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

initial presentation of symptomatic patient

1st line – intravenous correction of fluid and electrolyte imbalance + somatostatin analog

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ACUTE
|
initial presentation of symptomatic patient
1st line – 

intravenous correction of fluid and electrolyte imbalance + somatostatin analog

Initial treatment of VIPoma (pancreatic and extrapancreatic) should be focused on prompt management of symptoms associated with the clinical syndrome.

Includes correction of dehydration with saline-based intravenous fluids, repletion of electrolytes with standard electrolytes (e.g., potassium chloride, magnesium sulfate, phosphorus), and controlling diarrhea with somatostatin analogs (e.g., octreotide, lanreotide, which decrease vasoactive intestinal peptide [VIP] hormone secretion).[3]​​[35]​​[36]

Most patients with VIPoma (up to 80%) achieve a clinical response (improvement in diarrhea) with somatostatin analogs, and a small percentage also have tumor shrinkage.[37][38]

Long-term symptom management is continued with long-acting somatostatin analogs, and increased oral fluid and electrolyte supplementation as guided by regular blood testing.[3] Long-acting somatostatin analogs should be dose-titrated to optimize symptom control. Short-acting somatostatin analogs may be used for rapid symptom control and managing breakthrough symptoms.

Patients receiving somatostatin analogs in the long term may develop gallstones due to biliary stasis.[39]​ Cholecystectomy may be performed if long-term use of somatostatin analogs is expected.

Drug resistance can occur with long-term use of somatostatin analogs; dose escalation may be required.

Primary options

octreotide: 200-300 micrograms/day subcutaneously given in 2-4 divided doses for at least 2 weeks, then titrate dose according to response, usual dose range 150-750 micrograms/day; 20 mg intramuscularly (long-acting depot) every 4 weeks for 2 months, then titrate dose according to response every 2 months, usual dose range 10-30 mg every 4 weeks

More

Secondary options

lanreotide: 120 mg subcutaneously (long-acting depot) every 4 weeks

ONGOING

localized disease

1st line – curative resection of primary tumor

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ONGOING
|
localized disease
1st line – 

curative resection of primary tumor

Complete surgical resection of localized disease offers the only opportunity for cure of VIPoma, and is recommended where feasible.[3]

The type of surgery performed should be based on the location and size of the primary tumor.[3] Pancreaticoduodenectomy is the standard approach for large primary tumors (>2 cm) located at the head of the pancreas. Distal pancreatectomy (with or without splenectomy) is the standard approach for large tumors located in the body or tail of the pancreas.

Removal of regional lymph nodes (peripancreatic lymphadenectomy) is recommended if surgical resection is undertaken.[3] However, the prognostic implication of lymphadenectomy in VIPoma patients is unclear.[41]

In rare cases where the primary tumor is small (<2 cm), enucleation or local excision of the tumor may be considered.[3]

Plus – oral fluid and electrolyte correction

Back
ONGOING
|
localized disease
Plus – 

oral fluid and electrolyte correction

Treatment recommended for ALL patients in selected patient group

Patients require increased oral intake and electrolyte supplementation as guided by regular blood testing.[3]

2nd line – medical treatment

Back
ONGOING
|
localized disease
2nd line – 

medical treatment

If curative resection is not possible consider medical treatment to control tumor growth and tumor-related symptoms.[24] Optimal sequencing of medical treatment is unclear.[3]

Somatostatin analogs (e.g., octreotide, lanreotide) are recommended for initial medical treatment if not already used.[3][35]​​​ As well as controlling diarrhea, these agents may have an antiproliferative effect.[34]​​​​[47]​​​​ In phase 3 studies, octreotide and lanreotide both significantly prolonged progression-free survival compared with placebo.[48][49]

Long-acting somatostatin analogs should be used for long-term symptom management, with dose titration to optimize symptom control.[3] Short-acting somatostatin analogs may be used for rapid symptom control and managing breakthrough symptoms.

Patients receiving somatostatin analogs in the long term may develop gallstones due to biliary stasis.[39]​ Cholecystectomy may be performed if long-term use of somatostatin analogs is expected.

Drug resistance can occur with long-term use of somatostatin analogs; dose escalation may be required.

