Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

localised disease: sporadic

1st line – proton-pump inhibitor (PPI)

Back
ACUTE
|
localised disease: sporadic
|
surgical candidate
1st line – 

proton-pump inhibitor (PPI)

PPIs have been shown to be efficacious for fast and prolonged acid suppression. They are the most effective antisecretory medicines for managing gastric acid hypersecretion and promoting ulcer healing.[1][40][80]

Retrospective analyses suggest an association between PPI use and increased mortality, type 2 diabetes mellitus, increased fracture risk, hypergastrinaemia, development of pneumonia, development of enteric infections, microscopic colitis, dementia, magnesium malabsorption, drug interactions, and multidrug-resistant organisms.[46][47][48][49][50]​ However, these studies have been unable to establish a causal relationship. In one of the largest prospective randomised PPI trials for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow-up), aside from a possible increase in enteric infection in patients taking pantoprazole.[51] One smaller prospective, multicentre double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI had no clinically meaningful effects on bone homeostasis.[52] Based on data from cumulative case studies, the UK Medicines and Healthcare products Regulatory Agency (MHRA) reports that PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus.[53] PPIs should therefore only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients with ZES.

Discontinuation of PPIs is very risky in patients with ZES and appropriate protocols should be followed.[44][54][55]

Higher doses are generally required for the treatment of ZES compared with other indications. Doses may differ between countries, and may be lower than the doses presented here, which are based on US guidance. Consult local drug formulary for further guidance on dose.

Primary options

omeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 360 mg/day given in 1-3 divided doses

OR

rabeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 120 mg/day given in 1-2 divided doses

OR

pantoprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses; 80 mg intravenously every 12 hours initially, increase gradually according to response, maximum 240 mg/day given in 3 divided doses

OR

lansoprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 180 mg/day given in 1-2 divided doses

OR

esomeprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

Plus – surgery

Back
ACUTE
|
localised disease: sporadic
|
surgical candidate
Plus – 

surgery

Treatment recommended for ALL patients in selected patient group

Exploratory surgical resection with curative intent is recommended in patients with sporadic gastrinoma even if preoperative imaging fails to localise the tumour. It has been shown that experienced surgeons can find gastrinoma in most patients and achieve a cure rate and disease-free survival similar to patients with positive imaging findings.[56] Successful resection of sporadic gastrinomas can protect against morbidity and death due to malignant change and metastatic spread.

Laparoscopic surgery is controversial in ZES compared with other pancreatic neuroendocrine tumours, owing to the need for more extensive exploration for diagnostic purposes and lymphadenectomy. Its role for gastrinomas is limited to patients in whom preoperative imaging gives an accurate definition of tumour location. In most patients undergoing surgical treatment for ZES, laparotomy is necessary.[18]

Gastrinomas in the duodenum are treated with duodenotomy and intraoperative ultrasound with local resection or enucleation of tumours and periduodenal node dissection. Gastrinomas in the head of the pancreas that are exophytic or peripheral (as determined by imaging) and are not immediately adjacent to the pancreatic duct should be enucleated. The periduodenal nodes should also be removed. Pancreatic gastrinomas should be enucleated if located 3 mm or further from the main pancreatic duct. Deeper or invasive pancreatic head gastrinomas, and those close to the main pancreatic duct, should be managed with pancreatoduodenectomy. Gastrinomas in the distal pancreas should be managed by distal pancreatectomy and splenectomy.[24] Regional lymph nodes should always be removed because nodal metastases are present in 30% to 70% of patients with duodenal or pancreatic gastrinomas and lymphadenectomy has been associated with increased disease-free survival.[57][58]

Guidelines have been published regarding the management of subepithelial lesions, including gastrinomas, encountered during routine endoscopy. Surgical resection of the primary gastrinoma is recommended; however, if it is not resected, surveillance and endoscopic resection of small (<2 cm) gastric lesions could be considered.[59]

If the gastrinoma can be resected completely, the 5-year survival rate is >90%.[60]

Up to 40% of patients will require prolonged antisecretory therapy after curative resection to control hyperacidity, which occurs due to a residual excess of gastric parietal cells, leading to chronic hypergastrinaemia.

