Emerging therapies for advanced insulinomas and glucagonomas

in Endocrine-Related Cancer
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Krystallenia I Alexandraki Department of Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Gregory A Kaltsas Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Simona Grozinsky-Glasberg Department of Endocrinology and Metabolism, Neuroendocrine Tumor Unit, ENETS Center of Excellence, Hadassah Medical Organization and Faculty of Medicine, the Hebrew University, Jerusalem, Israel

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Correspondence should be addressed to S Grozinsky-Glasberg: simonag@hadassah.org.il

This paper is part of a themed collection celebrating the Discovery of Insulin and Glucagon. The Guest Editors for this collection were Günter Klöppel and Wouter de Herder.

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Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

Abstract

Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

Introduction

Pancreatic neuroendocrine neoplasms (panNENs) are considered rare malignancies despite a steady increase in their incidence as shown by recent epidemiological studies (Dasari et al. 2017). PanNENs are considered slow-growing neoplasms compared to pancreatic adenocarcinomas, but they do have the capacity to metastasize based on their size and proliferative index. They may be nonfunctioning or functioning based on the absence or presence, respectively, of a concrete hormonal syndrome, which is generally present at the time of diagnosis (Alexandraki et al. 2017). However, the prolonged survival of panNEN patients and their evolving therapies are a flourishing ground for acquired changes in tumor biology permitting switching phenomena from an originally nonfunctioning (nonsecreting) to a functioning (hypersecreting) tumor (de Mestier et al. 2015, Crona et al. 2016) with a more aggressive biological behavior (Alexandraki et al. 2021); these features are associated with an overall negative prognosis (de Mestier et al. 2015, Alexandraki et al. 2021). The main aim of this review is to address the unique hormonal presentation and dismal potential of advanced/metastatic insulinoma and glucagonoma, highlighting new emerging therapeutic avenues. To enable the reader an easier comprehension of the data, we will use the term ‘advanced’ for all metastatic/locally advanced insulinomas and glucagonomas throughout the present manuscript.

In the context of epidemiology, a large series originating from the Surveillance, Epidemiology, and End Results (SEER) Program databases documented 401 patients with functional panNENs; 24% had insulinomas and 13% glucagonomas (Keutgen et al. 2016). About 4–14% of insulinomas are expected to be malignant (Service et al. 1991, Deguelte et al. 2018, Peltola et al. 2018, Kurakawa et al. 2021, Peltola et al. 2021, Oziel-Taieb et al. 2022). Similarly, glucagonomas can be malignant in up to 50% (Ferrer-García et al. 2013).

Methods

To identify studies and determine eligibility, we conducted a systematic review of the literature using the PubMed database within the last decade. The search terms strategy included ((((((((((((malignant insulinoma [MeSH Terms]) OR (metastatic insulinoma [MeSH Terms])) OR (malignant glucagonoma [MeSH Terms])) OR (metastatic glucagonoma [MeSH Terms])) OR (malignant glucagonoma syndrome [MeSH Terms])) OR (metastatic glucagonoma syndrome [MeSH Terms])) OR (malignant glucagonoma syndromes [MeSH Terms])) OR (metastatic glucagonoma syndromes [MeSH Terms])) OR (malignant glucagonomas [MeSH Terms])) OR (metastatic glucagonomas [MeSH Terms])) OR (malignant syndrome, glucagonoma [MeSH Terms])) OR (metastatic syndrome, glucagonoma [MeSH Terms])) OR (glucagonoma [MeSH Terms]). The databases were searched through until August 2022. We screened 1008 articles: all articles were independently evaluated for their relevance by two authors (K I A, S G G); studies identified through reference lists were also included. The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1).

Figure 1
Figure 1

The research strategy included the following Medical Subject Headings (MeSH): [(((((((((((malignant insulinoma [MeSH Terms]) OR (metastatic insulinoma [MeSH Terms])) OR (malignant glucagonoma [MeSH Terms])) OR (metastatic glucagonoma [MeSH Terms])) OR (malignant glucagonoma syndrome [MeSH Terms])) OR (metastatic glucagonoma syndrome [MeSH Terms])) OR (malignant glucagonoma syndromes [MeSH Terms])) OR (metastatic glucagonoma syndromes [MeSH Terms])) OR (malignant glucagonomas [MeSH Terms])) OR (metastatic glucagonomas[MeSH Terms])) OR (malignant syndrome, glucagonoma [MeSH Terms])) OR (metastatic syndrome, glucagonoma [MeSH Terms]) Filters: in the last 10 years Sort by: Most Recent]. Only the research studies published in 2012 and onward were included in the analysis.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0020

Malignant insulinomas

In general, the estimated incidence of advanced insulinomas is reaching 0.6–4.0/106/year (Service et al. 1991, Peltola et al. 2018, Yamada et al. 2020, Oziel-Taieb et al. 2022). In the SEER database series (Alexandraki et al. 2022), the incidence of advanced insulinomas has steadily increased over time from 0 between 1973 and 1976 to an incidence of 0.27 cases/106/person years during 2011 and 2012 (Sada et al. 2020). In a seminal study involving 224 patients that were recruited between 1927 and 1986, the incidence reported was four cases/106/year and 5.8% had malignant neoplasms (Service et al. 1991). In the Finnish registry, the incidence increased from 0.5/106/year in the 1980s to 0.9/106/year in the 2000s (Peltola et al. 2018, 2021). More recently, in Japan, the incidence of insulinoma was estimated to be 3.27 individuals/106/year (Keutgen et al. 2016). In general, advanced insulinoma has been defined by the evidence of locoregional extension into the surrounding soft tissue or spread to lymph nodes or distant metastases mainly to the liver (Baudin et al. 2013, Ferrer-García et al. 2013, Okabayashi et al. 2013, Yu et al. 2017, Oziel-Taieb et al. 2022). Advanced insulinomas are usually well-differentiated but the presence of liver metastases worsens their prognosis (Oziel-Taieb et al. 2022). The overall survival (OS) reaches a median value of 3.3–3.4 years (Veltroni et al. 2020, Peltola et al. 2021), with a 10-year survival of approximately 29–33% (Service et al. 1991, Peltola et al. 2021). As opposed to these numbers, prolonged survival times 6–30 years have also been reported (Peltola et al. 2021). Surgical treatment and a Ki67 ≤10% are prognostic factors associated with a better survival (Veltroni et al. 2020). It is estimated that approximately 4–8% of insulinomas are associated to multiple endocrine neoplasia (MEN)1 (Deguelte et al. 2018, Sada et al. 2021). In one study, MEN1 syndrome was documented in 5.7% of the total patients with insulinoma, but it was more prevalent in patients with advanced insulinomas (10.8% vs 5.1%) (Kurakawa et al. 2021), as opposed to the Finnish series where no MEN1 patient was seen among patients with advanced insulinomas (Peltola et al. 2021). In a series of 121 patients with advanced insulinomas from the SEER registries, at the time of diagnosis, the largest proportion of patients had localized disease (39.7%), 15.7% had regional, and 38.8% had distant metastatic disease (Sada et al. 2020).

Advanced insulinoma treatment

Physicians treating patients with functioning NENs are often facing dual therapeutic challenges: the control of hormonal hypersecretion, on the one hand, and the tumor growth control, on the other hand. The circulating products have to be reduced for achieving a safe platform before considering surgical excision. However, the hypoglycemic syndrome is often refractory to symptomatic treatment either because of the extent of the disease or because of a more aggressive secreting behavior of these neoplasms. The only potentially curative therapy for advanced insulinomas is the surgical removal (enucleation less frequently compared to benign neoplasms, distal pancreatectomy with splenectomy, spleen-preserving distal pancreatectomy, central pancreatectomy, pancreaticoduodenectomy, and total pancreatectomy in a minority) of the neoplasm (Giannis et al. 2020). Systemic and local therapies can be used in combination or sequentially to target either symptoms or tumor growth, or both goals of treatment. When surgical treatment fails to achieve cure, systemic drug therapies such as first-generation somatostatin analogs (SSAs) (octreotide or lanreotide), second-generation SSAs (pasireotide), molecular-targeted therapies (MTT) (mTOR inhibitors (mTORi; everolimus)), or tyrosine kinase inhibitors (TKI; sunitinib) have been used. A further systemic targeted therapy is peptide receptor radionuclide therapy (PRRT), whereas classic anticancer treatments such as chemotherapy and local therapies such as debulking surgery, hepatic trans-arterial (chemo)embolization (TA(C)E), selective internal radiation therapy (SIRT), percutaneous local tumor ablation (radiofrequency ablation (RFA)) have been variably used (Oziel-Taieb et al. 2022). However, the dual and complex goal of treating advanced insulinomas, e.g., to control both symptoms and tumor growth, may demand combination of therapies. In the largest multicenter study of 31 patients with advanced insulinoma, most of the patients (25/31, 80.6%) received multiple lines of treatments with different sequences including PRRT (12 cases), everolimus (19 cases), chemotherapy (8 cases), TACE/TAE/RFA (3 cases), radiotherapy (2 cases), and liver transplantation (LT) (1 case) (Veltroni et al. 2020). From this therapeutic armamentarium, the more recent therapeutic advances include data on pasireotide, everolimus, and PRRT (Alexandraki et al. 2017, Peltola et al. 2021, Spyroglou et al. 2021).

General supportive measures and medical therapy aimed to control hypoglycemia

A number of supportive measures have been suggested to control hypoglycemic syndrome (Table 1). It is important to educate at least one of the members of the family on how to react in case of a severe hypoglycemic episode precluding other activities (Baudin et al. 2013, Sada et al. 2020).

Table 1

Case reports on pasireotide use on malignant insulinomas.