Everolimus (a mammalian target of rapamycin [mTOR] inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) prolonged progression-free survival in randomized placebo-controlled trials of patients with pancreatic neuroendocrine tumors.[50][51][52] These agents may be combined with a somatostatin analog or used as an alternative therapy; however, their specific use in VIPoma has not been evaluated in clinical trials.[3][53][54]

Chemotherapy can be considered for patients who have clinically significant tumor burden or symptomatic progressive disease.[3][35]​​ Combination chemotherapy regimens containing streptozocin or temozolomide are often used (e.g., streptozocin plus fluorouracil; streptozocin plus fluorouracil plus doxorubicin; temozolomide plus capecitabine).[55][56][57][58]​ A somatostatin analog can be used in combination with chemotherapy to improve the control of syndromic symptoms.[17]

Peptide receptor radionuclide therapy with lutetium Lu 177 dotatate (a radiolabeled somatostatin analog) is an option for patients with somatostatin receptor-positive tumors (confirmed by somatostatin receptor-based imaging) who have progressed following treatment with conventional and/or long-acting somatostatin analogs.[3][35][59]​​​​ In a phase 3 trial of patients with advanced or progressive somatostatin receptor-positive midgut neuroendocrine tumors, lutetium Lu 177 dotatate significantly improved progression-free survival and response rate compared with high-dose, long-acting octreotide.[60] Final analysis of overall survival favored lutetium Lu 177 dotatate, but was not statistically significant.[61]

Primary options

octreotide: 200-300 micrograms/day subcutaneously given in 2-4 divided doses, then titrate dose according to response, usual dose range 150-750 micrograms/day; 20 mg intramuscularly (long-acting depot) every 4 weeks for 2 months, then titrate dose according to response every 2 months, usual dose range 10-30 mg every 4 weeks

More

OR

lanreotide: 120 mg subcutaneously (long-acting depot) every 4 weeks

Secondary options

everolimus (oncologic): 10 mg orally once daily

OR

sunitinib: 37.5 mg orally once daily

OR

streptozocin: consult specialist for guidance on dose

and

fluorouracil: consult specialist for guidance on dose

OR

streptozocin: consult specialist for guidance on dose

and

fluorouracil: consult specialist for guidance on dose

and

doxorubicin: consult specialist for guidance on dose

OR

temozolomide: consult specialist for guidance on dose

and

capecitabine: consult specialist for guidance on dose

OR

lutetium Lu 177 dotatate: consult specialist for guidance on dose

More

Plus – oral fluid and electrolyte correction

Back
ONGOING
|
localized disease
Plus – 

oral fluid and electrolyte correction

Treatment recommended for ALL patients in selected patient group

Patients require increased oral intake and electrolyte supplementation as guided by regular blood testing.[3]

metastatic disease: surgical candidate

1st line – palliative resection of primary tumor and debulking of metastasis

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ONGOING
|
metastatic disease: surgical candidate
1st line – 

palliative resection of primary tumor and debulking of metastasis

Patients with metastatic disease (most commonly to the liver) may undergo surgical resection to remove the primary tumor and regional lymph nodes, and debulking of metastatic lesions (e.g., surgical resection, radiofrequency ablation, cryoablation) to reduce tumor burden and alleviate symptoms.[3][24][41]

Generally, ablation is only considered if hepatic metastases are small (<3 cm) and there are no more than 4 lesions.[3]

Surgical treatment in the metastatic setting is palliative and should be individualized based on patient factors (e.g., age, comorbidities) and disease factors (e.g., location, distribution, and grade of metastases).[34]

Pancreaticoduodenectomy is the standard approach for large primary tumors (>2 cm) located at the head of the pancreas. Distal pancreatectomy (with or without splenectomy) is the standard approach for large tumors located in the body or tail of the pancreas.

Removal of regional lymph nodes (peripancreatic lymphadenectomy) is recommended if surgical resection is undertaken.[3] However, the prognostic implication of lymphadenectomy in VIPoma patients is unclear.[41]

In rare cases where the primary tumor is small (<2 cm), enucleation or local excision of the tumor may be considered.[3]

Plus – oral fluid and electrolyte correction

Back
ONGOING
|
metastatic disease: surgical candidate
Plus – 

oral fluid and electrolyte correction

Treatment recommended for ALL patients in selected patient group

Patients require increased oral intake and electrolyte supplementation as guided by regular blood testing.[3]

Consider – liver transplant

Back
ONGOING
|
metastatic disease: surgical candidate
Consider – 

liver transplant

Treatment recommended for SOME patients in selected patient group

Liver transplantation has been successfully performed in highly selected patients with resected primary tumor who have long-term stable and unresectable metastatic disease limited to the liver.[45][46]​ However, it is rarely used.