Consider – somatostatin analogue

Back
ACUTE
|
localised disease: sporadic
|
surgical candidate
Consider – 

somatostatin analogue

Additional treatment recommended for SOME patients in selected patient group

Octreotide or lanreotide can be given if symptoms remain uncontrolled on PPI therapy. Gastric acid hypersecretion should be managed with high-dose PPIs.[24]

Primary options

octreotide: consult specialist for guidance on dose

OR

lanreotide: consult specialist for guidance on dose

1st line – proton-pump inhibitor (PPI)

Back
ACUTE
|
localised disease: sporadic
|
non-surgical candidate
1st line – 

proton-pump inhibitor (PPI)

PPIs have been shown to be efficacious for fast and prolonged acid suppression. They are the most effective antisecretory medicines for managing gastric acid hypersecretion and promoting ulcer healing.[1][40][80]

Retrospective analyses suggest an association between PPI use and increased mortality, type 2 diabetes mellitus, increased fracture risk, hypergastrinaemia, development of pneumonia, development of enteric infections, microscopic colitis, dementia, magnesium malabsorption, drug interactions, and multidrug-resistant organisms.[46][47][48][49][50]​ However, these studies have been unable to establish a causal relationship. In one of the largest prospective randomised PPI trials for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow-up), aside from a possible increase in enteric infection in patients taking pantoprazole.[51] One smaller prospective, multicentre double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI had no clinically meaningful effects on bone homeostasis.[52] Based on data from cumulative case studies, the UK Medicines and Healthcare products Regulatory Agency (MHRA) reports that PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus.[53] PPIs should therefore only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients with ZES.

Patients who decline surgery or are not candidates for operative treatment can be maintained on PPIs, provided that these are able to control their symptoms.

Discontinuation of PPIs is very risky in patients with ZES and appropriate protocols should be followed.[44][54][55]

Higher doses are generally required for the treatment of ZES compared with other indications. Doses may differ between countries, and may be lower than the doses presented here, which are based on US guidance. Consult local drug formulary for further guidance on dose.

Primary options

omeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 360 mg/day given in 1-3 divided doses

OR

rabeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 120 mg/day given in 1-2 divided doses

OR

pantoprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses; 80 mg intravenously every 12 hours initially, increase gradually according to response, maximum 240 mg/day given in 3 divided doses

OR

lansoprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 180 mg/day given in 1-2 divided doses

OR

esomeprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

Consider – endoscopic surveillance ± resection

Back
ACUTE
|
localised disease: sporadic
|
non-surgical candidate
Consider – 

endoscopic surveillance ± resection

Additional treatment recommended for SOME patients in selected patient group

For patients who decline surgery, or in whom the primary tumour cannot be resected, endoscopic surveillance and endoscopic resection of prominent tumours should be considered. Gastric acid hypersecretion should be managed with high-dose PPIs.[24]

Consider – somatostatin analogue

Back
ACUTE
|
localised disease: sporadic
|
non-surgical candidate
Consider – 

somatostatin analogue

Additional treatment recommended for SOME patients in selected patient group

Octreotide or lanreotide can be given if symptoms remain uncontrolled on PPI therapy. Gastric acid hypersecretion should be maintained with high-dose PPIs.[24]

Primary options

octreotide: consult specialist for guidance on dose

OR

lanreotide: consult specialist for guidance on dose

localised disease: MEN1

1st line – proton-pump inhibitor (PPI)

Back
ACUTE
|
localised disease: MEN1
1st line – 

proton-pump inhibitor (PPI)

PPIs have been shown to be efficacious for fast and prolonged acid suppression. They are the most effective antisecretory medicines for managing gastric acid hypersecretion and promoting ulcer healing.[1][40][80]

Retrospective analyses suggest an association between PPI use and increased mortality, type 2 diabetes mellitus, increased fracture risk, hypergastrinaemia, development of pneumonia, development of enteric infections, microscopic colitis, dementia, magnesium malabsorption, drug interactions, and multidrug-resistant organisms.[46][47][48][49][50]​ However, these studies have been unable to establish a causal relationship. In one of the largest prospective randomised PPI trials for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow-up), aside from a possible increase in enteric infection in patients taking pantoprazole.[51] One smaller prospective, multicentre double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI had no clinically meaningful effects on bone homeostasis.[52] Based on data from cumulative case studies, the UK Medicines and Healthcare products Regulatory Agency (MHRA) reports that PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus.[53] PPIs should therefore only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients with ZES.

