Introduction
Neuroendocrine neoplasms (NENs) constitute a rare group of tumours with an estimated
annual incidence of approximately 3–5 cases/100 000 inhabitants
[1]
[2]. NENs are predominately developed in the
gastrointestinal (GI) or bronchopulmonary systems but may rarely arise in other
sites such as the ovaries and/or the urinary bladder [3]. A subset of these tumours can secrete
bioactive compounds leading to distinct clinical syndromes (functioning NENs) or
cause symptoms due to mass effects to surrounding structures or through metastatic
deposits (non-functioning tumours) [4]
[5]. According to the proliferative index (PI)
Ki-67, defined by immunohistochemical staining for nuclear Ki-67 protein expression,
NENs are classified into grade 1 (G1) if Ki67 PI is ≤2% or 2 (G2) if
Ki-67 PI is between 3 and 20% and grade 3 (G3) if Ki-67 PI is >
20% [6]
[7]. However, it subsequently became apparent
that the natural history and prognosis of G3 NENs varied significantly according to
their morphological features and subsequent differentiation. Hence, the proposed
2017 WHO classification initially addressing pancreatic NENs (pNENs), divided G3
neoplasms into well-differentiated G3 NEN (defined as G3 NETs) or poorly
differentiated G3 neuroendocrine carcinomas (defined as G3 NECs). This
classification proved to be valid as it was found to correlate with response to
specific treatments and overall prognosis [7].
The recent WHO classification of 2019 has implemented this sub-classification of G3
tumours to all gastro-entero-pancreatic NENs [8].
The management of NENs aims at controlling symptoms related to hormonal
hypersecretion along tumour growth and related morbidity and mortality. Surgical
resection of the primary tumour and when possible of metastatic involvement is the
mainstary of treatment. However, in the presence of extensive disease not amenable
to surgical resection several medical therapies are used, either alone or in
combination, aiming at controlling tumour growth and imroving the symptoms
attributed to hormonal excess [5]
[9]
[10]. In addition, functioning neoplasms may
be associated with acute or chronic complications such as carcinoid crisis or
carcinoid heart disease that need to be promptly diagnosed and treated [4]
[9]. A number of parameters need to be
considered in order to select the most appropriate therapeutic modality in the
context of a multidisciplinary approach [11]
([Table 1]). The last decade a number of
phase III studies have provided good quality data regarding the efficacy of
treatments used for GEP-NENs that have set up the field for their medical management
([Fig. 1]).
Fig. 1 Evidence-based (phase III studies except chemotherapy)
therapeutic modalities for NENs. pNEN: Pancreatic neuroendocrine neoplasm;
GI-NEN: Gastrointestinal neoplasm; PRRT: Peptide receptor radionuclide
therapy.
Table 1 Factors determining the therapeutic choice of NENs
|
Primary tumour
|
 
|
Therapeutic decision by
a multidisciplinary team
Surgery
Systemic treatment
|
|
TNM stage
|
|
Tumour grade
|
|
Functionality
|
|
Tumour growth rate
|
|
Patient’s performance status
|
|
Presence of a familial syndrome
|
|
Local availability
|
|
Patient’s preference
|
Somatostatin analogues (SSAs)
Somatostatin is a neuropeptide secreted in the gastrointestinal tract and the
brain. It acts via interaction with five somatostatin receptor subtypes
(SSTR1-5) and inhibits the secretion of various hormones while it may also exert
immunomodulatory, cytotoxic and apoptotic actions [12]
[13]. SSTR2 is found predominately in NENs
of gastro-entero-pancreatic origin [14].
The somatostatin analogue octreotide was the first that became available and was
shown to be associated with significant clinical improvement when administered
subcutaneously three times daily in controlling the symptoms of carcinoid
syndrome (CS) [15]. Long acting SSAs
formulations, octreotide LAR and lanreotide Autogel are currently available and
are administered once monthly. These compounds have been shown to be equally
effective in the management of symptoms associated with functioning GEP-NENs.
Indeed, control of flushing and diarrhea related to the CS has been reported in
74.2 and 67% of cases treated with octreotide LAR and lanreotide
Autogel, respectively [16].
