Medical Treatment of Gastrointestinal Neuroendocrine Neoplasms
Marina Tsoli1, Krystallenia Alexandraki1, Christos Xanthopoulos1, Eva Kassi1, 2, Gregory Kaltsas
1 1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
2 Department of Biological Chemistry, National and
Kapodistrian University of Athens, Athens, Greece
neuroendocrine tumour, somatostatin analogues, radionu- clides, targeted treatment, carcinoid syndrome
DOI https://doi.org/10.1055/a-1110-7251 Published online: 2020
Horm Metab Res
© Georg Thieme Verlag KG Stuttgart · New York
Marina Tsoli MD
1st Department of Propaedeutic and Internal Medicine Laiko Hospital National and Kapodistrian University of Athens Agiou Thoma
11527 Athens Greece
Tel.: + 30 210 7462217, Fax: + 30 210 7462664
Neuroendocrine neoplasms (NENs) are rare tumours that arise mainly in the gastrointestinal or pulmonary system. Most NENs are well-differentiated and may obtain prolonged survival be- sides the presence of metastatic disease; however, a subset (poorly differentiated NENs) may display a truly aggressive behaviour exhibiting a poor prognosis. The recently developed classification systems along with advances in functional imag- ing have helped stratify patients to the administration of ap- propriate therapeutic options. Surgery is the mainstay of treat- ment of NENs, but in recent decades there has been a considerable evolution of medical treatments that are used for locally advanced or metastatic disease not amenable to surgi- cal resection. Long acting somatostatin analogues are the main therapeutic modality for patients with functioning and well-dif- ferentiated low grade NENs exhibiting symptomatic control and mainly stabilisation of tumour growth. Other systemic treatments include chemotherapy, molecular targeted agents, interferon-α, peptide receptor radionuclide therapy (PRRT), and immunotherapy. In addition, new agents such as telotristat may be used for the control of symptoms of carcinoid syn- drome. The choice and/or sequence of therapeutic agents should be individualized according to tumour origin and differ- entiation, disease burden, presence of clinical symptoms and patients’ performance status in the context of a multidiscipli- nary approach. Recent advances in the molecular pathogenesis of NENs set the field for a more personalised treatment ap- proach.
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Neuroendocrine neoplasms (NENs) constitute a rare group of tu- mours with an estimated annual incidence of approximately 3–5 cases/100 000 inhabitants [1, 2]. NENs are predominately devel- oped in the gastrointestinal (GI) or bronchopulmonary systems but may rarely arise in other sites such as the ovaries and/or the urinary bladder . A subset of these tumours can secrete bioactive com- pounds 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 immuno- histochemical 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 histo-
ry 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 neuroendo- crine 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 . The recent WHO classifica- tion of 2019 has implemented this sub-classification of G3 tumours to all gastro-entero-pancreatic NENs .
The management of NENs aims at controlling symptoms relat- ed 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,ither 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 car- cinoid heart disease that need to be promptly diagnosed and treat- ed [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  (▶ Table 1). The last decade a number of phase III studies have provided good quality data regard- ing the efficacy of treatments used for GEP-NENs that have set up the field for their medical management (▶ Fig. 1).
Somatostatin analogues (SSAs)
Somatostatin is a neuropeptide secreted in the gastrointestinal tract and the brain. It acts via interaction with five somatostatin re- ceptor subtypes (SSTR1-5) and inhibits the secretion of various hor- mones while it may also exert immunomodulatory, cytotoxic and apoptotic actions [12, 13]. SSTR2 is found predominately in NENs of gastro-entero-pancreatic origin .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) . 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 man- agement of symptoms associated with functioning GEP-NENs. In-deed, 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 .