Patients who decline surgery or are not candidates for operative treatment can be maintained on PPIs, provided that these are able to control their symptoms.

Discontinuation of PPIs is very risky in patients with ZES and appropriate protocols should be followed.[44][54][55]

Higher doses are generally required for the treatment of ZES compared with other indications. Doses may differ between countries, and may be lower than the doses presented here, which are based on US guidance. Consult local drug formulary for further guidance on dose.

Primary options

omeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 360 mg/day given in 1-3 divided doses

OR

rabeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 120 mg/day given in 1-2 divided doses

OR

pantoprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses; 80 mg intravenously every 12 hours initially, increase gradually according to response, maximum 240 mg/day given in 3 divided doses

OR

lansoprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 180 mg/day given in 1-2 divided doses

OR

esomeprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

Consider – surgery

Back
ACUTE
|
localised disease: MEN1
Consider – 

surgery

Additional treatment recommended for SOME patients in selected patient group

There is considerable controversy in the literature regarding the role of surgery in the management of ZES in patients with multiple endocrine neoplasia type 1 (MEN1). Surgical resection has not generally been recommended because the multifocal nature of tumours in MEN1 almost always precludes biochemical cure of gastrin hypersecretion. This may be related to the fact that patients with MEN1 often have small, multifocal tumours in the duodenum or pancreas.[24] These patients have therefore traditionally been maintained on PPIs alone. However, several small studies have demonstrated successful long-term cure of gastrin hypersecretion and prevention of distant metastases with early aggressive surgical resection of gastrinoma in MEN1 patients.[61][62]​ In the case of pancreatic neuroendocrine tumours in MEN1, National Comprehensive Cancer Network (NCCN) guidelines recommend surgical resection in cases of: 1) symptomatic functional tumours refractory to medical management; 2) a tumour larger than 2 cm in size; or 3) a tumour with a relatively rapid rate of growth over 6-12 months. Observation can be considered for non-functioning indolent tumours. Endoscopy with endoscopic ultrasound should be undertaken prior to pancreatic surgery to assess and localise tumours.[24]

Consider – somatostatin analogue

Back
ACUTE
|
localised disease: MEN1
Consider – 

somatostatin analogue

Additional treatment recommended for SOME patients in selected patient group

Octreotide or lanreotide can be given if symptoms remain uncontrolled despite PPI therapy with or without surgical treatment. Gastric acid hypersecretion should be managed with high-dose PPIs.[24]

Primary options

octreotide: consult specialist for guidance on dose

OR

lanreotide: consult specialist for guidance on dose

metastatic disease: predominantly hepatic

1st line – somatostatin analogue

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
limited hepatic metastases (suitable for resection)
1st line – 

somatostatin analogue

Inhibition of tumour growth and symptoms can be attempted with somatostatin analogues, because many of these tumours express subtype 2 and 5 somatostatin receptors.[63]

Primary options

octreotide: consult specialist for guidance on dose

OR

lanreotide: consult specialist for guidance on dose

Plus – proton-pump inhibitor (PPI)

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
limited hepatic metastases (suitable for resection)
Plus – 

proton-pump inhibitor (PPI)

Treatment recommended for ALL patients in selected patient group

PPIs have been shown to be efficacious for fast and prolonged acid suppression. They are the most effective antisecretory medicines for managing gastric acid hypersecretion and promoting ulcer healing.[1][40][80]

Retrospective analyses suggest an association between PPI use and increased mortality, type 2 diabetes mellitus, increased fracture risk, hypergastrinaemia, development of pneumonia, development of enteric infections, microscopic colitis, dementia, magnesium malabsorption, drug interactions, and multidrug-resistant organisms.[46][47][48][49][50]​ However, these studies have been unable to establish a causal relationship. In one of the largest prospective randomised PPI trials for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow-up), aside from a possible increase in enteric infection in patients taking pantoprazole.[51] One smaller prospective, multicentre double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI had no clinically meaningful effects on bone homeostasis.[52] Based on data from cumulative case studies, the UK Medicines and Healthcare products Regulatory Agency (MHRA) reports that PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus.[53] PPIs should therefore only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients with ZES.

