Introduction

Neuroendocrine tumors (NETs) originate from diffuse neuroendocrine cell system and can develop in many organs. Gastroenteropancreatic (GEP) NETs account for approximately 70%, followed by bronchopulmonary and thymic NETs.[1] The World Health Organization (WHO) classification divides GEP NETs into well-differentiated NETs and poorly differentiated neuroendocrine carcinoma (NEC). Well-differentiated NETs can be grade 1 (G1; mitotic count <2 xss=removed>i-67 < 3 xss=removed>i-67: 3?20%) tumors, and G3 (mitotic count >20, Ki-67 > 20%).[2] Poorly differentiated NECs are always G3 tumors with >20 mitotic count and Ki-67 index >20% and include small- and large-cell NECs.[2] A total of 10 to 13% of NETs do not have a primary site identified at the time of diagnosis and are called NETs of unknown primary.[1] [3] NETs can also be differentiated based on the secretion of vasoactive amines and hormones into functional (30%) and nonfunctional NETs (70%).[1] This article focuses on the management of well-differentiated NETs with attention to systemic therapy. Factors influencing initial medical decision-making in NET management include functional status, stage, and grade, burden of metastatic disease, and symptoms at presentation.

Case 1

A 61-year-old female presented with right hip pain, diarrhea, and weight loss over the past few months. Pelvic X-ray showed lytic lesions in right femoral acetabulum. Computerized tomography (CT) of abdomen showed multiple liver lesions and additional bony metastasis in ribs. Biopsy of a liver lesion showed a metastatic G2 well-differentiated NET with Ki-67 of 10%.

Diagnosis

CT and/or magnetic resonance (MR) scans are the commonly utilized imaging modalities for initial evaluation. Multiphasic CT/MRI is helpful in evaluating liver metastasis since NETs are highly vascular and can appear isodense on conventional scans. NETs with unknown primary site should be additionally evaluated with upper and lower endoscopy with attention to the terminal ileum or by CT enterography. Evaluation with somatostatin receptor (SSR)-based imaging, like 68-Ga-DOTATATE positron emission tomography (PET), or Cu-64-DOTATATE (preferred over Indium-111-pentetreotide SPECT), is utilized to assess receptor status for determining benefit of SSR-directed therapy and evaluate suspected metastasis if unclear on initial imaging.

When symptoms are suggestive of carcinoid syndrome (unclear in this case), the initial biochemical evaluation of choice is 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). The test has 90% sensitivity and 90% specificity to detect carcinoid syndrome.[4] Urinary 5-HIAA level in carcinoid syndrome was found to range between 99 and 2,070 mg/day; however, lower levels may be present with foregut and hindgut tumors. Chromogranin and serotonin levels lack sensitivity and specificity; however, it is useful in foregut, rectal, and pancreatic NETs where 5-HIAA level is not usually elevated.[5] Plasma 5-HIAA level has not been well validated. Serum VIP (VIPoma), glucagon (glucagonoma), gastrin (gastrinoma), and insulin/pro-insulin/C-peptide (insulinoma) levels are helpful in functional pancreatic NETs.

? 24-hour urine 5-HIAA level was 928 mg/day. While awaiting further workup, what treatment should be given for her symptomatic disease?

Management of Symptoms of Hormone Secretion

The most common symptoms from functional NETs are flushing and diarrhea and are associated with elevated urinary 5-HIAA. Since 80% of well-differentiated gastrointestinal (GI)-NETs express SSR, somatostatin analogs (SSA)-like octreotide and lanreotide are highly effective in controlling the symptoms. Initial therapy should be with octreotide of 50 to 750 ?g/day, two to four times a day subcutaneously (typically started at 100?150 ?g thrice a day with some patients requiring up to 1,500 ?g/day, although data limited). This not only provides rapid symptomatic relief but also acts as test dose before initiating long-acting depot. After 1 to 2 weeks on short-acting SSA confirming symptomatic relief and absence of adverse reactions, we initiate long-acting depot injections starting with Octreotide intramuscular (IM) depot injection (octreotide long acting release - LAR) 20 to 30 mg at every 4 weeks. Although dose can be decreased to 10-mg IM at every 4 weeks depending on the response, in our practice, we start at 30-mg IM every 4 weekly dose and usually do not deescalate due to its benefit in tumor stabilization as seen in PROMID randomized clinical trial.[6] Continue short-acting SSA for the first 2 weeks to maintain therapeutic levels. Temporary exacerbation of symptoms can be treated with additional subcutaneous injections. Lanreotide given 120-mg subcutaneous at every 4 weeks has similar efficacy and tolerability with additional progression-free survival (PFS) benefit and carcinoid syndrome control as noted in CLARINET and ELECT studies.[7] Phase-II randomized trials have not shown benefit of adding pasireotide, a second-generation SSA along to everolimus.[8] [9]