2nd line – medical treatment

Back
ONGOING
|
metastatic disease: surgical candidate
2nd line – 

medical treatment

Patients who have disease progression should be considered for medical treatment to control tumor growth and tumor-related symptoms.[24] Optimal sequencing of medical treatment is unclear.[3]

Somatostatin analogs (e.g., octreotide, lanreotide) are recommended for initial medical treatment if not already used.[3][35]​​​ As well as controlling diarrhea, these agents may have an antiproliferative effect.[34]​​​​[47]​​​​ In phase 3 studies, octreotide and lanreotide both significantly prolonged progression-free survival compared with placebo.[48][49]

Long-acting somatostatin analogs should be used for long-term symptom management, with dose titration to optimize symptom control.[3] Short-acting somatostatin analogs may be used for rapid symptom control and managing breakthrough symptoms.

Patients receiving somatostatin analogs in the long term may develop gallstones due to biliary stasis.[39]​ Cholecystectomy may be performed if long-term use of somatostatin analogs is expected.

Drug resistance can occur with long-term use of somatostatin analogs; dose escalation may be required.

Everolimus (a mammalian target of rapamycin [mTOR] inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) prolonged progression-free survival in randomized placebo-controlled trials of patients with pancreatic neuroendocrine tumors.[50][51][52] These agents may be combined with a somatostatin analog or used as an alternative therapy; however, their specific use in VIPoma has not been evaluated in clinical trials.[3][53][54]

Chemotherapy can be considered for patients who have clinically significant tumor burden or symptomatic progressive disease.[3][35]​​ Combination chemotherapy regimens containing streptozocin or temozolomide are often used (e.g., streptozocin plus fluorouracil; streptozocin plus fluorouracil plus doxorubicin; temozolomide plus capecitabine).[55][56][57][58]​ A somatostatin analog is sometimes used in combination with chemotherapy to improve the control of syndromic symptoms.[17]

Peptide receptor radionuclide therapy with lutetium Lu 177 dotatate (a radiolabeled somatostatin analog) is an option for patients with somatostatin receptor-positive tumors (confirmed by somatostatin receptor-based imaging) who have progressed following treatment with conventional and/or long-acting somatostatin analogs.[3][35][59]​​​​ In a phase 3 trial of patients with advanced or progressive somatostatin receptor-positive midgut neuroendocrine tumors, lutetium Lu 177 dotatate significantly improved progression-free survival and response rate compared with high-dose, long-acting octreotide.[60] Final analysis of overall survival favored lutetium Lu 177 dotatate, but was not statistically significant.[61]

Primary options

octreotide: 200-300 micrograms/day subcutaneously given in 2-4 divided doses, then titrate dose according to response, usual dose range 150-750 micrograms/day; 20 mg intramuscularly (long-acting depot) every 4 weeks for 2 months, then titrate dose according to response every 2 months, usual dose range 10-30 mg every 4 weeks

More

OR

lanreotide: 120 mg subcutaneously (long-acting depot) every 4 weeks

Secondary options

everolimus (oncologic): 10 mg orally once daily

OR

sunitinib: 37.5 mg orally once daily

OR

streptozocin: consult specialist for guidance on dose

and

fluorouracil: consult specialist for guidance on dose

OR

streptozocin: consult specialist for guidance on dose

and

fluorouracil: consult specialist for guidance on dose

and

doxorubicin: consult specialist for guidance on dose

OR

temozolomide: consult specialist for guidance on dose

and

capecitabine: consult specialist for guidance on dose

OR

lutetium Lu 177 dotatate: consult specialist for guidance on dose

More

Plus – oral fluid and electrolyte correction

Back
ONGOING
|
metastatic disease: surgical candidate
Plus – 

oral fluid and electrolyte correction

Treatment recommended for ALL patients in selected patient group

Patients require increased oral intake and electrolyte supplementation as guided by regular blood testing.[3]

Consider – liver transplant

Back
ONGOING
|
metastatic disease: surgical candidate
Consider – 

liver transplant

Treatment recommended for SOME patients in selected patient group

Liver transplantation has been successfully performed in highly selected patients with resected primary tumor who have long-term stable and unresectable metastatic disease limited to the liver.[45][46] However, it is rarely used.

metastatic disease: nonsurgical candidate

1st line – medical treatment

Back
ONGOING
|
metastatic disease: nonsurgical candidate
1st line – 

medical treatment

Patients unsuitable for surgery, or who have unresectable tumors, should be considered for medical treatment to control tumor growth and tumor-related symptoms.[24] Optimal sequencing of medical treatment is unclear.[3]

Somatostatin analogs (e.g., octreotide, lanreotide) are recommended for initial medical treatment if not already used.[3][35]​​​ As well as controlling diarrhea, these agents may have an antiproliferative effect.[34]​​[47]​​​​​ In phase 3 studies, octreotide and lanreotide both significantly prolonged progression-free survival compared with placebo.[48][49]​

Long-acting somatostatin analogs should be used for long-term symptom management, with dose titration to optimize symptom control.[3] Short-acting somatostatin analogs may be used for rapid symptom control and managing breakthrough symptoms.