Discontinuation of PPIs is very risky in patients with ZES and appropriate protocols should be followed.[44][54][55]

Higher doses are generally required for the treatment of ZES compared with other indications. Doses may differ between countries, and may be lower than the doses presented here, which are based on US guidance. Consult local drug formulary for further guidance on dose.

Primary options

omeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 360 mg/day given in 1-3 divided doses

OR

rabeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 120 mg/day given in 1-2 divided doses

OR

pantoprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses; 80 mg intravenously every 12 hours initially, increase gradually according to response, maximum 240 mg/day given in 3 divided doses

OR

lansoprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 180 mg/day given in 1-2 divided doses

OR

esomeprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

Consider – resection of metastases with curative intent

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
limited hepatic metastases (suitable for resection)
Consider – 

resection of metastases with curative intent

Additional treatment recommended for SOME patients in selected patient group

In some cases, patients with limited hepatic metastases can undergo complete resection of the primary tumour and metastases with curative intent.[24][65]​ Most patients with resected metastatic disease, however, will eventually experience recurrence.[81]

1st line – somatostatin analogue

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
1st line – 

somatostatin analogue

Inhibition of tumour growth and symptoms can be attempted with somatostatin analogues, because many of these tumours express subtype 2 and 5 somatostatin receptors.[63]

Primary options

octreotide: consult specialist for guidance on dose

OR

lanreotide: consult specialist for guidance on dose

Plus – proton-pump inhibitor (PPI)

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
Plus – 

proton-pump inhibitor (PPI)

Treatment recommended for ALL patients in selected patient group

PPIs have been shown to be efficacious for fast and prolonged acid suppression. They are the most effective antisecretory medicines for managing gastric acid hypersecretion and promoting ulcer healing.[1][40][80]

Retrospective analyses suggest an association between PPI use and increased mortality, type 2 diabetes mellitus, increased fracture risk, hypergastrinaemia, development of pneumonia, development of enteric infections, microscopic colitis, dementia, magnesium malabsorption, drug interactions, and multidrug-resistant organisms.[46][47][48][49][50]​ However, these studies have been unable to establish a causal relationship. In one of the largest prospective randomised PPI trials for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow-up), aside from a possible increase in enteric infection in patients taking pantoprazole.[51] One smaller prospective, multicentre double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI had no clinically meaningful effects on bone homeostasis.[52] Based on data from cumulative case studies, the UK Medicines and Healthcare products Regulatory Agency (MHRA) reports that PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus.[53] PPIs should therefore only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients with ZES.

Patients who decline surgery or are not candidates for operative treatment can be maintained on PPIs, provided that these are able to control their symptoms.

Discontinuation of PPIs is very risky in patients with ZES and appropriate protocols should be followed.[44][54][55]

Higher doses are generally required for the treatment of ZES compared with other indications. Doses may differ between countries, and may be lower than the doses presented here, which are based on US guidance. Consult local drug formulary for further guidance on dose.

Primary options

omeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 360 mg/day given in 1-3 divided doses

OR

rabeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 120 mg/day given in 1-2 divided doses

OR

pantoprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses; 80 mg intravenously every 12 hours initially, increase gradually according to response, maximum 240 mg/day given in 3 divided doses

OR

lansoprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 180 mg/day given in 1-2 divided doses

OR

esomeprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

Consider – liver-directed therapies

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
Consider – 

liver-directed therapies

Additional treatment recommended for SOME patients in selected patient group

Cytoreductive surgery of >90% of metastatic disease may provide symptomatic relief, prevent future symptoms, and improve progression-free survival for patients with functioning tumours. This strategy is particularly appropriate for patients with relatively indolent metastatic small bowel neuroendocrine tumours, and less appropriate for patients in whom rapid progression of disease is expected after surgery.[24]

Non-curative debulking surgery can also be considered in select cases, especially if the patient is symptomatic either from tumour bulk or hormone production.[24]