However, long acting SSAs can also be used for their antiproliferative effect
although the molecular basis for their antitumour effect is largely unknown
[17]. PROMID was the first randomized
placebo-controlled phase III study that showed a significantly prolonged time to
progression (TTP) in patients with well differentiated locally advanced or
metastatic intestinal NENs on treatment with octreotide LAR [hazard ratio (HR)
= 0.34; 95% confidence interval (CI), 0.20–0.59; p
= 0.000072] [18]. Subsequently,
CLARINET study, another randomized placebo-controlled phase III trial,
demonstrated significantly increased progression free survival (PFS) in patients
with various GEP-NENs treated with lanreotide compared to placebo (HR =
0.47; 95% CI, 0.3–0.73) [19]. Thus, SSAs are considered as first line systemic therapy for
tumour growth control in cases of stable or slowly progressive disease. Although
there is no established Ki-67 cut off value, SSAs are generally recommended in
patients suffering from NENs with a Ki-67 value up to 10% [9]. In selected cases of uncontrolled CS
despite adequate treatment with SSAs, decreasing the interval of administration
or administration of higher than the labelled doses are associated with higher
efficacy [20]
[21].
Pasireotide (SOM230), a new synthetic analogue displaying high affinity for all
SSTRs except for SSTR4, has also been shown to be efficacious in patients with
advanced NENs but recent studies showed no advantage of this agent compared to
other SSAs [22]
[23].
Common adverse events of SSAs are abdominal pain, diarrhea, nausea, gallstone
development and glucose intolerance [12].
Pasireotide is a potent hyperglycaemic agent associated with alterations of
glucose metabolism in up to 25% of patients treated [22]
[24].
Targeted agents
Molecular studies have revealed that two main pathways are involved on
neuroendocrine tumour growth, the vascular endothelial growth factor (VEGF) and
the mammalian target of rapamycin (mTOR) pathway and drugs that target these
pathways have been proved to be effective in patients with advanced
GEP-NENs.
Everolimus is an mTOR inhibitor that has demonstrated anti-proliferative action
in different NENs. The RADIANT trial program that involved a phase II and three
randomized phase III trials has shown significant prolongation of PFS with
everolimus versus placebo in patients with advanced G1 or G2 pancreatic and
intestinal NENs [25]
[26]
[27]
[28]. Therefore, everolimus is recommended
as a second or third-line treatment after failure of SSAs or other agents mainly
in well-differentiated NENs. In addition, a recent meta-analysis reported a
significantly high efficacy of the combination treatment of SSAs with everolimus
[10]. Careful observation is warranted
as everolimus is associated with potential adverse events such as glucose
intolerance or diabetes, stomatitis and pneumonitis [29].
The tyrosine kinase inhibitor (TKI) sunitinib inhibits various kinases including
the VEGF receptor and displays an anti-angiogenic effect. A randomized phase III
study including patients with progressive pNENs has shown significant
prolongation of PFS and increased overall survival (OS) after treatment with
sunitinib compared to placebo (HR = 0.42; 95% CI:
0.26–0.66; p <0.001) [30].
Common adverse events include nausea, diarrhea, fatigue, neutropenia,
hypertension, hypothyroidism and palmar-plantar erythrodysesthesia [24]. There are not enough published data
regarding treatment with sunitinib in non-pancreatic NENs. Pazopanib and
axitinib, that are multi-targeted TKI and bevacizumab, a mono-clonal anti-VEGF
antibody have been shown to be effective in NENs but further studies are
required to establish their use in clinical practice [31]
[32]
[33].
A recent study showed that there was no significant difference in PFS and OS
among patients who received sequential treatment with both everolimus and
sunitinib irrespectively of the order of administration while the majority of
patients tolerated treatment relatively well [34].
Chemotherapy
Before the introduction of molecular targeted agents, chemotherapy was the main
option of systemic treatment of NENs. Streptozotocin based chemotherapy in
combination with 5-fluorouracil or doxorubicin was shown to be effective in the
treatment of pNENs and especially in G2 neoplasms, and in those with relatively
rapid growth or high tumour load [35]
[36]
[37]. However, other well differentiated
GI-NENs did not respond well to systemic chemotherapy, while in G3 NECs
platinum-based chemotherapy is considered as a first-line option [36]
[38]
[39]
[40]. Recent studies have shown that
temozolomide as monotherapy or in combination with capecitabine may be an
effective treatment option in advanced NENs from various anatomical sites with
tolerable toxicity exhibiting response rates in up to 30-40% of patients
([Fig. 2]) [41]
[42].
Fig. 2 Significant liver disease response according to criteria
RECIST 1 after one year of treatment with temozolomide-capecitabine.