However, long acting SSAs can also be used for their antiprolifer- ative effect although the molecular basis for their antitumour effect is largely unknown . PROMID was the first randomized place- bo-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 octreo- tide LAR [hazard ratio (HR) = 0.34; 95 % confidence interval (CI), 0.20–0.59; p = 0.000072] . Subsequently, CLARINET study, another randomized placebo-controlled phase III trial, demonstrat- ed significantly increased progression free survival (PFS) in patients with various GEP-NENs treated with lanreotide compared to place- bo (HR = 0.47; 95 % CI, 0.3–0.73) . 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 estab- lished Ki-67 cut off value, SSAs are generally recommended in pa- tients suffering from NENs with a Ki-67 value up to 10 % . In se- lected 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 effica- cy [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
Common adverse events of SSAs are abdominal pain, diarrhea, nausea, gallstone development and glucose intolerance . Pa- sireotide is a potent hyperglycaemic agent associated with altera- tions of glucose metabolism in up to 25 % of patients treated [22, 24].
Molecular studies have revealed that two main pathways are in- volved on neuroendocrine tumour growth, the vascular endothe- lial 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.
Evidence-based (phase III studies except chemotherapy) therapeutic modalities for NENs. pNEN: Pancreatic neuroendocrine neoplasm;
GI-NEN: Gastrointestinal neoplasm; PRRT: Peptide receptor radionuclide therapy.Everolimus is an mTOR inhibitor that has demonstrated anti-pro- liferative 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 [25–28]. 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 re- ported a significantly high efficacy of the combination treatment of SSAs with everolimus . Careful observation is warranted as everolimus is associated with potential adverse events such as glu- cose intolerance or diabetes, stomatitis and pneumonitis .
The tyrosine kinase inhibitor (TKI) sunitinib inhibits various ki- nases including the VEGF receptor and displays an anti-angiogenic effect. A randomized phase III study including patients with pro- gressive pNENs has shown significant prolongation of PFS and in- creased overall survival (OS) after treatment with sunitinib com- pared to placebo (HR = 0.42; 95 % CI: 0.26–0.66; p < 0.001) .
Common adverse events include nausea, diarrhea, fatigue, neutro- penia, hypertension, hypothyroidism and palmar-plantar erythro- dysesthesia . 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 mo- no-clonal anti-VEGF antibody have been shown to be effective in NENs but further studies are required to establish their use in clin- ical practice [31–33].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 .
Before the introduction of molecular targeted agents, chemother- apy was the main option of systemic treatment of NENs. Strepto- zotocin 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 [35–37]. However, other well differ- entiated GI-NENs did not respond well to systemic chemotherapy, while in G3 NECs platinum-based chemotherapy is considered as a first-line option [36, 38–40]. Recent studies have shown that te- mozolomide as monotherapy or in combination with capecitabine may be an effective treatment option in advanced NENs from var- ious anatomical sites with tolerable toxicity exhibiting response rates in up to 30-40 % of patients (▶ Fig. 2) [41, 42].
In clinical practice, systemic chemotherapy is recommended in G1 or G2 NENs with a high tumour load or displaying significant tu- mour 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 ef- ficacious as in pNENs except in cases of poorly differentiated tu- mours 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, radi- olabelled somatostatin analogues have traditionally been used for tumour diagnosis and recently they have been introduced as a ther- apeutic 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 signifi- cant prolongation of PFS and symptomatic improvement in pa- tients with advanced progressive SSTR-positive intestinal NENs (HR = 0.21; 95 % CI, 0.13 to 0.33; p < 0.001) [29, 45]. A recent me-ta-analysis showed also that the combination treatment of PRRT with SSAs is considered significantly effective . 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 .
It has been recently observed that patients with negative fluo- rodeoxyglucose PET imaging (FDG-PET/CT) displayed better re- Significant liver disease response according to criteria RECIST 1 after one year of treatment with temozolomide-capecitabine.sponse rates to treatment with PPRT compared to those with pos- itive FDG-PET/CT [47, 48]. Thus, a scintigraphic assessment esti- mating 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 combina- tion 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 leu- kaemia have been reported [51–53].
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 rand- omized multicentre study showed that SSAs, IFN-α, or their com- bination had comparable antiproliferative effects in the treatment of metastatic neuroendocrine GEP-NENs. However, IFN-α was as- sociated 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].
Immune checkpoint inhibitors have been shown to be effective in several cancer types such as melanoma and lung carcinoma as anti- bodies against programmed death receptor 1 (PD-1) and pro- grammed death ligand 1 (PD-L1) enhance T-cell antitumour activity. Recent studies have reported PD-L1 expression in GEP-NENs where- as a significant correlation between PD-L1 expression and tumour grade has been observed . Currently there is only limited experi- ence of immunotherapy in NENs but recent case series report prom- ising results while there are multiple ongoing phase II trials that study the efficacy of immune checkpoint inhibitors in NENs .
Management of secretory syndromes
A significant number of NENs secrete biologically active substanc- es and result to development of secretory syndromes. The treat- ment 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 tech- niques fail to control symptoms, medical treatment is utilised aim- ing 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 . 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 secreto- ry syndrome refractory to standard doses . In case of insulino-
mas, SSAs should be used with caution as worsening of hypogly- caemia may be observed due to inhibition of counter-regulatory hormones . Furthermore, treatment with continuous intrave- nous infusion of octreotide is required in patients with CS before and during any kind of intervention in order to prevent carcinoid crisis . SSAs can also be used for the treatment of other rare syndromes secondary to the secretion of VIP, glucagon and ectop- ic 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 . In addi- tion, PRRT is considered an effective way to ameliorate symptoms of CS . 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 sig- nificant reduction in the number of bowel movements, 5-hydrox- yindoleacetic acid (5-HIAA) levels and flushing episodes while weight gain was observed in some cases [64–66]. However, this agent has no effect on tumour mass. Common side effects of tel- otristat include nausea, abdominal pain and a low rate of depres- sion. 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 . 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 [67–69]. Zollinger–Elli- son syndrome, secondary to hypersecretion of gastrin from a du- odenal or pancreatic NEN may occur sporadically or in approximate- ly 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 hyperse- cretion while add-on treatment with histamine-2 receptor block- ers or antacids may also be required  (▶ Fig. 3).
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 in- vestigated on multiple ongoing clinical trials while current efforts focus on personalized treatment and precision oncology that tar- get 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 . There are multiple studies investigating the role of several biomarkers as well as of genetic and epigenetic alterations, in- cluding 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 devel- oped multigene liquid biopsy (NETest), that is based on transcrip- tomic evaluation of NENs, has been shown to have numerous clin- ical 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 .
Preclinical in vitro and in vivo models have recently been devel- oped to capture the heterogeneity of human NENs aiming at de- lineating the biological behaviour of these tumours as well as to in- vestigate the efficacy of new antitumour agents. The patient-de- rived xenografts (PDX) in mice and zebrafish embryos are considered as the most promising preclinical models for the intro- duction of personalized medicine .
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 . However, prospective studies are required to further clarify this issue. The rationale of medical treatment taking into consideration factors that could af- fect the choice of specific treatment for well differentiated GEP- NENs is shown in the therapeutic algorithm
NENs are rare tumours that display heterogeneity of biological be- haviour and response to treatment. Recent advances regarding the
molecular pathways involved in tumour development and new im- aging techniques that are associated with the biology of the neo- plasms have led to the introduction of new therapeutic modalities such as molecular targeted agents and PRRT that have optimized the treatment of NENs. The management of patients suffering from NENs should be individualized and decisions taken in a multidisci- plinary context to improve patients’ outcome. Central registration of the patients and response to treatments would be beneficial and would probably ameliorate the management of NENs based on a personalized approach.
Conflict of Interest
Gregory Kaltsas declare that has received lecture fees from Novo Nordisk and Novartis. All other authors declare that no conflicts of interest exists.
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