Neuroendocrine Tumors Management

Evaluation

Staging  

The American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) developed the TNM System for NETs of all anatomical sites. There are some differences between these systems, particularly for primary tumors of the pancreas and appendix, but there is also a considerable overlap. The staging criteria for both systems depend on the tumor size and extent of invasion into similar landmarks as used for the staging of non-neuroendocrine carcinomas of the same sites.  

American Joint Committee on Cancer Prognostic Staging of Neuroendocrine Tumors of the Stomach

Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Neuroendocrine tumors and adrenal tumors. Version 2.2024.

Principles of Therapy

The management of neuroendocrine tumors depends on tumor size and primary site as well as the general condition of the patient. The therapeutic management should be based on proliferative activity, SSTR expression, tumor growth rate and extent of disease. The optimal therapy by a multidisciplinary team should include surgical and medical treatment modalities.  

Goals of Therapy  

The goals of therapy are to increase survival, for symptom, biochemical and tumor control and to improve quality of life. 

Pharmacological therapy

Somatostatin Analogs  

Example drugs: Octreotide, Lanreotide  

Somatostatin analogs bind selectively to SSTRs to block the release of bioactive peptides and amines. These are the drug of choice in patients with symptomatic functional gastroenterohepatic NETs to decrease hormone production, control symptoms and minimize the risk of carcinoid crises. These are first-line agents for functional NETs and low- to intermediate-grade small intestinal carcinoids. The recommended therapy for locoregional unresectable and metastatic carcinoid tumors with asymptomatic, low to clinically significant tumor burden and carcinoid syndrome. Somatostatin analogs are the mainstay for the control and relief of symptoms in carcinoid syndrome by decreasing or normalizing 5-HIAA levels. These prevent carcinoid crisis during procedures such as surgery or hepatic arterial infusions; thus, Octreotide is given perioperatively and intraoperatively. These improve time to progression among patients with metastatic, well-differentiated, midgut NETs and should be an alternative for tumor stabilization in patients with or without carcinoid syndrome. Their use should also be considered in all patients with elevated 5-HIAA levels even if asymptomatic because increased 5-HIAA is a predictor of cardiac complications and a marker of tumor growth or progression. Somatostatin analogs decrease circulating serotonin levels and may stabilize progression of carcinoid heart disease.  

Octreotide long-acting release (LAR) is recommended in patients with non-functional tumors and is an alternative in patients with metastatic colorectal NETs, especially in cases where radiotracer uptake on octreoscan indicates SSTR expression. This is used for chronic management of symptomatic patients with carcinoid syndrome. This prevents proliferation in functioning and non-functioning small intestinal carcinoids. In long-term therapy of some NETs (eg glucagonomas, somatostatinomas), they may cause symptomatic breakthrough, in which increased dose, more frequent administration, shortened interval, or temporarily discontinuation is needed.  

Lanreotide or Octreotide LAR are options for patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract. These may also be used in patients with distant metastases from NETs of the lung or thymus. These may be considered in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors. These are first-line management for symptom control in glucagonomas and VIPomas in addition to correction of electrolyte imbalance prior to surgery. These may be used in patients with gastrinoma to manage gastric hypersecretion with high-dose PPIs. These should be used with caution in patients with insulinomas that do not express SSTR because they may worsen hypoglycemia.  

Mammalian Target of Rapamycin (mTOR) Inhibitors  

Example drugs: Everolimus, Rapamycin  

Mammalian target of rapamycin is a conserved serine/threonine kinase regulating cell growth and metabolism in response to environmental factors and signaling downstream of receptor tyrosine kinases, which includes insulin-like growth factor receptor, VEGF receptor, and epidermal growth factor. This may control hypoglycemia in patients with metastatic insulinomas. Everolimus is used in patients with advanced carcinoid and malignant pancreatic NETs and for advanced NETs of the gastrointestinal tract, lungs and thymus. Everolimus is also used in patients with symptoms and unresectable neuroendocrine pancreatic and carcinoid tumors that initially present with clinically significant disease progression. Everolimus is recommended for patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract.