Patients receiving somatostatin analogs in the long term may develop gallstones due to biliary stasis.[39]​ Cholecystectomy may be performed if long-term use of somatostatin analogs is expected.

Drug resistance can occur with long-term use of somatostatin analogs; dose escalation may be required.

Everolimus (a mammalian target of rapamycin [mTOR] inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) prolonged progression-free survival in randomized placebo-controlled trials of patients with pancreatic neuroendocrine tumors.[50][51][52] These agents may be combined with a somatostatin analog or used as an alternative therapy; however, their specific use in VIPoma has not been evaluated in clinical trials.[3][53][54]

Chemotherapy can be considered for patients who have clinically significant tumor burden or symptomatic progressive disease.[3][35]​​ Combination chemotherapy regimens containing streptozocin or temozolomide are often used (e.g., streptozocin plus fluorouracil; streptozocin plus fluorouracil plus doxorubicin; temozolomide plus capecitabine).[55][56][57][58]​ A somatostatin analog is sometimes used in combination with chemotherapy to improve the control of syndromic symptoms.[17]

Peptide receptor radionuclide therapy with lutetium Lu 177 dotatate (a radiolabeled somatostatin analog) is an option for patients with somatostatin receptor-positive tumors (confirmed by somatostatin receptor-based imaging) who have progressed following treatment with conventional and/or long-acting somatostatin analogs.[3][35][59]​​​​ In a phase 3 trial of patients with advanced or progressive somatostatin receptor-positive midgut neuroendocrine tumors, lutetium Lu 177 dotatate significantly improved progression-free survival and response rate compared with high-dose, long-acting octreotide.[60] Final analysis of overall survival favored lutetium Lu 177 dotatate, but was not statistically significant.[61]

Primary options

octreotide: 200-300 micrograms/day subcutaneously given in 2-4 divided doses, then titrate dose according to response, usual dose range 150-750 micrograms/day; 20 mg intramuscularly (long-acting depot) every 4 weeks for 2 months, then titrate dose according to response every 2 months, usual dose range 10-30 mg every 4 weeks

More

OR

lanreotide: 120 mg subcutaneously (long-acting depot) every 4 weeks

Secondary options

everolimus (oncologic): 10 mg orally once daily

OR

sunitinib: 37.5 mg orally once daily

OR

streptozocin: consult specialist for guidance on dose

and

fluorouracil: consult specialist for guidance on dose

OR

streptozocin: consult specialist for guidance on dose

and

fluorouracil: consult specialist for guidance on dose

and

doxorubicin: consult specialist for guidance on dose

OR

temozolomide: consult specialist for guidance on dose

and

capecitabine: consult specialist for guidance on dose

OR

lutetium Lu 177 dotatate: consult specialist for guidance on dose

More

Plus – oral fluid and electrolyte correction

Back
ONGOING
|
metastatic disease: nonsurgical candidate
Plus – 

oral fluid and electrolyte correction

Treatment recommended for ALL patients in selected patient group

Patients require increased oral intake and electrolyte supplementation as guided by regular blood testing.[3]

Consider – liver-directed therapies

Back
ONGOING
|
metastatic disease: nonsurgical candidate
Consider – 

liver-directed therapies

Treatment recommended for SOME patients in selected patient group

Patients who are not candidates for surgical resection of hepatic metastasis may undergo liver-directed therapies such as transarterial embolization, transarterial chemoembolization, radiofrequency ablation, cryoablation, or selective internal radiation therapy to ablate functional tumors.[3][43][44]

Generally, ablation is only considered if hepatic metastases are small (<3 cm) and there are no more than 4 lesions.[3]

refractory disease

1st line – corticosteroid or clinical trial

Back
ONGOING
|
refractory disease
1st line – 

corticosteroid or clinical trial

For patients with persistent refractory symptoms despite medical and surgical therapy, corticosteroids may be used for short-term symptom control.[62]

Enrollment in a clinical trial should be considered where feasible.[3]

Plus – oral fluid and electrolyte correction

Back
ONGOING
|
refractory disease
Plus – 

oral fluid and electrolyte correction

Treatment recommended for ALL patients in selected patient group

Patients require increased oral intake and electrolyte supplementation as guided by regular blood testing.[3]

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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

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