Percutaneous thermal ablation - which typically utilises microwave energy - can be considered for oligometastatic liver disease, generally up to four lesions no larger than 3 cm. Radiofrequency and cryoablation can also be considered.[24]

Hepatic arterial embolisation is predominantly used as a palliative treatment in patients with symptomatic hepatic metastases who are not candidates for surgical resection. It may be performed with or without hepatic artery infusion of chemotherapy. It is rarely used as a treatment, however, and it is not recommended as part of routine management of these patients. Radioembolisation with selective internal radiotherapy using yttrium microspheres is also used. Prospective studies comparing one type of embolisation with another have not been completed.[66]

In highly selected patients with liver-only metastases and fulfilling strict inclusion criteria, liver transplantation may be considered.[67]​ However, its use remains controversial and the risk of tumour recurrence is a problem.[68][69]​ The European Society of Medical Oncology (ESMO) recommends that liver transplantation may be a valid option in very selected patients with unresectable liver metastases when the following criteria are met: absence of extrahepatic disease, histological confirmation of a well-differentiated neuroendocrine tumour, previous removal of primary tumour, metastatic diffusion <50% of the total liver volume, stable disease in response to therapy for at least 6 months before transplant consideration, and age <60 years. In these selected patients with good baseline prognostic factors, a 5-year overall survival of 69% to 97.2% has been reported.[68]

2nd line – somatostatin analogue

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
2nd line – 

somatostatin analogue

Inhibition of tumour growth and symptoms can be attempted with somatostatin analogues, because many of these tumours express subtype 2 and 5 somatostatin receptors.[63]

Primary options

octreotide: consult specialist for guidance on dose

OR

lanreotide: consult specialist for guidance on dose

Plus – proton-pump inhibitor (PPI)

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
Plus – 

proton-pump inhibitor (PPI)

Treatment recommended for ALL patients in selected patient group

PPIs have been shown to be efficacious for fast and prolonged acid suppression. They are the most effective antisecretory medicines for managing gastric acid hypersecretion and promoting ulcer healing.[1][40][80]

Retrospective analyses suggest an association between PPI use and increased mortality, type 2 diabetes mellitus, increased fracture risk, hypergastrinaemia, development of pneumonia, development of enteric infections, microscopic colitis, dementia, magnesium malabsorption, drug interactions, and multidrug-resistant organisms.[46][47][48][49][50]​ However, these studies have been unable to establish a causal relationship. In one of the largest prospective randomised PPI trials for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow-up), aside from a possible increase in enteric infection in patients taking pantoprazole.[51] One smaller prospective, multicentre double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI had no clinically meaningful effects on bone homeostasis.[52] Based on data from cumulative case studies, the UK Medicines and Healthcare products Regulatory Agency (MHRA) reports that PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus.[53] PPIs should therefore only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients with ZES.

Patients who decline surgery or are not candidates for operative treatment can be maintained on PPIs, provided that these are able to control their symptoms.

Discontinuation of PPIs is very risky in patients with ZES and appropriate protocols should be followed.[44][54][55]

Higher doses are generally required for the treatment of ZES compared with other indications. Doses may differ between countries, and may be lower than the doses presented here, which are based on US guidance. Consult local drug formulary for further guidance on dose.

Primary options

omeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 360 mg/day given in 1-3 divided doses

OR

rabeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 120 mg/day given in 1-2 divided doses

OR

pantoprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses; 80 mg intravenously every 12 hours initially, increase gradually according to response, maximum 240 mg/day given in 3 divided doses

OR

lansoprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 180 mg/day given in 1-2 divided doses

OR

esomeprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

Consider – everolimus or sunitinib

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
Consider – 

everolimus or sunitinib

Additional treatment recommended for SOME patients in selected patient group

Everolimus is an inhibitor of mTOR proliferation signal inhibitor with antiproliferative and immunosuppressant properties. It inhibits growth factor-stimulated cell proliferation by causing cell cycle arrest in the late G1 stage. In addition to inhibiting growth factor-driven proliferation of vascular smooth muscle cells, everolimus prevents clonal expansion of activated T cells. It has been shown to inhibit vascular remodelling and intimal thickening. To date, everolimus has been well tolerated in combination with octreotide. Trials have shown promising anti-tumour activity and additional trials are underway to evaluate this compound in larger patient groups.[70] Everolimus is approved by the US Food and Drug Administration (FDA) for the treatment of pancreatic neuroendocrine tumours that have progressed and cannot be treated with surgery.[24]