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Surgery

Surgical management should be individualized, with the ultimate therapeutic decisions and approaches decided after a full multidisciplinary evaluation. Surgery can be curative (primary tumor resection) or palliative (tumor cytoreduction). This has curative potential and can improve survival. It can lessen or remove the risk of progressive symptoms such as bowel obstruction. Early intervention can also increase the chance of successful surgery and decrease technical complications.  

Definitive resection of the primary tumor should always be performed whenever it is technically feasible. It is the primary treatment approach for most localized carcinoid tumors and pancreatic NETs. Primary tumor removal by segmental resection and lymphadenectomy are recommended. Most patients with advanced metastatic gastrointestinal NETs will have liver metastasis. Prophylactic cholecystectomy is also advised in patients undergoing surgery for NETs of the digestive tract in order to mitigate biliary toxicity of somatostatin analogs and prevent chemical cholecystitis if transcatheter arterial chemoembolization is done. Octreotide should be given preoperatively and intraoperatively to avoid intraoperative carcinoid crisis in patients with functional tumors. Trivalent vaccines (ie H influenzae B, meningococcal group C, pneumococcus) should be given preoperatively to patients who will require splenectomy.  

Curative Surgery  

Resection of the primary tumor should be accompanied by a thorough intraoperative evaluation for synchronous tumors or metastatic disease. Resectable liver metastasis should be removed. Selective portal vein embolization is considered in patients with borderline liver reserve in order to induce liver hypertrophy.  

Liver transplantation is an option in young patients <50 years old if:

• Primary tumor originates from the gastrointestinal tract
• Tumor is drained by the venous portal system
• Disease progression is controlled for at least 6 months before transplantation

Palliative Surgery  

Cytoreductive surgery is recommended in patients when complete resection of the tumor is not possible. This consists of a combination of multiple techniques such as hepatectomy, local ablative therapies (eg radiofrequency ablation, cryotherapy, microwave therapy), intra-abdominal organ resection and bypass procedures. This aims to stabilize or improve symptoms and decrease or normalize hormone levels. This can reduce tumor bulk, prevent or delay complications from local or distant disease, decrease hormone levels, and prolong survival. This requires the assessment by a multidisciplinary team to ensure care and provide case-specific palliative options. Hepatic arterial embolization (eg bland transarterial embolization, chemoembolization, radioembolization) with or without chemotherapy is another cytoreductive option for patients who are not surgical candidates, especially for patients with unresectable, metastatic liver-dominant, well-differentiated NETs. This is indicated for patients symptomatic or with disease progression on somatostatin analog therapy or other forms of systemic therapy, or those with bulky hepatic disease.

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• Transduodenal local excision with regional lymphadenectomy
• Pancreatoduodenectomy: May also be considered for rare ampullary tumors not amenable to local or endoscopic excision

Jejunum/Ileum/Colon  

Bowel resection with regional lymphadenectomy is recommended. Manual palpation of the entire bowel is done to assess the presence of synchronous tumors. An intra-operative assessment of the superior mesenteric artery and vein is also recommended. Well-differentiated colonic NETs have the worst prognosis among NETs arising from the gastrointestinal tract.  

Pancreas  

Local resection (distal pancreatectomy/splenectomy or pancreatoduodenectomy) or enucleation of pancreatic NETs is recommended whenever feasible. Observation can be considered for small (≤1 cm), low-grade, non-functional tumors. Lymph node resection should be considered because of the high risk of metastasis. The cure rates of other pancreatic NETs are lower because they are diagnosed during advanced disease states.  

Rectum  

For small (<1 cm) incidental lesions, complete endoscopic resection with negative margins may be sufficient. Indeterminate margins may warrant endoscopy after 6-12 months to assess residual disease. It is recommended to have endoscopic or transanal excision in tumors ≤2 cm. For tumors 1-2 cm, consider radical resection if with tumor invasion in muscularis propria or node positive. A low anterior resection or abdominoperineal resection is recommended for tumors >2 cm with tumor invasion of the muscularis propria or tumors associated with lymph node metastases.  

Stomach  

For early-stage, smaller tumors, endoscopic or wedge resection can be considered if there is no evidence of regional lymphadenopathy. Endoscopic resection should be reserved for small (<1 cm), superficial, low-grade tumors. Endoscopic resection is recommended for patients with locoregional type 1 (atrophic gastritis or high gastric pH) and 2 (Zollinger-Ellison; no atrophic gastritis, low gastric pH) gastric NETs. Radical resection with regional lymphadenectomy should be done to patients with non-metastatic gastric NETs with normal gastrin levels (type 3) because of its more aggressive quality.  