Telotristat ethyl, a serotonin synthesis inhibitor is Food and Drug Administration (FDA)-approved for the management of carcinoid syndrome diarrhea refractory to SSA and is usually very well tolerated.[10] Low-dose interferon alfa can improve symptoms in patients refractory to SSA.[11] However, the treatment is rarely used due to its high toxicity profile of fatigue, depression, and flu-like symptoms. Antidiarrheal therapy with loperamide and/or diphenoxylate-atropine should also be considered. Reducing the SSA intervals, and increasing the dose may offer some benefit.

Initial therapy for insulinomas is carbohydrates and diazoxide which inhibit hormone release. For gastrinomas, oral proton pump inhibitors should be considered. SSA can be used in all refractory disease.[12]

? CT chest showed no disease. Upper and lower GI endoscopic evaluation was unremarkable. What is the initial treatment for this patient?

Treatment

Surgery remains the mainstay for local or locoregional resectable NETs. With selective low surgical risk patients, early surgical exploration can be considered even in the setting of unknown primary.[13] There is no clear role of adjuvant radiation or chemotherapy and observation is the preferred approach. Surgical resection can also be considered in metastatic disease with refractory symptoms from hormone secretion. Resection of an asymptomatic primary site in the setting of unresectable metastases is generally not recommended.[14]

For low-volume and asymptomatic unresectable disease, watchful waiting until symptomatic disease or radiological progression is reasonable and acceptable. Consider CT scan in 3 to 4 months to assess tumor growth rate. Low-grade well-differentiated NETs with very low burden of metastatic disease which is stable on the repeat scan can be watched closely without initiating further systemic therapy and extending the scanning interval to 6 months. However, in symptomatic, functional, moderate-to-high-volume tumors, or tumors with documented radiological growth, treatment initiation should be considered.

SSAs have also been found to provide disease stabilization and PFS benefit.[6] [7] These should be considered as first-line therapy due to their favorable side-effect profile and proven benefit in randomized controlled trials. GETNE-TRASGU nomograms could be used to estimate PFS in patient receiving SSA based on other factors, like tumor location, Ki-67 index, and symptoms; however, it is not widely used in the United States.[15] Benefit of lanreotide and octreotide LAR in advanced well-differentiated nonfunctioning GEP NET was shown in randomized controlled trials (RCTs).[16] [Table 1] summarizes some key clinical trials in NETs.

|?Fig. 1 (A) ? Celiac artery angiogram demonstrating multiple enhancing metastatic NET throughout the liver. (B) Left hepatic artery angiogram demonstrating enhancing metastatic NET in the left lobe of the liver (representative images; source: Department of Radiology, University of Kentucky). NET, neuroendocrine tumors.|

? She underwent right and left lobe liver bland embolization without complication. Also received palliative radiation therapy to the right hip. What systemic therapy is ideal now?

Progression

In functional NETs, SSAs may be continued for symptom management. Systemic therapy options on progression include everolimus, sunitinib, or Lu-DOTATATE radionuclide therapy ([Table 1]).

Everolimus improves PFS without overall survival (OS) benefit in advanced nonfunctional GI and lung NETs. Grade 1/2 skin, GI side effects, and fatigue were mainly reported.[23] In advanced G1/2 NETs, treatment with octreotide plus everolimus showed clinically meaningful prolongation of PFS but only trended toward statistical significance.[24] An open-label extension of the study failed to show any OS benefit as many patients received everolimus off-study.[25] In our experience, everolimus is active in NETs and is able to stabilize disease in most patients for several months. Oral mucositis can be prevented with prophylactic steroid mouth wash, especially during first 4 to 6 weeks of therapy and dose adjustments are often required.