In clinical practice, systemic chemotherapy is recommended in G1 or G2 NENs with
a high tumour load or displaying significant tumour progression in less than
6–12 months and in G3 NENs. In G3 NECs platinum based chemotherapy is
the first line treatment while FOLFOX (folinic acid, 5-fluorouracil,
oxaliplatin) or FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) are used as
second line treatments [40]
[43]. Systemic chemotherapy in small bowel
NENs is not as efficacious as in pNENs except in cases of poorly differentiated
tumours albeit the responses obtained are moderate and usually of short duration
[29]
[44].
Peptide Receptor Radionuclide Therapy (PRRT)
As the majority of GEP-NENs express somatostatin receptors, radiolabelled
somatostatin analogues have traditionally been used for tumour diagnosis and
recently they have been introduced as a therapeutic option for NENs. A phase III
randomized controlled trial (NETTER-1) showed that 177Lu-DOTATATE was
more effective than high dose octreotide LAR (60 mg) and was associated with
significant prolongation of PFS and symptomatic improvement in patients with
advanced progressive SSTR-positive intestinal NENs (HR = 0.21;
95% CI, 0.13 to 0.33; p <0.001) [29]
[45]. A recent meta-analysis showed also
that the combination treatment of PRRT with SSAs is considered significantly
effective [10]. In addition, PRRT is
associated with a substantial improvement of quality of life in patients with
progressive midgut NENs [10]
[46]. Currently, there is no established
indication for treatment of pNENs with PRRT but it is generally recommended in
case of failure of other therapeutic options [29].
It has been recently observed that patients with negative fluorodeoxyglucose PET
imaging (FDG-PET/CT) displayed better response rates to treatment with
PPRT compared to those with positive FDG-PET/CT [47]
[48]. Thus, a scintigraphic assessment
estimating both SSTR expression and glucose metabolism may be required in order
to identify patients with more aggressive FDG-positive NENs as these patients
may benefit from combination treatment with capecitabine and PRRT [49]
[50].
In most cases, adverse events associated with PRRT are mild and transient. They
include nausea, vomiting, myelosuppression and kidney failure. Co-administration
of amino acids is recommended for kidney protection. Rarely, myelodysplastic
syndrome and leukaemia have been reported [51]
[52]
[53].
Interferon Alpha (IFN-α)
IFN-α was initially introduced in 1980s as a treatment of advanced small
bowel NENs and has been associated with control of the symptoms and tumour
stabilization [54]
[55]. However, a randomized multicentre
study showed that SSAs, IFN-α, or their combination had comparable
antiproliferative effects in the treatment of metastatic neuroendocrine
GEP-NENs. However, IFN-α was associated with significant adverse events
such as fatigue, fever, liver toxicity, bone marrow suppression and autoimmune
disorders leading occasionally to treatment discontinuation [55]
[56]. Thus, due to poor tolerability,
IFN-α is currently rarely recommended and its use is restricted in
patients with refractory carcinoid syndrome as an add-on treatment to SSAs [57]
[58].
Immunotherapy
Immune checkpoint inhibitors have been shown to be effective in several cancer
types such as melanoma and lung carcinoma as antibodies against programmed death
receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) enhance T-cell
antitumour activity. Recent studies have reported PD-L1 expression in GEP-NENs
whereas a significant correlation between PD-L1 expression and tumour grade has
been observed [59]. Currently there is
only limited experience of immunotherapy in NENs but recent case series report
promising results while there are multiple ongoing phase II trials that study
the efficacy of immune checkpoint inhibitors in NENs [59].
Management of secretory syndromes
A significant number of NENs secrete biologically active substances and result to
development of secretory syndromes. The treatment of patients with functional
symptoms should aim primarily in reducing the tumour load either with radical
resection or with debulking techniques. However, pre- and perioperative medical
treatment is usually necessary while it may also be required in a palliative
setting [60]
[61]. When surgery or the cytoreductive
techniques fail to control symptoms, medical treatment is utilised aiming at
counteracting the effects of the secretory component and/or control of
tumour mass.
Long acting SSAs are considered the most effective option for symptomatic control
in patients with several functioning tumours albeit without substantial effect
on tumour load [16]. However, an escape
phenomenon or tachyphylaxis may occur after a few months or years of treatment
with SSAs that it is attributed to a probable down-regulation of SSTRs or tumour
progression [5]
[20] Dose escalation of SSAs may be
recommended in case of secretory syndrome refractory to standard doses [20]. In case of insulinomas, SSAs should be
used with caution as worsening of hypoglycaemia may be observed due to
inhibition of counter-regulatory hormones [62]. Furthermore, treatment with continuous intravenous infusion of
octreotide is required in patients with CS before and during any kind of
intervention in order to prevent carcinoid crisis [60]. SSAs can also be used for the
treatment of other rare syndromes secondary to the secretion of VIP, glucagon
and ectopic hormonal secretion that is occasionally encountered in patients with
NENs.