Thymus  

Thymus NETs are generally treated with surgical resection (thymectomy via median sternotomy and/or thoracotomy with lymph node dissection) without adjuvant therapy for localized and resectable disease with negative margins.

Metastatic Neuroendocrine Tumors  

For metastatic NETs of the gastrointestinal tract, when possible, surgical cytoreduction (ie resection of primary tumor + regional lymph nodes + metastasis) is done followed by surveillance and pharmacological treatment. If surgical cytoreduction is not possible, surveillance and pharmacological treatment can be started if the tumor burden is low, but if there is significant tumor burden, primary tumor resection should still be considered. Given that the liver is a common site of metastasis for NETs, liver-directed therapy (ie surgical resection, hepatic arterial embolization [including bland transarterial embolization, transarterial chemoembolization, transarterial radioembolization], percutaneous thermal ablation and radiotherapy) is also used for the treatment of metastasis.  

Pancreas  

Pancreatic neuroendocrine tumors have highly variable growth patterns. Almost all insulinomas are benign while more than half of other symptomatic pancreatic NETs and non-functional pancreatic NETs have hepatic metastasis. A high 5-year survival rates are noted in patients with resected pancreatic NETs, with incomplete resections and with diffuse hepatic disease. Surgical resection of all visible tumor is only feasible in a few number of patients with pancreatic NETs with liver metastasis. Studies showed no evidence of symptom control or prolonged survival. Despite this, surgical resection should still be attempted because of the low efficacies of other tumor treatments.  

Hepatic arterial embolization is also recommended in patients with pancreatic NETs with hepatic metastasis who are not surgical candidates, with disease limited to the liver with patent portal vein and preserved functional status. Similar response rates of more than half are also observed with gastric and carcinoid tumors. This is especially considered in patients with functional pancreatic NETs in which the hormone excess state cannot be controlled by other treatment modalities. Radiofrequency ablation and cryoablation, with or without cytoreductive surgery, via percutaneous or laparoscopic approach are considered in selected patients with advanced pancreatic NETs.  

Stomach  

Hepatic resection provides long-term symptomatic relief and prolongs survival in patients with hepatic metastasis localized to one lobe. Orthotopic liver transplantation is only attempted in a small number of patients. There is a 5-year survival rate if there are poor prognostic factors such as prior extensive upper abdominal surgery, neuroendocrine primary tumor in the duodenum or pancreas, and hepatomegaly. There is an increased 5-year survival rate in the absence of risk factors. Thus, liver transplantation cannot be routinely performed in patients with liver-isolated metastatic NETs but it can be an option for some young patients without risk factors.  

Hepatic arterial embolization is recommended as a palliative option in patients with liver metastasis who cannot undergo surgical resection but have preserved performance status, and disease confined to the liver with a patent portal vein. This is considered in patients with functional carcinoid tumors in which hormone excess cannot be controlled by other methods. The response rates are decreased hormonal secretion or radiographic regression by half. The techniques used are bland embolization, chemoembolization, embolization with chemotherapy beads, and embolization using radioisotopes. Radiofrequency ablation and cryoablation, used alone or in combination with surgical cytoreduction, should be considered only in selected patients. The clinical benefit is not clearly established in patients with asymptomatic small-volume disease and may not be applicable in patients with large-volume liver metastatic disease. For distant metastasis of the gastrointestinal tract, resection of the primary tumor, regional lymph nodes, and metastasis is recommended. In cases where cytoreduction of metastasis is not possible, resection of the primary tumor and/or treatment with Octreotide or Lanreotide is recommended.

Functional Pancreatic Neuroendocrine Tumors  

For patients with pancreatic NETs or malignant-appearing non-functional and functional pancreatic NETs >2 cm in size, resection should include total removal of the tumor with negative margins and regional lymph nodes.  