Peptide receptor radionuclide therapy: The evidence of PFS benefit from radiolabeled SSA, Lu-DOTATATE was demonstrated in NETTER-1 trial with an interim analysis, also demonstrating OS benefit.[26] Objective response rate was higher among patients on peptide receptor radionuclide therapy PRRT (18 vs. 3%). The most common side effect was nausea (59%) from the amino acid infusions administered during treatment for renal protection. Mild cytopenias were also common with nadir counts expected around 4 to 6 weeks after infusion and resolved by 8 weeks.[27] Later studies also showed improved quality of life.[28] Patients with G1/2 inoperable and metastatic SSR + NET, with expected survival of >3 months, Karnofsky?s performance status >50, sufficient bone marrow reserve, and creatinine clearance >50 mL/min were included in the clinical trial and should be the ideal candidates for this treatment. The Lu-DOTATATE is acceptable as second- or third-line treatment option for metastatic progressive midgut and pancreatic NET with SSR expression, although pancreatic NETs were not studied in NETTER-1 phase-III clinical trial.[28] In our practice, we often consider?177Lu-DOTATATE as second line if patient has symptomatic disease, bone metastasis, or need for cytoreduction. Lu-DOTATATE has the most superior PFS and overall recurrence rate (ORR) data among the approved therapies for NETs. It can be potentially deferred to third- or fourth-line treatment option in patients with mesenteric disease, as PRRT often does not work well for peritoneal metastasis and in young patients due to concern for long-term myelotoxicity and less than 5% long-term risk of myelodysplasias or leukemia.[29]

The presence of SSR can be determined by diagnostic imaging using a radiolabeled SSA Indium-111 pentetreotide (OctreoScan) or PET scan using Gallium-68 DOTATATE. The higher sensitivity of the later one makes it the preferred option, especially in patients with low tumor volume. Uptake of radiolabeled isotope is predictive of response to therapy.

Tyrosine kinase inhibitors: Although sunitinib, sorafenib, surufatinib, pazopanib, lenvatinib, and cabozantinib have been evaluated in advanced GI-NET in phase-2 and -3 trials, only sunitinib is currently FDA approved for metastatic progressive pancreatic NETs.[30] [31] [32] In lung and GI-NETs, pazopanib showed PFS improvement compared with placebo without OS benefit. Nintedanib, was evaluated in a phase-2 trial for G1/2 NET and was associated with disease stabilization and delayed deterioration of quality of life.[33]

Bevacizumab had a PFS benefit when given with octreotide compared to interferon alfa in a phase-II trial.[34] However, the confirmatory larger randomized trial with 427 patients failed to show any PFS benefit.[35] We do not recommend use of bevacizumab in the management of NETs.

Interferon alfa (IFNa) is recommended only if other treatment options are unavailable due to the relatively low level of evidence of benefit and significant side-effect profile.[36] [37] Low-dose IFNa can reduce symptoms of hormonal hypersecretion and result in tumor stabilization in some patients, but tumor regression is rare.[34] [38] [39] IFNa is dosed at 3 to 5 MU three times weekly and dose should be titrated to a leukocyte count of 3,000/?L. Pegylated IFN (80?150 ?g per week subcutaneous) has better tolerability compared with IFNa.

Cytotoxic chemotherapy ([Table 2]) should be considered in patients with progressive metastatic disease with no standard approved treatment options. Regimens that have shown evidence of activity include capecitabine plus temozolomide (CAPTEM) and short-term infusional 5 FU with leucovorin plus oxaliplatin (FOLFOX); however. confirmatory studies are needed.[40] [41] Based on emerging data and toxicity profile, we consider CAPTEM as the initial chemotherapy regimen especially for G2/3 well-differentiated midgut and pancreatic NET after progression on other treatments. The poor PFS from Eastern Cooperative Oncology Group (ECOG) E1281 trial and toxicity of the drugs have questioned the use of 5 FU, streptozocin, and doxorubicin in the treatment of NET.[42]

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    |?Fig. 1 (A) ? Celiac artery angiogram demonstrating multiple enhancing metastatic NET throughout the liver. (B) Left hepatic artery angiogram demonstrating enhancing metastatic NET in the left lobe of the liver (representative images; source: Department of Radiology, University of Kentucky). NET, neuroendocrine tumors.|