Age (yrs)/sex aPrevious treatments bExtra symptomatic therapy postPASI Grade (Ki67, %) Pasireotide therapy Disease free (m postPASI)
Baratelli et al. (2014) 60, Male High-dose OCT LAR (20/m → 30/m → 60/m, BEVA + metronomic CAP, 3 cy PRRT + EVE → CARBO + EVE GLU infusions, PRE, DIAc, glucagon PRN, frequent meals, nocturnal infusions EVE 2 (NR) PASI 2, deceased
Tirosh et al. (2016) 78, Male Surgery + LMmy; LAN autogel 60/m → 90/m NR EVE; SIRT 2 (3–5) PASI LAR 20/m → 40/m 21, alive
Hendren et al. (2018)# 53, Female OCT sc → OCT LAR 30/m iv 10% DW infusion; DIA TEMCAP; TACE; LAN 120 mg; CAP 2 (4) PASI LAR 60/m 15, alive
Siddiqui et al. (2021)# 53, Female OCT sc → OCT LAR 30/m DIA TEMCAP; TACE; LAN 120 mg; CAP 2 (4) PASI LAR 60/m 48, alive

aCommon doses for the first-generation somatostatin analogs 150–2000 μg/day subcutaneously; after demonstration of its efficacy, it can be given as octreotide LAR 10–30 mg intramuscularly or lanreotide Autogel 60–120 mg subcutaneously given monthly. Second-generation somatostatin analog, pasireotide, is given initially at doses 0.9 mg subcutaneously every 12 h and then switched to LAR from 60 mg to 20 mg monthly as maintenance therapy. bin an outpatient setting, frequent meals with products rich in complex carbohydrates at regular intervals, throughout the day and evening; in the setting of hypoglycemic crisis, 15–20 g of glucose may be given every 15 min until its resolution or if unable to ingest carbohydrates, an intramuscular injection of 1 mg of glucagon may be given. In an inpatient setting, 25 g boluses of 50% glucose until the hypoglycemia is controlled, followed by an infusion of 10–20% glucose. In cases with severe and protracted symptoms, central venous catheterization with continuous intravenous glucose infusion is recommended (Brown et al. 2018, Hendren et al. 2018, Peltola et al. 2018, Siddiqui et al. 2018, Veltroni et al. 2020). cThe commonly used therapeutic dose of diazoxide is wide ranging (200–600 mg/day) with a fractionated dosing twice or thrice daily and dose titration (3–8 mg/kg/day) according to glycemic control and tolerability; an average starting dose would be 50–300 mg/day but the dose may be increased up to 600–800 mg/day (Jin et al. 2018).

BEVA, bevacizumab; CAP, capecitabine; CARBO, carboplatin; cy, cycles; DIA, diazoxide; EVE, everolimus; GLU, glucose; LAN, lanreotide; LAR, long-acting repeatable; LMmy, liver metastasectomy; m, month; NR, not reported; OCT, octreotide; PASI, pasireotide; PRE, prednisolone; PRN, pro re nata; PRRT, peptide receptor radionuclide therapy; sc, subcutaneously; SIRT, selective internal radiation therapy; TACE, transarterial chemo-embolization (usual therapy with DOXO 50 mg/m2); TEMCAP, temozolomide and capecitabine; #, the same patient described in different published papers; ×, numbers of times.

The first-line drug therapy to reduce hypoglycemic symptoms is diazoxide, a nondiuretic benzothiadiazide. A success rate in 50–60% of cases has been usually reported (Maggio et al. 2020). The drug has a rapid onset of action but it is effective in about 50% of patients. Adverse effects (AEs) are common such as gastrointestinal (nausea, anorexia), hirsutism, congestive heart failure, headache, and fluid retention (Baudin et al. 2013). In the preoperative setting, it should be stopped at least 1 week prior to the surgery to avoid intraoperative hypotension (Giannis et al. 2020).

Other drugs have also been tried for their hyperglycemic action. Glucocorticoids are rarely used because of their immunosuppressive effect along with the increased risk of sepsis (Baudin et al. 2013, Matej et al. 2016). Beta-blockers, phenyntoin, calcium antagonists, and interferon have been used in the past albeit with inconsistent results (Baudin et al. 2013, Maggio et al. 2020).

Somatostatin analogs

In general, in insulinomas, SSAs, octreotide and lanreotide, represent the second-line drugs used when diazoxide fails or cannot be tolerated, achieving a control of hypoglycemia in about 50% of patients. Somatostatin receptor (sstr)2 is the dominant receptor in both α-cells (glucagon-producing) and β-cells (insulin-producing); since in benign insulinomas, there is a usually low expression of sstr2, SSAs therapy may result in paradoxical worsening of hypoglycemia (Brown et al. 2018). In contrast, advanced insulinomas usually express sstr2 and sstr5 (Brown et al. 2018); therefore, following a first subcutaneous (s.c.) administration of short-acting SSA is recommended to switch to a long-acting (LA) formula (Okamoto et al. 2013, Wang et al. 2022). SSAs are usually well-tolerated with some gastrointestinal discomfort (Alexandraki et al. 2020). In the absence of efficacy, SSAs should be discontinued but a long-lasting benefit of more than 3 years has been documented (Baratelli et al. 2014). No benefit of combining SSA with diazoxide has been observed (Baudin et al. 2013, Matej et al. 2016). Octreotide is the most commonly prescribed drug in patients with advanced insulinomas (55.9%) (Kurakawa et al. 2021), whereas most Japanese patients with advanced insulinomas were more likely to receive lanreotide (31.6% vs 2.2%) and everolimus (31.2% vs 0.5%) compared to benign counterparts (Kurakawa et al. 2021). In another series of 18 patients with insulinomas referred as malignant, 3 (16.7%) received diazoxide, 12 (66.7%) SSA, and 11 (61.1%) mTORi (Yamada et al. 2020). SSAs have been also used in a grade 3 (G3) advanced insulinoma resulting in a stable disease (SD) for more than 7 months (Sandoval et al. 2016).

On top of that, the second-SSA, pasireotide, which targets more sstr5 than sstr2, 1 and 3, has been reported in advanced insulinomas with favorable effects. Pasireotide induces hyperglycemia which is exploited to control the hormonal syndrome (Brown et al. 2018). In a case report of a heavily pre-treated patient with a G2-advanced insulinoma, the hypoglycemia was controlled with pasireotide only as monotherapy for 26 months with a rapid clinical status improvement (Oziel-Taieb et al. 2022). Another patient with advanced insulinoma and liver metastases responded for 24 months to pasireotide (Tirosh et al. 2016). Moreover, rechallenge with pasireotide was also shown as an effective strategy (Tirosh et al. 2016). A table summarizing the case reports on pasireotide use on advanced insulinomas for the last decade is provided (Table 1).

Pasireotide seems to be more effective in treating refractory hypoglycemia (Siddiqui et al. 2020). However, the CLARINET study demonstrated the anti-neoplastic effect of the first-generation SSAs, lanreotide, with a significant improvement of progression-free survival (PFS) vs placebo in patients with panNENs (Rinke et al. 2009, Caplin et al. 2014, Wolin et al. 2015, Alexandraki et al. 2017), but there are no data to support an additional antineoplastic role of pasireotide.

In a real-life multicenter study of 31 patients, 10 patients with advanced insulinoma did not undergo surgical treatment, and they were treated either with SSAs alone or with combination therapies, e.g., two (20%) SSAs plus chemotherapy (20%), 2 (20%) SSAs plus PRRT, and 1 (10%) SSAs plus everolimus (Veltroni et al. 2020). However, additional therapy was needed to control hormonal syndrome together with first-generation SSAs; 20/31 (64%) patients received diazoxide, 7/31 (23%) corticosteroid therapy, 1 verapamil, whereas 2 received pasireotide intramuscularly (i.m.) as a compassionate use (Veltroni et al. 2020).

Molecular targeted therapies

Nowadays, the most effective emerged drug used for advanced insulinoma treatment is everolimus, an inhibitor of the PI3K/AKT/mTOR pathway, which is abnormally activated in NENs. Everolimus possesses both antineoplastic and antisecretory effects in insulinoma patients (Tovazzi et al. 2020) since the Akt/mTOR pathway is involved in the control of glucose homeostasis (Thomas et al. 2013, Matej et al. 2016, Brown et al. 2018). It is of note that in several reports, a fast hyperglycemic response is noted from 48 h to 2 weeks even in the absence of tumor growth inhibition (Thomas et al. 2013, Maggio et al. 2020). Glucose fluctuations improve (Yanagiya et al. 2018), but insulin and C-peptide levels in the blood remain elevated despite normoglycemia (Thomas et al. 2013). In a series of 12 patients treated with everolimus for refractory hypoglycemia caused by stage IV advanced insulinomas after many previous lines of treatment (diazoxide; liver metastasectomy; TACE; chemotherapy; octreotide; corticosteroids, continuous/nocturnal glucose infusion, interferon, sunitinib), its median duration of therapeutic effect was 6.5 months in 11/12 (91%) patients who experienced a complete symptomatic response (Bernard et al. 2013); this response was not correlated to morphological improvement, implying that everolimus acts independently as antineoplastic and antisecretory agent (Bernard et al. 2013). This notion was documented later in a case report, where, after the exhaustion of the antineoplastic effect of everolimus which lasted 2 years, the glucose levels could not be controlled but with the rechallenge of everolimus together with temozolomide (TEM) (Tovazzi et al. 2020). The authors proposed continuing everolimus beyond progression in symptomatic insulinoma patients in order to control hypoglycemia (Baratelli et al. 2014, Tovazzi et al. 2020). Another case report of a patient heavily pre-treated reported long-term efficacy of monotherapy with everolimus for 32 months (Feitosa et al. 2015). A rechallenge with everolimus can be considered in individual cases following initial decreased efficacy since this phenomenon appears to be transient (Baratelli et al. 2014, Maggio et al. 2020), and it seems to be due to desensitization or downregulation of mediators involved in the mTOR pathway instead of a true resistance (Baratelli et al. 2014).