Gastrinomas  

Exploratory surgery, including duodenotomy and intraoperative ultrasound with enucleation or local resection of tumors and removal of periduodenal nodes, is recommended. Pancreatoduodenectomy is recommended for invasive/deep gastrinomas located within the head of the pancreas or proximal to the main pancreatic duct. Distal pancreatectomy with splenectomy with removal of regional nodes may be considered for distal tumors.  

Insulinomas  

Enucleation is the primary treatment for exophytic insulinomas as they are primarily benign. Peripheral insulinomas may have an open or laparoscopic enucleation/local resection or spleen-preserving distal pancreatectomy. If enucleation is not possible because of deeper or invasive tumors and those in proximity to the main pancreatic duct, options include:

• Pancreatoduodenectomy for tumors in the head of the pancreas
• Distal pancreatectomy with preservation of the spleen for small tumors not involving the splenic vessels

All insulinomas regardless of size should undergo resection due to hypoglycemic complications. Surgical cure rates are high for insulinomas and for sporadic gastrinomas.  

Glucagonomas  

Glucagonomas are mostly malignant, calcified and located in the tail of the pancreas. Distal pancreatectomy with resection of the peripancreatic lymph nodes and splenectomy is recommended. Enucleation or local excision with peripancreatic lymphadenectomy may be considered for peripheral tumors <2 cm. Pancreatoduodenectomy with peripancreatic lymphadenectomy may be done for tumors in the head of the pancreas (rare). Perioperative anticoagulation should be considered due to increased risk of pulmonary emboli.

VIPomas  

Enucleation or local excision with peripancreatic lymph node dissection may be considered in peripheral tumors <2 cm. Distal pancreatectomy with resection of the peripancreatic lymph nodes with or without splenectomy is recommended. Pancreatoduodenectomy with peripancreatic lymph node dissection is suggested for tumors within the head.  

Non-functional Pancreatic Neuroendocrine Tumors  

Surgical resection is recommended except in:

• Patients with other life-limiting comorbidities
• High surgical risk
• Widely metastatic disease

Observation can be considered for small (≤2 cm), low-grade, incidentally discovered, non-functional tumors. For non-functional tumors >1 to ≤2 cm in size, patients may have an open or laparoscopic enucleation/local resection (pancreatectomy) with or without regional lymphadenectomy. For patients who have non-functional pancreatic NETs that are 1-2 cm in size with a small but measurable risk of having lymph node metastases, lymph node resection is considered, and serial imaging is recommended. For patients with >2 cm in size pancreatic NETs or malignant-appearing non-functional and functional pancreatic NETs, resection should include total removal of the tumor with negative margins and regional lymph nodes. If the head of the pancreas is involved, may do pancreatoduodenectomy with regional lymphadenectomy. If the distal part of the pancreas is involved, may do distal pancreatectomy with splenectomy and regional lymphadenectomy.

Radiation Therapy

Radioisotope Therapy  

Peptide Receptor Radionuclide Therapy (PRRT) or Radioisotope Therapy  

Peptide receptor radionuclide therapy (PRRT) or radioisotope therapy can be considered in both functional and non-functional NETs with a positive SSTR scintigraphy regardless of the site of the primary tumor. This is a recommended treatment for NETs of the small intestine (if SSTR positive and with progression on Octreotide LAR/Lanreotide). Lutetium ¹⁷⁷Lu-dotatate is a radiolabeled somatostatin analog used as PRRT. This is approved for the treatment of SSTR-positive gastroenteropancreatic NETs, including foregut, midgut and hindgut. This is an option for patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract. This may be used in patients with distant metastases from SSTR-positive NETs of the lung or thymus with disease progression on somatostatin analogs. This may also be considered in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors.  

Tumor-targeted treatment with radioactive Octreotide derivatives ¹¹¹In-D-Phe(1)-Tyr(3)-octreotide (¹¹¹In-DOTAoctreotide) or ⁹⁰Y-DOTA-octreotide and ¹⁷⁷Lu-DOTA-octreotate and with ¹³¹I-MIBG are associated with varied response rates and clinical benefit. Patients with malignant NETs treated with [¹⁷⁷Lu-DOTA-Tyr³]-octreotide found a complete response in 2% of patients, a partial response in 32% of patients, and stabilization in 34% of patients. Radiolabeled somatostatin analogs may also be considered for advanced pancreatic NETs.

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