Sunitinib is also approved by the FDA to treat pancreatic neuroendocrine tumours that have progressed and cannot be treated with surgery. Sunitinib is a multi-targeted tyrosine kinase inhibitor that inhibits cellular signalling. This helps to stop or slow the spread of cancer cells and may help to shrink tumours. In clinical trials, this agent was well tolerated with little severe haematological toxicity.[71]

Primary options

everolimus: 10 mg orally once daily

OR

sunitinib: 37.5 mg orally once daily

Consider – peptide receptor radionuclide therapy (PRRT)

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
Consider – 

peptide receptor radionuclide therapy (PRRT)

Additional treatment recommended for SOME patients in selected patient group

PRRT combines octreotide with a radionuclide (lutetium 177Lu-dotatate). 177Lu-dotatate is a radiolabelled somatostatin analogue that is specifically targeted to neuroendocrine tumours and destroys tumour cells by radioactive emission of gamma- and/or beta-radiation. An intravenous infusion of amino acids is given concurrently for nephroprotection.[24] In study data, PRRT with 177Lu has been associated with a decrease in tumour size, a reduction in symptoms, and a halt in tumour progression.[72] Currently, there are no randomised data. Common side effects of PRRT therapy include nausea, vomiting, and abdominal pain; more severe adverse effects including renal failure, hepatic toxicity, embryo-fetal toxicity, infertility, and bone marrow disease (e.g., acute myelogenous leukaemia, myelodysplastic syndrome) have also been reported.[73][74]​​ Pregnancy status should be verified in females of reproductive age and all patients should be advised on the use of effective contraception for up to 7 months (females) and 4 months (males) after the last dose. Generally, patients with hormonally functional tumours should continue long-acting octreotide or lanreotide along with 177Lu-dotatate. However, the long-acting somatostatin analogue should be discontinued for 4 weeks prior to each 177Lu-dotatate treatment, as there is concern about theoretical competition for somatostatin receptor binding.[24]

PRRT with 177Lu-dotatate is approved by the FDA for the treatment of patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, including foregut, midgut, and hindgut neuroendocrine tumours in adults.[24]

See local specialist protocol for dosing guidelines.

Primary options

lutetium Lu 177 dotatate

Consider – systemic chemotherapy

Back
ACUTE
|
metastatic disease: predominantly hepatic
|
extensive hepatic metastases (not suitable for resection)
Consider – 

systemic chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Evidence for the use of systemic chemotherapy for metastatic gastrinoma is limited. The traditional regimen of choice has been streptozocin, fluorouracil, and doxorubicin in combination with radiotherapy.[75][76][77] However, these treatments have limited benefit in many patients and adverse effects, which can include prolonged myelosuppression and renal failure, have limited the widespread acceptance of chemotherapy as a standard first-line therapy for patients with metastatic gastrinoma.

National Comprehensive Cancer Network (NCCN) guidelines list fluorouracil, capecitabine, dacarbazine, oxaliplatin, and temozolomide as options for cytotoxic chemotherapy for advanced gastrinomas, but note that tumour response rates are generally low and no benefit to progression-free survival has been clearly demonstrated.[24]

Retrospective trial data have shown that temozolomide-based chemotherapy is effective in the treatment of pancreatic neuroendocrine tumours, either alone or combined with capecitabine.[78] Temozolomide is an orally active alkylating agent. A prospective multicentre randomised phase 2 trial (ECOG2211) comparing temozolomide versus capecitabine/temozolomide in patients with advanced pancreatic neuroendocrine tumours reported similar response rates in both groups (approximately 30%), but there was a significant improvement in progression-free survival from 14.4 months with temozolomide alone to 22.7 months with capecitabine/temozolomide (hazard ratio 0.58, P=0.022). A clinically meaningful but not statistically significant improvement was seen in overall survival. As a result of this study, use of capecitabine plus temozolomide has become routine for advanced pancreatic neuroendocrine tumours.[79]

See local specialist protocol for dosing guidelines.