In the recent ESMO guidelines, everolimus is recommended in G1/G2 panNENs (Pavel et al. 2020). Everolimus in combination with SSAs in advanced and metastatic panNENs demonstrated benefit vs everolimus monotherapy in RADIANT-1 (Yao et al. 2010) and RADIANT-3 (Yao et al. 2011) trials. As opposed to these data, the combination of everolimus with pasireotide did not prove to exert any further benefit in advanced panNENs (Kulke et al. 2017). Everolimus was used in G3 advanced insulinoma with good results in both tumor growth and symptom control (Lowette et al. 2016). A table collecting the case reports and small case series on everolimus use in advanced insulinomas for the last decade is provided (Table 2).

Table 2

Case reports and small case series on everolimus use on malignant insulinomas.

Age (yrs), sex aPrevious treatments bExtra symptomatic therapy PostEVE Grade (Ki67, %) Everolimus therapy (dose, mg/d) Disease free (m postEVE)
Walter et al. (2013) 57, Female 2 cy STZ + DOXO→ 4 cy epirubicin + CARBO + CAP + 3 cy PRRT 111In- octreotide; OCT LAR 30; 5 cy PRRT 90Y- octreotide cDIA None 1 (1) EVE 10 → 5 5, deceased
Thomas et al. (2013) 58, Male 131I-MIBG (1200 mCi in 5 fractions (2 yrs); 3cy TEM DIA + OCT sc → continuous infusion 500 mg/d + PRE 30 mg/d; continuous iv GLU, GLU drinks/h + jam sandwiches/2 h NR NR EVE (10) + PRE → 5 45, alive
Ferrer-Garcia et al. (2013) 63, Male Partial pancreatic resection + splenectomy; OCT LAR 20/m 2 mg DEXA × 2/d; DIA NR NR EVE (5) 18, alive
Ferrer-Garcia et al. (2013) 78, Male TACE; OCT LAR 20/m DIA; DEXA NR NR EVE (10 → 5) 24, deceased
Bozkirli et al. (2013) 61, Female OCT sc 200 × 3; SIRT Continuous DW infusion TACE (5FU+DOXO+DC beat microparticles) 1 (<2) EVE + RT (45 Gray) 2
Cuesta Hernández et al. (2014) 56, Female STZ + adriamycin; OCT LAR 30/m; SUN 37.5 mg/d; HYPO DIA, PRE 30 mg/d; continuous iv 10% GLU → DEXA 2mg/ 8h, DW CARBO + ETOP; 30 mg OCT LAR/ 28 d; TEMCAP WD EVE (10→5) → EVE + OCT 15, deceased
Eriksson et al. (2014) NR, Female Distal pancreatic resection+ splenectomy iv GLU infusions TAE 2 (5–10) EVE 10 +STZ+5-FU → EVE 5 11, alive
Scharf et al. (2014) 45, Male Debulking surgeryd iv GLU infusion; DIA DACA + CAP; PRRT 177Lu-DOTATOC 3 (70) 5 cy CARBO + ETOP + EVE (5) + SIRT + TACE 14, deceased
Asayama et al. (2014) 57, Female OCT, TACE × 2 DIA, nocturnal GLU infusion none 1 (low) EVE 10 → 5 >12, alive
Baratelli et al. (2014) 60, Male high-dose OCT LAR (20/m → 30/m → 60/m, BEVA + metronomic CAP, 3 cy PRRT GLU infusions, PRE, DIA, glucagon PRN, frequent meals, nocturnal infusions none 2 (NR) PRRT + EVE → CARBO + EVE→ PASI → EVE 26, deceased
Nahmias et al. (2015) 45, Female LAN Autogel 30/2 wks, PRRT 90Y-DOTATOC → HYPO NR STZ + DDP + 5-FU→ Salvage PRRT 2 (5–7 → 20) EVE 18, deceased
Nahmias et al. (2015) 63, Male LAN Autogel 120/m; 6 PRRT 177Lu-DOTATATE → HYPO Continuous nasogastric tube nutrition + DIA + DEXA TACE 2, NR EVE 8, NR
Nahmias et al. (2015) 66, Male 5-FU + STZ, OCT LAR 60/m, 2cy 90Y-DOTATOC → 177Lu-DOTATOC + surgery, RFA; EVE → HYPO NR NR NR EVE NR
Feitosa et al. (2015) 68, Female OCT sc; TACE; 1 cy 131I-MIBG (3.7 GBq) Frequent meals; DIA; DEXA none 1 (<2) EVE 32, deceased
Dubey & Viswanath (2016) 55, Female surgery + LMmy; OCT sc; OCT LAR Dextrose infusions, OCT EVE 10 + OCT LAR 10, alive
Tirosh et al. (2016) 78, Male Surgery + LMmy; LAN autogel 60/m → 90/m; PASI LAR 20/m → 40/m NR PASI LAR 40/m; LAN autogel 90/m; PASI LAR 40/m; SIRT 2 (3–5) EVE 10 15, alive
Lowette et al. (2016) 24, Female None Hypertonic GLU, DIA, acetazolamide 2 cy CISP + ETOP; TACE 3 (28) EVE (10) → EVE+OCT (3x 500 μg/d) → LAR 30/m; EVE 5 + 4 cy 177Lu-octreotate/ 8 wks (29.6 GBq) 26, deceased
Lowette et al. (2016) 53, Male 4 cy CISP + ETOP; SUN 37.5 mg/d Hypertonic GLU; DIA; corticosteroids FOLFOX; TACE 3 (21) EVE 10 → OCT 500 μg × 3/d → LAR 30/m) +EVE 10 17, deceased
Lowette et al. (2016) 31, Female 3cy CARBO + ETOP + 4cy DOXO + CYCLOPH + CISP + OCT 20/m; SUN 37,5 → 25 mg/d; 4cy 90Y dotatoc/8 wks (10.5 GBq) Parenteral nutrition, DIA TACE 2 (20) OCT + EVE 10→ 5 3, deceased
Lowette et al. (2016) 53, Male OCT LAR 30/m Hypertonic GLU + DIA SUN (37.5 mg/d); CISP + ETOP; 4 cy 90Y-DOTATOC 8 wks→ OCT 3 × 0.5 mg/d 3 (40) RADIANT-3 trial 35, deceased
Lowette et al. (2016) 57, Female Debulking surgeryb Hypertonic GLU; DIA TACE 2 (2–20) RADIANT-3 trial: PLACEBO → OCT 3 × 500/d + EVE → LAR 30/m + EVE 10→ TACE→ EVE 10 + OCT 30/m 61, alive
Yu et al. (2017) 29, Female OCT GLU infusion None 2 (10–20) EVE 12, deceased
Yu et al. (2017) 56, Female OCT; pancreatectomy + LMmy DIA TEM, OCT 1 (2) EVE + BEVA+OCT 43, alive
Yu et al. (2017) 79, Male None NR NR NR EVE + OCT 6, alive
Yu et al. (2017) 37, Male Pancreatectomy, PRRT NR None 1 (2→5) EVE 12, alive
Yu et al. (2017) 39, Female Pancreaticoduodenectomy + CHEMO, PRRT, OCT, LMmy CAPTEM, SUN, LAN, FOLFOX 2 (10–15) EVE 2, alive
Yanagiya et al. (2018) 76, Male Surgery, TACE, OCT LAR 10→ HYPO → OCT sc Frequent GLU ingestion, nocturnal GLU infusion 2 (5.3) EVE 10 + OCT sc 6, alive
Clover et al. (2019) 53, Male 3 cy CISP + ETOP + LAN; 3 cy TEMCAP; bone RT; SUN 50 → 37.5 mg/d; TACE Require i.v. dextrose infusions postEVE Debulking surgery; TACE; cabozantinib; TACE NEC, >50 EVE 10 <24, deceased
Iglesias et al. (2019) 51, Female Surgery; LAN autogel 120/m; SUN 37.5 mg/d; 6 cy CISP + ETOP Frequent meals; methylPRE 32 mg/d, DIA 4 cy 177Lu-DOTATATE; OCT LAR 30/3 wks 3 (60); 2 (2–20) EVE 10 mg/d + OCT LAR 30/2 wks 66, alive
Tovazzi et al. (2020) 48, Female SSA Iv GLU; DIA None NR EVE 10 + SSA→ SUN 37.5 mg/d +SSA → EVE 10 + SSA→ 2 cy Oxaliplatin + 5-FU → EVE 10→ EVE 10 +TEM → EVE 10 + FOLFOX 28, deceased
Oziel-Taieb et al. (2022) 45, Female OCT LAR 30/m; TACE, LAN 120/m DIA TACE; SUN 37.5 mg/d; SUN+PASI 0.9 mg × 2/d; TEMCAP + PASI 0.9 × 2/d; PASI LAR 60/m →20/m 2.4–18 EVE 54, alive

aCommon doses for the first-generation somatostatin analogs 150–2000 μg/day subcutaneously; after demonstration of its efficacy, it can be given as octreotide LAR 10–30 mg intramuscularly or lanreotide Autogel 60–120 mg subcutaneously given monthly. Second-generation somatostatin analog, pasireotide, is given initially at doses 0.9 mg subcutaneously every 12 h and then switched to LAR from 60 mg to 20 mg monthly as maintenance therapy. bIn an outpatient setting, frequent meals with products rich in complex carbohydrates at regular intervals, throughout the day and evening; in the setting of hypoglycemic crisis, 15–20 g of glucose may be given every 15 min until its resolution or if unable to ingest carbohydrates, an intramuscular injection of 1 mg of glucagon may be given. In an inpatient setting, 25 g boluses of 50% glucose until the hypoglycemia is controlled, followed by an infusion of 10–20% glucose. In cases with severe and protracted symptoms, central venous catheterization with continuous intravenous glucose infusion is recommended (Brown et al. 2018, Hendren et al. 2018, Peltola et al. 2018, Siddiqui et al. 2018, Veltroni et al. 2020). cThe commonly used therapeutic dose of diazoxide is wide ranging (200–600 mg/day) with a fractionated dosing twice or thrice daily and dose titration (3–8 mg/kg/day) according to glycemic control and tolerability; an average starting dose would be 50–300 mg/day but the dose may be increased up to 600–800 mg/day (Jin et al. 2018). dDistal pancreatectomy, splenectomy, liver metastasectomy: 80–90% tumor mass.

BEVA, bevacizumab; CAP, capecitabine; CARBO, carboplatin; CHEMO, chemotherapy; CISP, cisplatin; cy, cycles; CYCLOPH, cyclophosphamide; DACA, dacarbazine; DDP, dischlorodiammine platinum; DEXA, dexamethasone; DIA, diazoxide; DOXO, doxorubicin; DW, dextrose in water;ETOP, etoposide; EVE, everolimus; iv, intravenously; FOLFOX, folinic acid+ fluorouracil + oxaliplatin; GLU, glucose; h, hour; HYPO, hypoglycemia; LAN, lanreotide; LAR, long-acting repeatable; LMmy, liver metastasectomy; m, month; MIBG, metaiodobenzylguanidine; NR, not reported; OCT, octreotide; PASI, pasireotide; PRE, prednisolone; PRN, pro re nata; PRRT, peptide receptor radionuclide therapy; RFA, radiofrequency ablation; RT, radiotherapy; sc, subcutaneously; SIRT, selective internal radiation therapy; SSAs, somatostatin analogs; STZ, streptozocin; SUN, sunitinib; TACE, transarterial chemo-embolization; TAE, transarterial embolization; TEM, temozolomide; TEMCAP, temozolomide and capecitabine; WD, well differentiated; yrs, years; wk, week; /d, per day; ×, numbers of times; 111In, indium 111; 131I, iodine 131; 177Lu, lutetium 177; 5-FU, 5-fluorouracil; 90Y, yttrium 90.

AEs of everolimus include rash, aphthous stomatitis, fatigue, weight loss, gastrointestinal upset, and interstitial pneumonitis and/or opportunistic infections that have been associated with potentially significant morbidity and mortality (Baudin et al. 2013). Everolimus should be carefully co-administrated with glucocorticoids since in the RADIANT-3 their combination resulted in a fatal episode of acute respiratory distress (Yao et al. 2010, Bernard et al. 2013). A special care is needed in heavily pre-treated patients to whom everolimus is given because of its immunosuppressive effect (Walter et al. 2013).

Sunitinib, a multitarget TKI, is approved for the treatment of advanced/metastatic panNENs. In a phase III trial of metastatic or unresectable panNENs, including two patients with advanced insulinomas, sunitinib showed a benefit compared to controls but the outcome of these patients was not reported (Raymond et al. 2011). Evaluation of other TKIs may reveal further antineoplastic effect for advanced insulinomas as for the rest of panNENs (Spyroglou et al. 2021). Despite this benefit in controlling tumor growth, sunitinib showed an increased prevalence of hypoglycemia deterioration in several case reports, which is making it less popular as a therapeutic choice for advanced insulinomas (Raymond et al. 2011, Ferrer-García et al. 2013, Cuesta Hernández et al. 2014, Lowette et al. 2016, Tovazzi et al. 2020). However, it has stabilized the disease in G3 advanced insulinomas, with a benefit lasting from 6 to 12 months (Lowette et al. 2016). The combination of sunitinib and lanreotide was reported to result in disease-free survival lasting more than 4 years (Maekawa et al. 2022).

Surgery

In advanced insulinomas, surgical excision has been shown to be associated with a better survival rate for more than 20 years (Andreassen et al. 2019, Veltroni et al. 2020); a possible selection bias of patients with better performance status and less progressed disease admitted for surgery has to be considered. Surgery can be curative in a localized stage, after a neoadjuvant tentative or as debulking surgery in metastatic liver disease when all the macroscopically visualized lesions can be resected in more than 90%, which correlates with an improved survival (Bettini et al. 2009, Baudin et al. 2013, Machairas et al. 2021). Cytoreduction is proposed as a palliative mean when the hormonal syndrome is not well controlled (Baudin et al. 2013, Maekawa et al. 2022), inducing not only a symptomatic improvement but also an improved efficacy of systemic or locoregional therapies (Veltroni et al. 2020). In a small series, 3/8 patients with advanced insulinomas remained asymptomatic post-surgery, despite residual hepatic disease, and with no need to continue antisecretory medication (Maekawa et al. 2022). Overall, it has been reported that the majority of patients with advanced insulinoma and unresectable metastasis will be operated (95.6%) as opposed to 4.4% that can be managed by medical therapy (Mehrabi et al. 2014). The type of surgical resection is related to the patient’s general condition, the number and location of liver metastases, the complexity of the liver lesions resection, and the estimation of the potential remnant of liver parenchyma (Doi 2015). Patients with advanced insulinoma less often underwent pancreatic surgery (57.8% vs 72.0%), the laparoscopic procedure was performed less often (20.3% vs 30.1%), and they were more likely to receive other medications vs patients with benign insulinoma (71.6% vs 49.6%) (Kurakawa et al. 2021). Distal pancreatectomy was the most common procedure in both groups, whilst enucleation was not performed in patients with advanced insulinoma (Kurakawa et al. 2021). In a small series, the surgical outcome was improved by performing hormonal tumor mapping via a selective arterial secretagogue injection technique in six out of eight patients with advanced insulinoma (Maekawa et al. 2022). In another series of 21 patients, curative surgery was obtained in 2 patients with only lymph nodal metastases, and surgery alone or associated with the additional treatments resulted in a hypoglycemic control in 42.9% of the patients (alone: 7; plus SSA: 8; plus SSA/TACE/TAE/RFA: 3; plus SSA/everolimus: 2; plus SSA/chemotherapy: 1) (Veltroni et al. 2020).

Liver transplantation (LT) has also been reported for advanced insulinomas. The first orthotopic LT for liver metastases associated with endocrine tumors was reported in 1989 (Makowka et al. 1989). LT for multiple liver metastases may be considered in patients with no extrahepatic metastases (Okabayashi et al. 2013). Five-year survival after transplantation in the absence of risk factors was reported to reach 66% (Baudin et al. 2013). Sporadic cases of LT have been reported in patients with metastatic insulinoma, such as of a young female patient who showed liver failure after TAE and LT-induced disease control for 13-year without recurrence (Ohya et al. 2021) or of a young 37-year-old male patient with liver metastases only and disease-free for at least 18 months (Ferrer-García et al. 2013).

Local therapies

Liver-directed therapy (LDT) (RFA, TAE, TACE, SIRT-radioembolization) is recommended as second-line treatment for unresectable liver metastasis with symptomatic hormonal hypersecretion or continued liver progression despite medical management (Habibollahi et al. 2020).

Radiofrequency ablation can be used to reduce the tumor mass in the liver, improving hormonal syndrome (Okabayashi et al. 2013) and was associated with a better response when metastatic foci have a size less than 3 cm (Baudin et al. 2013). Several older studies in advanced insulinomas support TACE’s rapid effect and effective symptom control, with a better response when the liver is involved in less than 30%, the metastases size is less than 3–5 cm, and with a good vascularization (Baudin et al. 2013). Recently, a retrospective analysis of 7 patients with advanced insulinomas, assessing 30 sessions of TACE and 3 sessions of radioembolization (Habibollahi et al. 2020) documented a technical success rate reaching 97% (32/33) (Habibollahi et al. 2020). The initial clinical success rate, defined as the absence of symptomatic hypoglycemia within 1 month after the first cycle of LDT was 100%, and the overall clinical success rate was 85%. One patient developed hypoglycemia resistant to LDT 2 years after the first chemoembolization whereas the mean time to recurrence of intractable hypoglycemia was 21 months with a median of 1.8 years (Habibollahi et al. 2020). Overall, complete response or partial response were achieved in 11 of 16 treatments for an objective response rate of 69%, whereas stable disease (SD) or progressive disease (PD) was seen in 5 (31%) of 16 treatments (Andreassen et al. 2019). There are case reports that described a long-term effect with repeated courses of TACE, up to six courses in a heavily treated patient who lived for up to 10 years after the administration of all the available treatments (Ferrer-García et al. 2013, Giuroiu & Reidy-Lagunes 2015) or for 14 months after one cycle of TACE only (Feitosa et al. 2015). In most cases, a rapid and temporary improvement of hormonal symptoms is seen lasting from 6 to 20 months (Maekawa et al. 2022). TACE was successful in four patients with liver metastases but in one that had also extrahepatic disease (Kennedy et al. 2012). In earlier cases, repeated TACE (six cycles) with or without microwave thermal ablation maintained an SD for more than 8 months with a rapid onset of action (Koshy et al. 2013).

In an earlier study, a combination of surgical excision, intravenous STZ, and transcatheter intra-arterial chemoperfusion with STZ and TACE resulted in hormonal syndrome control in 6/10 patients (Starke et al. 2005). In another single-center report, 5/15 patients underwent cytoreductive surgery and/or combined with TAE/TACE and/or SSA (Yu et al. 2018). Nevertheless, TACE with doxorubicin was toxic resulting in liver failure in two patients in one series, whereas in a third patient, it was stopped because of poor performance and induced in a fourth patient SD for 4 months (Lowette et al. 2016). Overall, it has been shown that aggressive sequential multimodal therapy (TACE, RFA, liver resection, LT) can prolong the survival of patients with advanced insulinoma (Okabayashi et al. 2013).

Other more recent and more selective techniques have been elaborated. In a multi-treated patient with a Ki67 of 25% (G3) tumor, SIRT with beats coated with yttrium-90 (Y-90) was administered to treat liver metastases, with a good control 16 months post-diagnosis (Ferrer-García et al. 2013) or as an additional treatment (Tirosh et al. 2016). SIRT controlled also hypoglycemia for 16 months after the failure of distal pancreatectomy, capecitabine, everolimus, SSAs, diazoxide, and corticosteroids (Chandra et al. 2010). However, in a G3 patient, each LDT session resulted in a transient reduction only of the daily glucose infusion dose, lasting 2––3 weeks (Scharf et al. 2014).

Recently, ablation via endoscopic ultrasound (EUS) was used as an alternative for benign insulinomas when too small or when the patient is not willing to be operated (Oleinikov et al. 2019). Moreover, in a patient with an advanced insulinoma, EUS ethanol injection was performed to both the primary lesion and metastatic lymph node; the patient remained asymptomatic for 3, 11, and 9 months after the first, second, and third injections with no AEs (Mittal et al. 2017). The intraoperative ultrasound (IOUS)-guided ethanol injection may also be used for limited lesions (Brown et al. 2018). Generally, few AEs were reported including upper abdominal pain, localized bleeding, and rarely pancreatitis (Brown et al. 2018).

Peptide receptor radionuclide therapy

PRRT represents an effective treatment option for hormonal syndromes in NENs together with symptomatic relief and reduction or stabilization of tumor burden as was shown in midgut NENs (Strosberg et al. 2017). The prerequisite for its use is the positivity in sstrs imaging (SRI), either by 111In-octreotide scan (Octreoscan) or 68Gallium (68Ga) DOTA Positron Emission Tomography (PET)/Computed Tomography (CT). The most frequently used radiopeptides for targeted therapy include 90Y or 177Lu linked to an SSA (Strosberg et al. 2017). A higher sstrs expression in advanced insulinomas was confirmed by the increased avidity on 68Ga-DOTATATE PET/CT compared to benign insulinomas (Wild et al. 2011, Veltroni et al. 2020), implying the use of 177Lutetium (Lu) ‐DOTATATE based PRRT in unresectable disease as an adjunct to other pharmacological management when surgical resection is non‐curative (Shah et al. 2022). Advanced insulinomas preferentially express sstrs compared to glucagon-like peptide-1 receptor (GLP‐1R) which is more prevalent in benign insulinomas (Fig. 2; personal experience, unpublished), defining the 'flip flop phenomenon' (Wild et al. 2011, Pattison & Hicks 2017, Shah et al. 2022), whereas the increase of malignant potential in parallel with switching of tumor avidity from GLP‐1R‐avid to sstr-avid to FDG-avid defined the 'triple flop' phenomenon (Pattison & Hicks 2017).

Figure 2
Figure 2

A female patient suffered from hypoglycemic episodes since 49-year-old. In her first presentation, imaging was negative to detect insulinoma. Five years later, the diagnostic work-up was repeated with MRI/CT and 68Ga-DOTATATE PET/CT all negative. One year later 68Ga-DOTA-Exendin4-PET/CT revealed an insulinoma measured 18 × 12 mm in the uncinate process of pancreas that was also seen in the axial CT imaging. Pancreatectomy confirmed the finding.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0020

Older studies showed the benefit of this approach to control hormonal syndrome even in cases with tumor growth progression (Ong et al. 2010, van Schaik et al. 2011, Brown et al. 2018). From 131 patients treated with 177Lu-DOTATATE with metastatic gastroenteropancreatic NENs (GEP-NENs), 2 had insulinomas; 1 achieved partial remission (PR) and the other PD post-therapy (Kwekkeboom et al. 2005). Recently, it was shown that PRRT-induced symptomatic responses in 67% of patients persisted despite radiological progression (Zandee et al. 2019). However, in 34 patients with functional panNENs, disease control rates were higher in 7 gastrinomas (100%) and 8 glucagonomas (100%) compared to 14 insulinomas (50%). The decrease in hypoglycemic events occurred in 67% of metastatic insulinomas, eight patients pre-treated with SSAs, five had surgery, and two received concomitant chemotherapy (Zandee et al. 2017). In a cohort of 310 patients with GEP-NETs managed with 177Lu-DOTATATE between 2000 and 2006, including 5 advanced insulinomas, 3 had PR, 1 SD and 1 PD (Kwekkeboom et al. 2008). In another series of five patients with advanced insulinomas, SSAs failed in four patients with severe uncontrollable hypoglycemia but PRRT therapy resulted in SD and symptomatic control for a mean period of 22 months (van Schaik et al. 2011). Moreover, four patients with advanced insulinomas and refractory hypoglycemia pre-treated with diazoxide and SSAs received PRRT after surgery, or chemotherapy and surgery, or sunitinib and surgery, demonstrating PD at 15 and 13 months, and mortality in 17 and 22 months postPRRT in two patients, respectively, whereas two other patients remained asymptomatic at 23 and 16 months, respectively (Magalhães et al. 2019). Finally, in the largest series of advanced insulinomas, PRRT was given as first-, second-, or third-/fourth-line of treatment after surgery, depending on the availability of the radionuclide or the responses to previous therapies, and resulted in a high response rate (93%) (Veltroni et al. 2020). In 2/14 (14%) patients, PRRT was given as the first-line with SSA, in 8/14 (57%), as the second-line, and in 4/14 (28%), as third- or fourth-line of therapy after surgery. Two patients received PRRT in association with everolimus for hypoglycemic syndrome control at a low dose (5 mg/day) in order to avoid cumulative hematological toxicity (Veltroni et al. 2020). A complete hypoglycemic control was seen in 6/14 (42.9%), and a reduction in hypoglycemic episodes in 7/14 (50%) (Veltroni et al. 2020). Single case reports also outlined the positive effects of PRRT in advanced insulinomas for both symptomatic and tumor control in sporadic (Costa et al. 2013, Makis et al. 2016, Iglesias et al. 2019) or syndromic cases (Novruzov et al. 2019). On the contrary, when it was given in patients with G3, the results were short-lasting (Lowette et al. 2016). PRRT was given in two patients with inoperable advanced insulinomas, either together with everolimus in one or together with chemotherapy, after the failure of diazoxide and SSA to control severe hypoglycemia (Ong et al. 2010); symptomatic control and decrease of liver metastases were achieved. One patient was asymptomatic for 10 months and the other had PD after 24 months

A table collecting the literature on PRRT use in advanced insulinomas is provided (Table 3).

Table 3

Case reports and small case series on peptide receptor radionuclide therapy use on malignant insulinomas.

Age (yrs), sex aPrevious treatments bExtra symptomatic therapy PostPRRT Grade (Ki67, %) PRRT Disease free (m postPRRT)
Costa et al. (2013) 32, Female OCT LAR 30/m continuous i.v. GLU NR Low-grade (NR) 2 cy 177Lu 3, alive
Walter et al. (2013) 57, Female 2 cy STZ + DOXO cDIA EVE 10 → 5 1 (1) 3 cy PRRT 111In- OCT + 4 cy epirubicin + CARBO + CAP; OCT LAR 30; 5 cy PRRT 90Y- octreotide 50, deceased
Scharf et al. (2014) 45, Male dDebulking surgery; OCT 600/d → LAN 90 /m; CARBO+ ETOP + EVE + SIRT + TACE; DACA + CAP iv GLU-infusion; DIA None 3 (70) 177Lu-DOTATOC 2, deceased
Baratelli et al. (2014) 60, Male High-dose OCT LAR (20/m → 30/m → 60/m, BEVA + metronomic CAP GLU, PRE, DIA, high-dose OCT LAR 60/m CARBO/ wk+ EVE, PASI, EVE 2 (NR) 3 cy 177Lu-OCTREOTATE

+ EVE
33, deceased
Nahmias et al. (2015) 45, Female LAN Autogel 30/2 wks, PRRT 90Y-DOTATOC → HYPO → EVE; STZ +DDP +5-FU NR none 2, 2(5–7) → 20 Salvage PRRT 0, deceased
Lowette et al. (2016) 24, Female EVE (10) → EVE+OCT (3 × 500/d) → LAR 30/m Hypertonic GLU, DIA, acetazolamide 2 cy CISP + ETOP; TACE 3 (28) EVE 5 + 4 cy 177Lu-octreotate/8wks (29.6 GBq) 2, deceased
Lowette et al. (2016) 31, Female 3cy CARBO + ETOP + 4cy DOXO + CYCLOPH + CISP + OCT 20/m; SUN 37,5 → 25 mg/d Parenteral nutrition, DIA OCT + EVE 10→ 5; TACE 2 (20) 4 cy 90Y dotatoc / 8-wk (total activity 10.5 GBq) 11, deceased
Lowette et al. (2016) 53, Male OCT LAR 30/m; RADIANT-3 trial; SUN 37.5 mg/d; CISP + ETOP hypertonic GLU + DIA OCT 3x 0.5 mg/d 3 (40) 4 cy 90Y-dotatoc/8 wks 7, deceased
Makis et al. (2016) 70, Female Surgery + LMmy Continuous iv GLU + snacks NR 2 (15) 6 cy (4 induction & 2 maintenances) 24, alive
Yu et al. (2017) 37, Male Pancreatectomy NR EVE 1 (2→5) PRRT 60, alive
Yu et al. (2017) 39, Female Pancreaticoduodenectomy + CHEMO OCT, LMmy, EVE, CAPTEM, SUN, LAN, FOLFOX 2 (10–15) PRRT 2, alive
Novruzov et al. (2019) 60, Male, MEN1 None NR NR 2 (8–10) 2 cy 177Lu-DOTATATE 12, alive
Andreassen et al. (2019) 53, Female Surgery, RFA NR NR 2 (8) PRRT 26, alive
Magalhães et al. (2019) 30, Female Surgery; OCT 100 ×3/d DIA; frequent meals; PRE OCT LAR 20/m → 30/m; TACE 2 (NR) 3 cy 177Lu-DOTATATE (15.3 GBq) 22, deceased
Magalhães et al. (2019) 74, Female OCT LAR; 4 cy STZ + epirubicin, surgery DIA NR NR 3 cy 177Lu-DOTATATE (17 GBq) 17, deceased
Magalhães et al. (2019) 52, Female 5 cy STZ + 5-FU×5, surgery ×5, OCT LAR 30/2 wks Frequent meals/2 h, DIA 75 mg/d OCT LAR 30/m 1→2 (NR) 2 cy 177Lu-DOTATATE (11.1 GBq) 23, alive
Magalhães et al. (2019) 50, Female Surgery, SUN→ HYPO Frequent meals/2h, DIA 75 mg/d, glucagon PRN OCT LAR 30 mg 2 (NR) 3 cy 177Lu-DOTATATE (14.4 GBq) 16, alive
Iglesias et al. (2019) 51, Female Surgery; LAN autogel 120/m; SUN 37.5 mg/d; 6 cy CISP + ETOP; EVE 10+ OCT LAR 30/2 wks Frequent meals; methylPRE 32 mg/d, DIA 150 mg/d OCT LAR 30 mg/3 wks 3 (60) & 2 (2–20) 4 cy 177Lu-DOTATATE 18, alive
Kumar et al. (2022) 96, Male OCT LAR 30/m NR NR 1 (2–3) 4 cy 177Lu-DOTATATE (32 GBq) 74, alive
Verma et al. (2022) 48, Male TACE (LM) DIA none 2 (NR) 5 cy 177Lu-DOTATATE (1044 mCi) 42, alive

