
- Lanreotide in metastatic enteropancreatic neuroendocrine tumors.New England Journal of Medicine. 2014; 371: 224-233
- 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 (PROMID): results on long term survival.Neuroendocrinology. 2016;
- Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study.Endocrine-Related Cancer. 2016; 23: 191-199
- Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors.Endocrine-Related Cancer. 2015; 22: 1-9
- Review article: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours.Alimentary Pharmacology and Therapeutics. 2010; 31: 169-188
- Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: a phase I study.European Journal of Nuclear Medicine and Molecular Imaging. 2003; 30: 207-216
- Treatment with the radiolabeled somatostatin analog [177 LuDOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival.Journal of Clinical Oncology. 2008; 26: 2124-2130
- 177-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours: results of the phase III NETTER-1 trial.in: Late Breaking Abstract (6LBA) at the 2015 European Cancer Congress (ECC), Vienna, Austria2015
- Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study.Lancet. 2016; 387: 968-977
- 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.Neuroendocrinology. 2015; 102: 131
- Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours.British Journal of Cancer. 2013; 109: 1414-1419
- Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE).Annals of Oncology. 2015; 26: 1987-1993
- Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study.Lancet Oncology. 2015; 16: 695-703
- SWOG S0518: Phase III prospective randomized comparison of depot octreotide plus interferon alpha-2b versus depot octreotide plus bevacizumab (NSC #704865) in advanced, poor prognosis carcinoid patients.Journal of Clinical Oncology. 2015; 33 (abstract 4004 [NCT00569127])
- Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors.Journal of Clinical Oncology. 2012; 30: 2963-2968
- Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) – a phase II non-randomised trial.European Journal of Cancer. 2014; 50: 3098-3106
NET01: A randomised phase II study comparing capecitabine plus streptozocin with or without cisplatin chemotherapy as treatment for unresectable or metastatic neuroendocrine tumours. http://www.ukinets.org/clinical/docs/NET1-Trial.pdf.
- Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours.European Journal of Cancer. 2015; 51: 1253-1262
- New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).European Journal of Cancer. 2009; 45: 228-247
- ENETS consensus guidelines for the standards of care in neuroendocrine tumours: follow-up and documentation.Neuroendocrinology. 2009; 90: 227-233
- Elevated plasma chromogranin A is the first indication of recurrence in radically operated midgut carcinoid tumors.Neuroendocrinology. 2009; 89: 302-307
- Chromogranin A in diagnosing and monitoring patients with gastroenteropancreatic neuroendocrine neoplasms: a large series from a single institution.Neuroendocrinology. 2014; 100: 240-249
- Chromogranin A as a predictor of radiological disease progression in neuroendocrine tumours.Annals of Translational Medicine. 2015; 3: 118
Article info
Publication history
Published online: May 19, 2016
Accepted:
April 15,
2016
Received:
July 30,
2015
Identification
Copyright
© 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