Primary options

fluorouracil

OR

capecitabine

OR

dacarbazine

OR

oxaliplatin

OR

temozolomide

metastatic disease: extrahepatic

1st line – somatostatin analogue

Back
ACUTE
|
metastatic disease: extrahepatic
1st line – 

somatostatin analogue

Inhibition of tumour growth and symptoms can be attempted with somatostatin analogues, because many of these tumours express subtype 2 and 5 somatostatin receptors.[63]

Primary options

octreotide: consult specialist for guidance on dose

OR

lanreotide: consult specialist for guidance on dose

Plus – proton-pump inhibitor (PPI)

Back
ACUTE
|
metastatic disease: extrahepatic
Plus – 

proton-pump inhibitor (PPI)

Treatment recommended for ALL patients in selected patient group

PPIs have been shown to be efficacious for fast and prolonged acid suppression. They are the most effective antisecretory medicines for managing gastric acid hypersecretion and promoting ulcer healing.[1][40][80]

Retrospective analyses suggest an association between PPI use and increased mortality, type 2 diabetes mellitus, increased fracture risk, hypergastrinaemia, development of pneumonia, development of enteric infections, microscopic colitis, dementia, magnesium malabsorption, drug interactions, and multidrug-resistant organisms.[46][47][48][49][50]​ However, these studies have been unable to establish a causal relationship. In one of the largest prospective randomised PPI trials for any indication (n=17,958 patients with cardiovascular disease), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years (53,000 patient years of follow-up), aside from a possible increase in enteric infection in patients taking pantoprazole.[51] One smaller prospective, multicentre double blind study, including 115 healthy postmenopausal women, found that 26 weeks of treatment with a PPI had no clinically meaningful effects on bone homeostasis.[52] Based on data from cumulative case studies, the UK Medicines and Healthcare products Regulatory Agency (MHRA) reports that PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus.[53] PPIs should therefore only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients with ZES.

Patients who decline surgery or are not candidates for operative treatment can be maintained on PPIs, provided that these are able to control their symptoms.

Discontinuation of PPIs is very risky in patients with ZES and appropriate protocols should be followed.[44][54][55]

Higher doses are generally required for the treatment of ZES compared with other indications. Doses may differ between countries, and may be lower than the doses presented here, which are based on US guidance. Consult local drug formulary for further guidance on dose.

Primary options

omeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 360 mg/day given in 1-3 divided doses

OR

rabeprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 120 mg/day given in 1-2 divided doses

OR

pantoprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses; 80 mg intravenously every 12 hours initially, increase gradually according to response, maximum 240 mg/day given in 3 divided doses

OR

lansoprazole: 60 mg orally once daily initially, increase gradually according to response, maximum 180 mg/day given in 1-2 divided doses

OR

esomeprazole: 40 mg orally twice daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

Consider – everolimus or sunitinib

Back
ACUTE
|
metastatic disease: extrahepatic
Consider – 

everolimus or sunitinib

Additional treatment recommended for SOME patients in selected patient group

Everolimus is an inhibitor of mTOR proliferation signal inhibitor with antiproliferative and immunosuppressant properties. It inhibits growth factor-stimulated cell proliferation by causing cell cycle arrest in the late G1 stage. In addition to inhibiting growth factor-driven proliferation of vascular smooth muscle cells, everolimus prevents clonal expansion of activated T cells. It has been shown to inhibit vascular remodelling and intimal thickening. To date, everolimus has been well tolerated in combination with octreotide. Trials have shown promising anti-tumour activity and additional trials are underway to evaluate this compound in larger patient groups.[70] Everolimus is approved by the US Food and Drug Administration (FDA) for the treatment of pancreatic neuroendocrine tumours that have progressed and cannot be treated with surgery.[24]

Sunitinib is also approved by the FDA to treat pancreatic neuroendocrine tumours that have progressed and cannot be treated with surgery. Sunitinib is a multi-targeted tyrosine kinase inhibitor that inhibits cellular signalling. This helps to stop or slow the spread of cancer cells and may help to shrink tumours. In clinical trials, this agent was well tolerated with little severe haematological toxicity.[71]