In patients with refractory to SSAs carcinoid syndrome, IFN-α is
considered a second line option for symptom control [57]. In addition, PRRT is considered an
effective way to ameliorate symptoms of CS [63]. Telotristat etiprate is an oral inhibitor of the enzyme
tryptophan hydroxylase which is the rate-limiting step in serotonin synthesis.
Recent studies have shown that addition of telotristat in patients inadequately
controlled with SSAs is associated with significant reduction in the number of
bowel movements, 5-hydroxyindoleacetic acid (5-HIAA) levels and flushing
episodes while weight gain was observed in some cases [64]
[65]
[66]. However, this agent has no effect on
tumour mass. Common side effects of telotristat include nausea, abdominal pain
and a low rate of depression. Further investigation is required regarding the
assumption that treatment with telotristat may decrease the development of
carcinoid heart disease or fibrosis [64]
[65].
In patients suffering from insulinoma, the primary treatment target is to avoid
hypoglycaemic episodes. Frequent small-volume meals enriched in long-acting
carbohydrates are recommended while in some cases, especially in metastatic
tumours, continuous feeding via a nasogastric or nasoduodenal tube may be
required [61]. Diazoxide decreases insulin
secretion through inhibition of adenosine triphosphate (ATP)-sensitive potassium
channels. It has been observed to be effective in controlling hypoglycaemia, in
doses 50–300 mg/day (maximum dose up to 600 mg/day), but
it is associated with significant adverse events such as hirsutism, oedema and
renal impairment [5]
[67]. In addition, everolimus has been
shown to be effective in reducing hypoglycaemia in cases of metastatic
insulinomas while there are some reports regarding the hyperglycaemic action of
glucocorticoids [67]
[68]
[69]. Zollinger–Ellison syndrome,
secondary to hypersecretion of gastrin from a duodenal or pancreatic NEN may
occur sporadically or in approximately 25–30% of cases in the
context of multiple endocrine neoplasia type 1 (MEN1) syndrome [5]
[70]. Patients should be treated with high
dose of a proton pump inhibitor to reduce the acid hypersecretion while add-on
treatment with histamine-2 receptor blockers or antacids may also be required
[61] ([Fig. 3]).
Fig. 3 Therapeutic algorithm of well differentiated NENs.
*Molecular targeted therapy. **MT: Molecular
targeted therapy.
Future Perspectives
The clinical management of NENs is complex and challenging due to the
heterogeneity of these tumours while their low incidence makes research efforts
difficult. Novel therapies are currently investigated on multiple ongoing
clinical trials while current efforts focus on personalized treatment and
precision oncology that target specific genetic and protein regulators of
neoplasms.
A biomarker based approach is currently under investigation with the intention to
inform the clinicians regarding the prognosis and to facilitate the
individualized management of patients with NENs [71]. There are multiple studies investigating the role of several
biomarkers as well as of genetic and epigenetic alterations, including
circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), histone
modifications and miRNAs, as prognostic factors and predictors of response to
treatment [71]
[72]. A recently developed multigene
liquid biopsy (NETest), that is based on transcriptomic evaluation of NENs, has
been shown to have numerous clinical applications as it may assess the
successful surgical removal of a NEN or predict the aggressive tumour behaviour
and the efficacy of SSAs and PRRT [73].
Preclinical in vitro and in vivo models have recently been developed to capture
the heterogeneity of human NENs aiming at delineating the biological behaviour
of these tumours as well as to investigate the efficacy of new antitumour
agents. The patient-derived xenografts (PDX) in mice and zebrafish embryos are
considered as the most promising preclinical models for the introduction of
personalized medicine [71].
Another issue that needs to be addressed and further studied in the future is the
sequential use of treatments available for NENs. A recent retrospective study,
comparing different sequences of treatments in patients with well differentiated
NENs that received first-line treatment with SSAs, observed no significant
difference regarding PFS between patients that received high dose SSAs,
everolimus, chemotherapy or PRRT [74].
However, prospective studies are required to further clarify this issue. The
rationale of medical treatment taking into consideration factors that could
affect the choice of specific treatment for well differentiated GEP-NENs is
shown in the therapeutic algorithm in [Fig.
3].