aCommon doses for the first-generation somatostatin analogs 150–2000 μg/day subcutaneously; after demonstration of its efficacy, it can be given as octreotide LAR 10–30 mg intramuscularly or lanreotide Autogel 60–120 mg subcutaneously given monthly. Second-generation somatostatin analog, pasireotide, is given initially at doses 0.9 mg subcutaneously every 12 h and then switched to LAR from 60 mg to 20 mg monthly as maintenance therapy. bIn an outpatient setting, frequent meals with products rich in complex carbohydrates at regular intervals, throughout the day and evening; in the setting of hypoglycemic crisis, 15–20 g of glucose may be given every 15 min until its resolution or if unable to ingest carbohydrates, an intramuscular injection of 1 mg of glucagon may be given. In an inpatient setting, 25 g boluses of 50% glucose until the hypoglycemia is controlled, followed by an infusion of 10–20% glucose. In cases with severe and protracted symptoms, central venous catheterization with continuous intravenous glucose infusion is recommended (Brown et al. 2018, Hendren et al. 2018, Peltola et al. 2018, Siddiqui et al. 2018, Veltroni et al. 2020). cThe commonly used therapeutic dose of diazoxide is wide ranging (200–600 mg/day) with a fractionated dosing twice or thrice daily and dose titration (3–8 mg/kg/day) according to glycemic control and tolerability; an average starting dose would be 50–300 mg/day but the dose may be increased up to 600–800 mg/day (Jin et al. 2018). dDistal pancreatectomy, splenectomy, liver metastasectomy: 80–90% tumor mass.

BEVA, bevacizumab; CAP, capecitabine; CARBO, carboplatin; CHEMO, chemotherapy; CISP, cisplatin; cy, cycles; CYCLOPH, cyclophosphamide; DACA, dacarbazine; DDP, dischlorodiammine platinum; DIA, diazoxide; DOXO, doxorubicin; ETOP, etoposide; EVE, everolimus; iv, intravenously; FOLFOX, folinic acid+ fluorouracil + oxaliplatin; GLU, glucose; h, hour; HYPO, hypoglycemia; LAN, lanreotide; LAR, long-acting repeatable; LM, liver metastases; LMmy, liver metastasectomy; m, month; MIBG, metaiodobenzylguanidine; NR, not reported; OCT, octreotide; PASI, pasireotide; PRE, prednisolone; PRN, pro re nata; PRRT, peptide receptor radionuclide therapy; RFA, radiofrequency ablation; sc, subcutaneously; SIRT, selective internal radiation therapy; STZ, streptozocin; SUN, sunitinib; TACE, transarterial chemo-embolization; TEM, temozolomide; TEMCAP, temozolomide and capecitabine; yrs, years; wk, week; /d, per day; ×, numbers of times; 111In, indium 111; 131I, iodine 131; 177Lu, lutetium 177; 5-FU, 5-fluorouracil; 90Y, yttrium 90.

PRRT AEs may outweigh the benefit in some patients; gastrointestinal disturbances, temporary hair loss, hematological toxicity, severe bone marrow disease, and renal toxicity have been reported (Magalhães et al. 2019, Alexandraki et al. 2020).

Before the introduction of PRRT, therapy with radiolabeled meta-iodo-benzyl guanidine (MIBG) analog has been also tried (Okabayashi et al. 2013, Feitosa et al. 2015) with limited efficacy.

Chemotherapy

The ESMO guidelines recommended the use of systemic chemotherapy in advanced panNENs and in G3-NEN of any site (Pavel et al. 2020), and the ENETS Guidelines in G2 or a higher grade (Ki67 >15%) GEP-NETs or in NENs with aggressive biological behavior (Garcia-Carbonero et al. 2017). Chemotherapy is the principal treatment for poorly-differentiated neuroendocrine carcinoma (NEC), either functioning or nonfunctioning and the combination cisplatin/etoposide is the most popular (Baudin et al. 2013). Overall, 5-fluorouracil (5-FU), doxorubicin, and streptozotocin have been commonly used in the treatment of advanced insulinomas as well as other agents (dacarbazine, cisplatin, etoposide, capecitabine, TEM); however, the number of patients was small with significant toxicity and with poor response (Brown et al. 2018). In a multicenter study, 16.7% were G3 NENs, but none were poorly differentiated (Veltroni et al. 2020). In one analysis from the NORDIC NEC registries, 88% out of 164 patients receiving first-line chemotherapy had platinum/etoposide treatment, whereas response rate (RR) was higher for NEC with Ki67 ≥55% (44%) compared to NEC Ki67 <55% (25%) and G3 NEN (24%) (Elvebakken et al. 2021). The median survival of the 252 patients included in the primary study was 11 months for palliative chemotherapy vs 1 month in 53 patients receiving the best supportive care only, whereas RR was 31% and SD 33% but no referral was made to advanced insulinomas patients in this study (Sorbye et al. 2013). Chemotherapy, in a neoadjuvant setting, is used to reduce the tumor load allowing a surgical intervention. Streptozotocin or TEM alone or combined with capecitabine (TEMCAP) has been also used for more than 30 years for well-differentiated panNEN (Spyroglou et al. 2021) with favorable results (Chatzellis et al. 2019). Streptozotocin was approved by the Food and Drug Administration (FDA) in 1976 for the treatment of panNENs (Karatas et al. 2018). Streptozotocin plus doxorubicin (S/D) regimen was replaced by the less toxic TEMCAP combination in advanced insulinomas. Nonetheless, S/D is one of the most effective treatment options (Karatas et al. 2018). Streptozotocin combined with 5-FU was superior to streptozotocin monotherapy in overall RR in an old study of 84 patients with recurrent or metastatic islet-cell carcinoma (15 insulinomas) (Moertel et al. 1980). The S/D scheme was proved to be superior to streptozotocin plus 5-FU or chlorozotocin alone in terms of RR in unresectable or metastatic islet-cell carcinomas (Moertel et al. 1992). In a recently published case report, S/D improved not only symptoms but also tumor growth control in a patient who discontinued treatment early after only the second course because of doxorubicin-related congestive heart failure and remained disease-free 30 months post-diagnosis (Karatas et al. 2018). The S/D, with or without 5-FU, has traditionally been used as the first-line treatment with response rates up to 70%; AEs include myocarditis, kidney or liver insufficiency, mucositis, asthenia, diarrhea, and/or myelosuppression (Cuesta Hernández et al. 2014).

In a recent series from the French Group of Endocrine Tumors, it was shown that 5-FU with oxaliplatin (FOLFOX) given in nine patients with advanced insulinomas demonstrated a better median PFS (22 months) compared to other panNENs (9 months) including four PR (44%) and five SD (56%) and a high rate (8/9) of serum glucose normalization and implying an anti-secretory action over the anti-neoplastic one (Girot et al. 2022). Hence, chemotherapy is recommended as an effective option for the third-/fourth-line of treatment for advanced insulinomas with refractory hypoglycemia after PD on everolimus or in case of major toxicity requiring the withholding of everolimus (Girot et al. 2022).

A G3 advanced insulinoma patient (ki67 60%) had PR (50% size reduction) and liver stabilization after six cycles of cisplatin/etoposide (Iglesias et al. 2019). On the other hand, a patient with NEC had only short-term responses to different chemotherapeutic schemes (Clover et al. 2019). Chemotherapy is therefore justified when grading increases and its effect may last between 4 months and 1 year (Lowette et al. 2016). Moreover, a multimodal therapeutic approach including the consecutive use of tumor debulking surgery, chemotherapy, TACE, SIRT, PRRT along with diazoxide, SSAs, and everolimus in a G3 advanced insulinomas patient (Ki-67 70%) demonstrated that chemotherapy with carboplatin/etoposide plus everolimus provided the longest normoglycemic period, whereas after tumor progress chemotherapy with dacarbazine had the most positive effect as opposed to debulking approaches (surgery, LDTs), and PRRT had only transient success (Scharf et al. 2014).