Primary options

everolimus: 10 mg orally once daily

OR

sunitinib: 37.5 mg orally once daily

Consider – peptide receptor radionuclide therapy (PRRT)

Back
ACUTE
|
metastatic disease: extrahepatic
Consider – 

peptide receptor radionuclide therapy (PRRT)

Additional treatment recommended for SOME patients in selected patient group

PRRT combines octreotide with a radionuclide (lutetium 177Lu-dotatate). 177Lu-dotatate is a radiolabelled somatostatin analogue that is specifically targeted to neuroendocrine tumours and destroys tumour cells by radioactive emission of gamma- and/or beta-radiation. It is administered intravenously every 8 weeks for a total of 4 treatments. An intravenous infusion of amino acids is given concurrently for nephroprotection.[24] In study data, PRRT with 177Lu has been associated with a decrease in tumour size, a reduction in symptoms, and a halt in tumour progression.[72] Currently, there are no randomised data. Common side effects of PRRT therapy include nausea, vomiting, and abdominal pain; more severe adverse effects including renal failure, hepatic toxicity, embryo-fetal toxicity, infertility, and bone marrow disease (e.g., acute myelogenous leukaemia, myelodysplastic syndrome) have also been reported.[73][74]​​ Pregnancy status should be verified in females of reproductive age and all patients should be advised on the use of effective contraception for up to 7 months (females) and 4 months (males) after the last dose. Generally, patients with hormonally functional tumours should continue long-acting octreotide or lanreotide along with 177Lu-dotatate. However, the long-acting somatostatin analogue should be discontinued for 4 weeks prior to each 177Lu-dotatate treatment, as there is concern about theoretical competition for somatostatin receptor binding.[24]

PRRT with 177Lu-dotatate is approved by the FDA for the treatment of patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, including foregut, midgut, and hindgut neuroendocrine tumours in adults.[24]

See local specialist protocol for dosing guidelines.

Primary options

lutetium Lu 177 dotatate

Consider – systemic chemotherapy

Back
ACUTE
|
metastatic disease: extrahepatic
Consider – 

systemic chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Evidence for the use of systemic chemotherapy for metastatic gastrinoma is limited. The traditional regimen of choice has been streptozocin, fluorouracil, and doxorubicin in combination with radiotherapy.[75][76][77] However, these treatments have limited benefit in many patients and adverse effects, which can include prolonged myelosuppression and renal failure, have limited the widespread acceptance of chemotherapy as a standard first-line therapy for patients with metastatic gastrinoma.

National Comprehensive Cancer Network (NCCN) guidelines list fluorouracil, capecitabine, dacarbazine, oxaliplatin, and temozolomide as options for cytotoxic chemotherapy for advanced gastrinomas, but note that tumour response rates are generally low and no benefit to progression-free survival has been clearly demonstrated.[24]

Retrospective trial data have shown that temozolomide-based chemotherapy is effective in the treatment of pancreatic neuroendocrine tumours, either alone or combined with capecitabine.[78] Temozolomide is an orally active alkylating agent. A prospective multicentre randomised phase 2 trial (ECOG2211) comparing temozolomide versus capecitabine/temozolomide in patients with advanced pancreatic neuroendocrine tumours reported similar response rates in both groups (approximately 30%), but there was a significant improvement in progression-free survival from 14.4 months with temozolomide alone to 22.7 months with capecitabine/temozolomide (hazard ratio 0.58, P=0.022). A clinically meaningful but not statistically significant improvement was seen in overall survival. As a result of this study, use of capecitabine plus temozolomide has become routine for advanced pancreatic neuroendocrine tumours.[79]

See local specialist protocol for dosing guidelines.

Primary options

fluorouracil

OR

capecitabine

OR

dacarbazine

OR

oxaliplatin

OR

temozolomide

Consider – palliative radiotherapy

Back
ACUTE
|
metastatic disease: extrahepatic
Consider – 

palliative radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Can be considered for oligometastatic disease and/or symptomatic metastases (excluding mesenteric masses).[24]

back arrow

Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer