After the accurate diagnostic assessment and staging of disease, the management of functional pancreatic neuroendocrine tumors remains challenging for clinicians (Fig. 1).

Fig. 1

Management of functional pancreatic neuroendocrine neoplasms. This figure represents a practical algorithm for the management of functional pNENs. Abbreviations: RFA, radiofrequency ablation; MEN 1, multiple endocrine neoplasia syndrome type 1; TAE, transarterial embolization; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; PRRT, peptide radio receptor therapy; SSAs, somatostatin analogs; PPIs, proton pump inhibitors; IFN-a, interferon alpha.

Management of local/locoregional disease

Surgery with radical intent represents the treatment of choice for locoregional or locally advanced functional G1 or G2 pNENs [2, 19]. However, before planning a surgical approach, tumor localization, tumor size, and local invasiveness need to be considered. In functional pNENs, surgery remains the cornerstone to achieve a cure and complete symptomatic relief. Standard pancreatectomy (distal or pancreaticoduodenectomy) with lymphadenectomy is the preferred approach; however, in cases of small benign insulinomas (<1 cm) localized in the head or tail of the pancreas, a more conservative approach by surgical enucleation should be considered [2, 10]. Pancreaticoduodenectomy or distal pancreatectomy may be necessary in cases of local recurrence after enucleation [20•].

In patients with gastrinomas located in the pancreas (approximately 25% of patients) and MEN1, the role of surgery remains debated, and a risk-benefit assessment should always be evaluated [2, 21, 22]. In this setting, gastrinomas are usually multifocal, and it is difficult to achieve a radical surgery. One study reported that only 16% of patients with MEN1 were free of disease after duodenectomy or pancreaticoduodenectomy whereas in more recent studies up to 77% were eugastrinemic after a surgical management [23]. Thus, in the setting of hereditary pancreatic gastrinomas, even if surgery of the primary tumor remains the only curative chance, the risks of a pancreatic surgery, especially when the lesion is in the head of the pancreas, the relatively indolent behavior of these tumors, the possibility of a multifocal localization, and the opportunity to control the syndrome with medical therapy, must be taken into account [2, 11, 23]. Unfortunately, other functional pancreatic NENs (glucagonoma, somatostatinoma, ectopic Cushing’s syndrome, etc.) are usually metastatic at the time of initial diagnosis; thus, surgical options should be considered only for debulking or symptom relief.

When an ectopic Cushing’s syndrome occurs in patients with resectable tumors, the radical surgery could be performed upfront or postponed after normalization of cortisol with medical therapy. This option should be preferred in cases of severe hypercortisolism [24].

For patients who are not eligible for surgery, EUS radiofrequency treatment represents a valid alternative to induce necrosis of the pNEN and stop hormonal hypersecretion, particularly if the tumor is smaller than 2 cm and hormone-related symptoms are present. Before planning EUS radiofrequency treatment, the distance between the lesion and pancreatic main duct must be considered [25]. Some studies have reported a complete response rate up to 95% with no additional procedure-related adverse events [26, 27••]. EUS-directed ablation using ethanol injection or CT-guided RFA appears to be a successful treatment for insulinomas in patients with sporadic disease or MEN1 [10].

Metastatic diseaseSurgery

In the setting of metastatic disease, surgery may play a role in both achieving symptom control and reducing the disease burden. However, before considering a surgical approach, some factors must be assessed: first, NEC G3 should be excluded because of the high risk of recurrence; metastases should be exclusive or predominant in the liver, the presence of extra-abdominal disease needs to be ruled out, and finally, the distribution and localization of liver metastases should be considered. Unfortunately, only 5–15% of patients with liver metastatic disease can be subjected to resection [2]. In patients with ectopic Cushing’s syndrome, a bilateral adrenalectomy could be taken into account to stop hypercortisolism-related symptoms. This condition could be life-threatening because of a high risk of thrombosis and cardiovascular events, hypokalemia, and sepsis. Bilateral adrenalectomy should be considered upfront in case of severe hypercortisolism, after medical therapy when not rapidly effective, or in case of toxicity or drug-drug interactions [28••].

Finally, in very selected cases, liver transplantation may be considered when a surgical approach is not feasible [2, 22, 29].

Locoregional therapy

In patients who are not eligible for transplantation or metastasis resection, an ablative locoregional approach (transarterial embolization (TAE), transarterial chemoembolization (TACE), radioembolization or selective internal radiotherapy (TARE), or radiofrequency ablation (RFA)) is recommended [29]. Since liver metastases from neuroendocrine tumors are highly vascularized by the hepatic artery, all these techniques are safe and effective. From the available data, TACE seems to be more effective than TAE in the setting of liver metastases from pancreatic NENs. However, both of these techniques improve symptoms and quality of life in 60–90% of patients. Future large prospective studies are needed to establish which treatment between TAE, TACE, or selective internal radiotherapy (SIRT) is the most effective one [30]. Finally, combining treatments (e.g., resection and RFA) may completely remove the tumor, but data on metastatic functional pNENs are scarce [2].

Antiproliferative therapy

Notably, somatostatin analogs (SSAs), including octreotide and lanreotide, represent the first-line therapy used to control both clinical symptoms and proliferative disease. SSAs are usually recommended for slowly progressive low proliferative pNENs [31]. This strategy is a long-term therapy with mild adverse effects that occur in approximately 50% of patients, including flatulence, diarrhea, nausea, gallstones, glucose intolerance, and exocrine pancreatic insufficiency [32, 33].

Among targeted agents, both everolimus and sunitinib are approved for advanced progressive pNENs. Everolimus is an oral m-TOR inhibitor whose role in pNENs has been well investigated in the phase 3 RADIANT-3 trial, showing an improvement in PFS (11.4 months in the everolimus arm vs. 5.4 months in the placebo arm), but no significant changes in OS were observed [34]. The side effects of everolimus include hyperglycemia, diarrhea, cytopenia, pneumonitis, and stomatitis [35]. Sunitinib (37.5 mg/day) is a tyrosine kinase inhibitor of the PDGF receptor and VEGF receptor subtype. The efficacy of this drug has been evaluated in a phase 3 trial, which demonstrated a significant improvement in PFS (11.4 months in the sunitinib arm vs. 5.5 months in the placebo arm) however with no significant OS benefit [36]. Sunitinib is approved for patients with advanced, progressive well-differentiated pNENs. Side effects associated with sunitinib include nausea, diarrhea, fatigue, cytopenia, thyroid dysfunction, heart failure, and arterial thromboembolism [2, 35].

Peptide radionuclide receptor therapy (PRRT) with 177-lutetium-labeled somatostatin analogs is a valid option for functional pNENs. Recently, PRRT was approved for all types of NENs expressing somatostatin receptors based on the NETTER-1 trial, showing antitumor efficacy in patients with advanced GEP NENs. Moreover, PRRT has demonstrated effective symptom control in refractory functional pancreatic syndromes [29, 35]. PRRT is usually considered a safe treatment; however, up to 3–4% of patients may develop myelotoxicity, including leukemia and bone marrow dysplasia [2]. Moreover, a final analysis of the phase 3 NETTER-1 trial showed that during long-term follow-up, 3 (3%) of 111 patients in the 177Lu-Dotatate group had serious adverse events, and 2 (2%) of these patients developed myelodysplastic syndrome, without any new cases of hematological events [37••]. Furthermore, preventing a hormonal crisis with dedicated pretreatments is important in the presence of a functional syndrome [38••]. According to the literature, gastrinomas seem to be one of the malignant pNENs that are most responsive to PRRT [11].

Finally, chemotherapy remains the treatment of choice for advanced progressive functional pNENs or in high-grade NEC G3. Many possible drug combinations are available, including streptozocin, doxorubicin, and fluorouracil [2]. Additionally, the combination of temozolomide and capecitabine has a role in this setting because it was associated with significantly improved PFS (22.7 months) and OS (38 months) compared to temozolomide alone [35].

Medical therapy for symptom control Insulinoma

The first step to control symptoms related to insulinoma is dietary modification with small and frequent feedings, which may be the only strategy used before surgical intervention. A valid option to control hyperglycemic symptoms includes diazoxide, which is an inhibitor of insulin release that acts on ATP-sensitive potassium channels on insulinoma cells and is effective in approximately 50% of cases. Unfortunately, diazoxide is associated with some adverse effects: edema (because of fluid retention and generally diazoxide is used with a diuretic), hirsutism, thrombocytopenia, and renal failure [4].

SSAs control hypoglycemic symptoms in up to 50% of patients with nonmetastatic insulinomas [32]. However, their use requires careful monitoring because they may inhibit not only ectopic insulin secretion but also the release of counterregulatory hormones, such as glucagon, which can worsen hypoglycemia in some patients [4].

If the disease is localized, this approach usually involves a limited period prior to surgery. However, if the insulinoma is not susceptible to resection, other therapeutic options are employed in the management of tumor symptoms.

Even if everolimus is not registered for this indication by the EMA and FDA, it could be used for uncontrolled insulinoma symptoms due to its direct suppressive role in insulin secretion [2]. Also, PRRT may be employed in the management of refractory insulinomas. One study that evaluated the efficacy of PRRT in 34 patients with functional pNENs (14 insulinomas) showed a median PFS of 18.1 months with a concurrent increase in quality of life [38••]. However, an acute aggravation of symptoms, such as worsening hypoglycemia, might occur in some cases [2].

Gastrinoma

In patients with ZES, the main category of drugs to control acid hypersecretion is proton pump inhibitors (PPIs). Since the 1980s, the use of PPIs has lessened the need for surgery. In uncomplicated PUD associated with ZES, a dosage of omeprazole equivalent to 60 mg/day is usually sufficient. However, in patients with severe PUD and in the presence of MEN1 or prior Billroth 2 resection, the dosage could be higher, up to an omeprazole equivalent of 40–60 mg BID [32]. When mucosal healing is achieved, the dosage of PPI could be reduced to 20 mg BID omeprazole equivalent. Importantly, this type of patient requires long-term therapy with PPIs; thus, adverse events, such as deficits in vitamin B12 and magnesium, may be considered [4, 10]. In general, PPIs have significantly decreased the morbidity and mortality resulting from severe ulcer disease. In 60% of patients, ulcer healing occurs within 2 weeks; in 90–100% of patients, healing occurs within 4 weeks [10]. When PPIs cannot be administered, patients can receive histamine H2 receptor antagonists. SSAs are useful to reduce levels of gastrin and acid secretion in patients with ZES, but they are rarely administered for this indication [32]. Finally, recent studies underline the efficacy and safety of PRRT in patients with gastrinoma who are nonresponders to previous therapy [38••].

Ectopic Cushing’s syndrome

Some of these patients present with severe Cushing’s syndrome with symptoms that could be difficult to control under long-term surveillance, and a proportion of them may need bilateral adrenalectomy to definitely achieve remission of hypercortisolism and related symptomatology.

Medical therapy to restore eucortisolemia is represented by steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat) and mitotane, an adrenolytic agent. These drugs need to be used cautiously because of the potential severe side effects and pharmacological interference with antiproliferative agents [4, 24]. Some cases with a significant response to SSAs have been reported, and these drugs are generally well tolerated. Besides octreotide and lanreotide, the panligand pasireotide and the D2-selective dopamine agonist cabergoline were reported to be potentially useful in ectopic Cushing’s syndrome [39, 40]. Finally, PRRT may be a valid option in malignant/refractory cases of Cushing’s syndrome of pNENs [38••].

Other functional pNENs

SSAs represent the treatment of choice to manage the symptoms of other functional pNENs (VIPoma, glucagonoma, somatostatinoma, and ectopic acromegaly), with partial symptomatic control in up to 70% of cases. Usually, these are drugs well tolerated, and they are administered monthly, e.g., 20–30 of mg/mo Octreotide or 60–120 of mg/mo Lanreotide Autogel. In case of uncontrolled symptoms, the SSA dose is commonly increased by shortening the injection interval to 3 or even 2 weeks [2].

Telotristat ethyl (oral inhibitor of tryptophan hydrolase) was recently registered for the treatment of patients with carcinoid syndrome, and it has demonstrated a significant improvement in diarrhea. It can be recommended for this indication as an add-on treatment to SSA [2].

Interferon alpha (IFN-a) may be used for symptom control (3–5 million IU s.c. three times weekly), particularly in patients with VIPoma or rare forms of carcinoid syndrome related to pNENs; however, its administration is discouraged because of its broad spectrum of side effects [2, 41].

Finally, other treatment options available to control hormone excess in these rarer functional pancreatic syndromes include targeted therapy, PRRT, and chemotherapy. Sunitinib seems to be effective in reducing diarrhea in VIPoma, whereas PRRT may be a valid therapeutic option in cases of refractory syndromes [4]. Some chemotherapeutic regimens, such as streptozotocin and 5-fluorouracil, resulted in symptom control other than tumor growth proliferation in glucagonoma [23].

Hormonal crisis prevention

Before planning an invasive treatment, such as surgery, locoregional therapy, and PRRT, it is mandatory to prevent a hormonal crisis due to the acute stress induced by the procedure with the release of high hormonal levels [41]. The prevention of hormonal crises should be considered in all patients, especially those with insulinoma, VIPoma, and gastrinoma.

In patients with gastrinoma, the administration of high-dose PPIs before and after procedures is mandatory because of predisposing gastrointestinal perforation and hemorrhage. A starting dose of 80 mg of pantoprazole administered via 15-min infusions every 8 h is recommended.

For patients with VIPoma, diarrhea inhibitors or, rarely, the IV administration of fluids and electrolytes should be prescribed to avoid severe loss of potassium and bicarbonate leading to metabolic acidosis. Patients with glucagonoma require SSA treatment, nutritional supplementation, and antibiotics to heal the skin lesion prior to surgery and perioperative anticoagulation (high-dose molecular heparin) to prevent thrombosis [42]. In patients with insulinoma treated with PRRT, a hormonal crisis may develop in up to 10% of patients; in this setting, the main goal is the prevention of hypoglycemia via glucose infusion or octreotide. Therapy needs to be initiated with dietary instructions, followed by a short-acting octreotide. Octreotide should be discontinued 24 h before PRRT, and it can then be restarted after the amino acid infusion [4, 38••]. During surgical procedure, infusion of glucose is discontinued to monitor glucose level, in particular the insulin/glucose ratio, because it seems relevant in assessing successful removal of an insulinoma. Instead, during the first period after surgery, in some cases, it could be necessary administration of small insulin doses. Otherwise, diazoxide is not always recommended before surgery because it can cause severe fluid retention [42].