The sequence of treatments and/or their different combinations represents unmet needs not only for advanced insulinomas but for all NENs (Table 4). The addition of TEM to everolimus achieved effective tumor growth control when everolimus-alone efficiency was abolished (Tovazzi et al. 2020). It is also important to underline that everolimus combined with cytotoxic agents was safe (Tovazzi et al. 2020), for both TEM and FOLFOX regimens. In isolated cases, their combination was associated with short-duration SD and glycemic control lasting for 5 and 2 months, respectively (Tovazzi et al. 2020). Moreover, since streptozotocin is the first-line treatment for advanced panNENs, and given that the response to streptozotocin is correlated with mTOR pathway activation, streptozotocin was combined with mTORi (Bollard et al. 2018). Everolimus seemed to display some effects in vitro (moderate synergy with no or mild apoptosis effects when used as a single agent or combined with streptozotocin), in one preclinical xenograft model, probably due to antitumor direct effects to both microenvironment and angiogenesis regulation (Bollard et al. 2018). An elegant study has shown that shutting down the mTOR pathway during streptozotocin treatment leads to more potent antitumor effects, supporting the rationale for a combination treatment or a pretreatment with everolimus prior to streptozotocin (Bollard et al. 2018). A dual compound, the BEZ235 (dual PI3K/mTORi) in combination with streptozotocin in reduced doses may have an acceptable toxicity profile for patients in phase I/II clinical trials (Bollard et al. 2018). In vitro studies confirmed the beneficial role of both mTORi and dual PI3K/mTORi (Zhan et al. 2012). Finally, inhibition of PI3K with BKM120 seems very efficient when used as a single agent or combined with streptozotocin. In the clinical context, the SEQTOR trial is evaluating the benefit of such combinations, aiming at determining which sequence (everolimus followed by streptozotocin/5-FU vs. streptozotocin/5-FU followed by everolimus) is the most beneficial together with a good understanding of the potential toxicity of these combining or sequencing therapies (Bollard et al. 2018).

Table 4

Examples of the combination of therapies represents in some case reports of patients with metastatic insulinomas.

Age (yrs)/ sex Treatments Grade (Ki67, %) Overall survival (m)
Iglesias et al. (2019) 51, Female LAN 120 AU + SUN → 3 cy CISP/ETOP → HYPO → 3 cy CISP/ETOP → EVE 10 + OCT LAR 30 mg/2 wks (48 m) + methyprednisolone + DIA → 4 cy PRRT → OCT LAR 30mg/2 wks + GCs 3 (60)→ 2 (2–20) 72, alive
Clover et al. (2019) 55, Male 3 cy CISP/ETOP + LAN AU → 3 cy TEMCAP → TEMCAP + bone meta RT → SUN (50 mg→37.5) → HYPO → TACE + EVE → SURGERY + LMmy → TACE + CABO→ TACE 2 (10) + 3 (>50) 24, deceased
Giuroiu & Reidy-Lagunes (2015) 60, Male TEMCAP (36 m) → OCT LAR 20 mg/2 wks + DIA + DEXA → MK-0646: anti-IGF-1 receptor antibody (5 m) → BEVA + temsirolimus (5 m) → Akt inhibitor MK-2206 → SUN → 2 TACE → EVE (3 m) → TACE +DIA + DEXA → STZ/DOXO/5-FU → TACE → GEMOX (17 ) → platinum/ETOP ND 120, deceased
Scharf et al. (2014) 45, Female DIA (300 mg/d) + OCT 600 mg /d → DIA (300 mg /d + LAN 90 mg sc/m (12 m) → SURGERY→ DIA (1 m) → 5cy CARBO + ETOP + EVE (5) (2 m) → SIRT +TACE → DIA + DACA + CAP → 2 cy PRRT 3 (70) 15.6, deceased
Walter et al. (2013) 57, Female 2 cy STZ → 3 cy PRRT + → 4 cy epirubicin/ CARBO/ CAP → OCT LAR (3 m) → 5 cy PRRT (3 m) → EVE (10→5) (5 m) 1 (1) 60, deceased

AU, autogel; BEVA, bevacizumab; CABO, cabozantinib; CAP, capecitabine; CARBO, carboplatin; CISP, cisplatin; cy, cycles; DACA, dacarbazine; DEXA, dexamethasone; DIA, diazoxide; DOXO, doxorubicin; ETOP, etoposide; EVE, everolimus; GEMOX, gemcitabine + oxaliplatin; HYPO, hypoglycemia; IGF, insulin-like growth factor; LAN, lanreotide; LAR: long-acting repeatable; LMmy: liver metastasectomy; m: month; ND, not determined; OCT, octreotide; PRRT, peptide receptor radionuclide therapy; RT, radiotherapy; sc: subcutaneously; SIRT, selective internal radiation therapy; STZ, streptozotocin; SUN, sunitinib; TACE, transarterial chemo-embolization; TEMCAP, temozolomide and capecitabine; wk, week; /d, per day; 5-FU, 5-fluorouracil.

External radiation therapy

External radiation therapy can be used as palliation for painful bone lesions or for cerebral metastases (Baudin et al. 2013). On top of that, the novel techniques of stereotactic surgery may offer a better-targeted role in treating these metastatic lesions (Baudin et al. 2013).

New trials

In the era of personalized medicine, the molecular profile of each neoplasm dictates novel therapies to be possibly tried. Recently, it was found that the IGF signaling pathway is downregulated in advanced insulinomas compared to benign well-differentiated insulinomas (Henfling et al. 2018). Particularly, low mRNA expression levels of IGF2, IGF1R, and INSR-A, together with high levels of IGFBP3 correlated with shorter 10-year overall and disease-free survival; decreased protein expression of IGF2, cytoplasmic IGF1R, and INSR also correlated with shorter survival rates with possible therapeutic implications. An anti-IGF-1 receptor (IGF-R1) antibody was tried in a phase II study of MK-0646 (ClinicalTrials.gov identifier: NCT00610129) with good tolerance and with SD for 5 months (Giuroiu & Reidy-Lagunes 2015).

Noteworthy, the molecular profile of advanced insulinomas may enable more specific treatments. Recently, it was suggested that the chromosomal instability from DAXX/ATRX mutations may represent a genomic basis for the more aggressive behavior of some insulinomas (Burns et al. 2023). EPHB4 encoding ephrin type-B receptor 4 was also mutated (Burns et al. 2023) suggesting the need for further investigation of these druggable molecules (Alexandraki et al. 2019). ROS1, encoding the proto-oncogene tyrosine-protein kinase ROS, and KMT2A (MLL), encoding the transcriptional regulator, lysine methyltransferase 2A, were found to be mutated in the genomic sequencing performed in liver metastasis of a patient with advanced insulinoma (Burns et al. 2023). In another series of 5 advanced insulinomas, ATRX/DAXX were mutated in 3 cases out of 35 insulinomas (1 with DAXX loss), whereas all liver metastases expressed immunohistochemically the transcription factor ARX as opposed to only 3 in their primary insulinomas and 4 with alternative lengthening of telomeres (ALT) – as opposed to none in the benign insulinomas (Hackeng et al. 2020). Finally, whether the transcription factor Yin Yang 1 (YY1), found mutated in a minority of insulinomas, has a role in advanced insulinomas it has to be determined (Chen et al. 2021).

In addition, it was recently shown that an insulinotropic imidazoline compound in combination with an AMPK activator had a specific cytotoxic effect on insulinoma, implying that in the already known beneficial effect of metformin in reducing the risk of developing solid tumors and pancreatic cancer (Gong et al. 2014); its beneficial effect on insulinoma treatment may be added (Zaitseva et al. 2016).

Several alternative radionuclides are studied such as 125I-GIP targeting glucose-dependent insulinotropic polypeptide receptor (GIPR), as possible future theranostic agent for sstr2 negative NENs or GLP-1 negative insulinomas (Refardt et al. 2021). The effort to develop exendin‐4–based tracers for PRRT may be proved to be useful to the few cases of advanced insulinomas expressing GLP-1R (Jansen et al. 2019).

Finally, since cancer stem cells (CSC) are considered unique subpopulations of a tumor, being solely responsible for tumor initiation, metastasis, and recurrence, targeting therapeutically CD90, a potential CSC marker, can be used both, not only as a potential diagnostic tracer for imaging and monitoring progression of advanced insulinomas but also as a therapeutical target (Buishand et al. 2016).

Glucagonomas

Glucagonomas are panNEN derived from α pancreatic cells (Cardoso Filho Fde et al. 2015) predominantly involving the tail of the pancreas (Martin et al. 2022, Bevere et al. 2023). Glucagonomas may behave aggressively, with high reported rates of locally, and regionally advanced disease or distant metastases (Keutgen et al. 2016). Delays in diagnosis reaching also 10 years make this neoplasm even more aggressive (Huo et al. 2016, Santucci et al. 2021). Glucagonoma syndrome is typically characterized by the triad of necrolytic migratory erythema (NME), diabetes mellitus, and weight loss or the 4D (dermatitis, diabetes, deep vein thrombosis (DVT), and depression); NME present in 70–80% of the patients has multifactorial pathogenesis including also amino acids and zinc deficiencies (Halperin et al. 2015, Martin et al. 2022, Bevere et al. 2023). Glucagon increases glycogenolysis and gluconeogenesis resulting in hyperglycemia; glucagon stimulates lipolysis and relaxation of smooth muscle in the gastrointestinal system (Martin et al. 2022). A rare and recently described entity defined as Mahvash disease must be taken is a consideration in the presence of a panNEN and extremely high glucagon levels without glucagonoma syndrome (Ro et al. 2013).

Traditionally, glucagonomas incidence is 1–2/20 million people (Cardoso Filho Fde et al. 2015, Li et al. 2022, Bevere et al. 2023) or 2.7/100 million in America (Santucci et al. 2021) or 0.05–0.1/106 people (Erdas et al. 2012). In 50–78% of cases, it is metastatic at the time of diagnosis (Erdas et al. 2012, Deguelte et al. 2018) and associated with MEN1 in 1–20% (Deguelte et al. 2018). A relatively large series was recently reported including seven patients and four had already metastatic disease (Li et al. 2022). Glucagonomas accompanied by NME were reported to bear a high probability to be malignant (Zhu & Zheng 2021). The diagnosis includes increased fasting plasma glucagon levels, usually elevated 10- to 20-fold to the upper normal of limit in the presence of a pancreatic neoplasm (Martin et al. 2022).

Few studies analyzed the molecular profile of glucagonomas, mostly characterized by MEN1 mutations; inactivation of DAXX and mutation of glucagon receptor gene mutations have been also reported (Bevere et al. 2023).

Advanced glucagonoma treatment

As for advanced insulinomas, the only potentially curative therapy for glucagonomas is the surgical removal (enucleation, distal pancreatectomy with splenectomy, spleen-preserving distal pancreatectomy, central pancreatectomy, pancreaticoduodenectomy, and total pancreatectomy) of the neoplasm, and it is frequently the only treatment that these patients receive including in patients with advanced disease (Pandey et al. 2012, Gilshtein et al. 2014, Tremblay & Marcil 2017, Feldmann et al. 2018) with disease-free survival of more than 5 years (Zhu & Zheng 2021). Since the most common metastatic site is the liver, hepatic metastasectomy or other local therapies targeting liver metastasis as described for advanced insulinomas may be adopted (Sandhu & Jialal 2023). Long-term disease-free survival, of more than 6 years, in advanced disease, has been described with surgical therapy only as in the case of an ovarian metastasis resected 16 months after the removal of the primary tumor (Watt et al. 2013). Symptomatic improvement can be seen within 1–2 weeks from the treatment at earliest, sometimes in such a grade to change the initial treatment plan even in patients with massive liver metastases (Kimbara et al. 2014).

SSAs have been given in a monthly regimen (Qin et al. 2021) with remission of symptoms when the neoplasm is inoperable or patients are not keen on surgery but also in a 2- to 3-week regimen prolonging the beneficial action of the drugs from 2 years to more than 5 years (Rui et al. 2012, Al-Faouri et al. 2016). However, the clinical suspicion or the diagnosis dictates a rapid induction of treatment with SSA to control symptoms before surgery (Thomaidou et al. 2016, Tamura et al. 2018, Saavedra et al. 2019) with or without additional supportive therapy (Thomaidou et al. 2016). Remission is documented rapidly in 1-month time even in the case of SSA monotherapy in patients with multiple liver metastases when surgery is not indicated (Tseng et al. 2013, Zhang et al. 2014, Aragón-Miguel et al. 2019, He et al. 2021); earlier benefits have been also described (Lo et al. 2014). SSAs seem to be the first-line treatment for glucagonomas, as in the case of metastatic or giant glucagonomas, everolimus, sunitinib, and radioactive microspheres targeting liver metastases were given with no good control of the hormonal syndrome as opposed to SSAs which improved symptoms within 24 h (Gaiser & Dhawan 2015, 2016). There are case reports in which SSAs were administrated upon residual disease with a long disease-free follow-up period (Halvorson et al. 2013).

Noteworthy, supportive therapy before surgery has to be always considered and includes nutritional supplementation and amino acid infusions, essential fatty acids, topic or oral zinc therapies, vitamins, minerals, and a good control of carbohydrates disturbances (Ferrer-García et al. 2013, Ro et al. 2013, He et al. 2021). Empirical supportive treatment with prednisolone and dapsone along with antibiotics, local skin care, and nutritional supplements have been given in cachectic patients before diagnosis and resulted in an improvement (Sahoo et al. 2014). The increased risk for DVT dictates the need for pre- and postoperative supportive treatment with heparin prophylaxis therapy (Ferrer-García et al. 2013, Krampitz & Norton 2013, Ro et al. 2013, Halperin et al. 2015, Jin et al. 2018). This is well-demonstrated in cases firstly presented with DVT (Halvorson et al. 2013, Daly et al. 2019) usually ab initio metastatic or in cases with disease control by surgical therapy but complicated with pulmonary embolism (PE) (Georgiou et al. 2015) and a fatal outcome (Toberer et al. 2019). As opposed to other neoplasms, a poor performance status of the patient may be improved by urgent surgical removal of the glucagonoma (Halvorson et al. 2013).

As in other NENs, advanced metastatic disease at presentation demands anti-tumor therapies to be given along with cytoreductive surgery (Ito et al. 2012). All the therapeutic modalities that were reported in advanced insulinomas can be adapted in advanced glucagonomas (Cardoso Filho Fde et al. 2015, Toberer et al. 2019) together with LT and LDTs (Cardoso Filho Fde et al. 2015). If there are contraindications to surgery, chemotherapy with S/D can be administered, leading to a selective damage to pancreatic islet cells (Cardoso Filho Fde et al. 2015). The combination of the different therapies, such as surgical excision combined with local therapies such as RFA, was described to control liver disease (Gao et al. 2015).

Glucagonomas can be very aggressive such as in the case of a 68-year-old woman who received six cycles of dacarbazine followed by SSA, but when relapsed 4 years later, none of the interventions such as TAE, 5-FU, and platinum-based treatment could control her disease (Corrias et al. 2017). Moreover, there are cases resistant to treatment such as a 57-year-old man who achieved SD after a sequence of treatment with different chemotherapeutical regimens including cisplatin, etoposide, 5-FU, irinotecan, and TEMCAP together with octreotide. In this later case, only prednisone at a dose of 1 mg/kg/day achieved clinical remission of NME that was substituted by cyclosporine along with TEMCAP at least for a 9-month period (Jiménez-Gallo et al. 2017). In another case report of a predominant secretion of glucagon over gastrin from a metastatic NEN following a couple of treatments combining SSAs and sunitinib or SSAs with everolimus, the tumor became resistant to treatment (Kido-Nakahara et al. 2014). In an old series, 19 out of 23 patients (18 with liver metastases and 9 with bone metastases) received chemotherapy at some point, almost in all (18) streptozotocin and 5-FU, resulting in a 50% objective radiological response. Interferon, SSAs, PRRT, and local therapies targeting liver metastases (TAE, RFA) were also used. Eleven patients died at a median period of 80 months from diagnosis as opposed to 11 patients who were still alive at a median follow-up of 52 months (Kindmark et al. 2007). More recently, in one series from China, six patients received amino acid infusions and underwent pancreaticoduodenectomy in one and distal pancreatectomy in the others with or without splenectomy followed by liver metastasectomy in three. SSAs s.c. were given in five and gemcitabine/capecitabine in one who also had TACE and RFA, whereas another had γ-knife therapy. Symptoms improvement was reported 1-2 days post-surgery in two patients and in one patient 1-day post-SSAs. Four out of six patients died after a mean of 5.7 years (range: 3–10.4), whereas two were alive 30- and 26-month post-diagnosis (Wei et al. 2018). The longest survival time reported in the literature is 24 years with an unresectable recurrence (Nightingale et al. 1999).

PRRT was given in isolated cases (Thomaidou et al. 2016) or in small series. In eight advanced glucagonomas, PRRT resulted in a disease control rate of 100% with an improvement of skin lesions or weight in five (71%), whereas the mean hormonal levels dropped significantly (87%) (Zandee et al. 2017). PRRT (four induction and two maintenance cycles) was proved to be an effective treatment in a recurrent advanced glucagonoma resulting in a progression-free period lasting 23 months (Makis et al. 2015).

In another recent series of seven patients, six were surgically treated, all received SSA, four had liver metastases, two of them with lymph node involvement as well, whereas three of them died from the disease (Li et al. 2022). One patient underwent TACE, RFA, and two cycles of PRTT due to liver metastasis on top of the surgery and another one received a novel TKI, sulfatinib, everolimus, and TACE (Li et al. 2022). In the six patients with Ki67 evaluation, four had G2 (Ki67 8% to 10%), one G1–2 (Ki-67 2.8%), and one G3 (Ki67 30%) (Veltroni et al. 2020). The mean time to disease-related death was 6.4 years from diagnosis and 7.2 years from initial clinical manifestations (Veltroni et al. 2020). PRRT may be considered also as in the neo-adjuvant setting for reducing tumor burden in patients with large tumor before considering surgery (Fig. 3; personal experience, unpublished).

Figure 3
Figure 3

The maximum intensity projection (MIP) images of the 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) of a patient with huge glucagonoma localized in the head of the pancreas treated with neo-adjuvant peptide receptor radionuclide therapy (PRRT) and then undergoing surgery with resection of most of her tumor. (A) 68Ga-DOTATATE PET/CT pre-PRRT; (B) 68Ga-DOTATATE PET/CT 2 months postPRRT; (C) 68Ga-DOTATATE PET/CT 3 months post-surgery.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-23-0020

Local ablative techniques, such as microwave ablation or RFA, are suitable in small number of lesions of less than 5 cm in size (Gao et al. 2015). In non-resectable cases, hepatic artery embolization to diminish hepatic arterial circulation can be used. Other options include TAE/TACE/SIRT to inhibit angiogenesis and destroy existing blood vessels (Ferrer-García et al. 2013).

Conclusion

Advanced insulinomas and glucagonomas management follow the therapeutic algorithm of panNENs aiming also at controlling the hormonal syndrome. In advanced insulinomas when first-SSAs fail to control the hypoglycemic syndrome, second-line with the addition of everolimus to SSAs is used. Everolimus can be also considered as a rechallenge as its hypoglycemic effect seems to be displayed by a dichotomous molecular pathway compared to its antitumor effect. PRRT seems to be a promising modality for both antisecretory and antitumoral effects. Similarly, in advanced glucagonomas, the management has to include supportive therapy and the first-line of treatment with SSAs to improve patient’s performance status enabling considering surgical options. PRRT seems to be an effective treatment mainly when SSAs and surgery fail to stabilize the disease. The emerging approaches such as second-lines with everolimus or PRRT possibly exert a beneficial effect and improve the OS for patients with malignant insulinomas or glucagonomas. Based on the rarity of these tumors and their heterogeneous clinical behavior and response to therapy, prospective multicenter trials, possibly using the ENETS platform of centers of excellence, seem essential in order to uncover the multiple diagnostic and therapeutic unmet needs in these unique cancers.

Declaration of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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