Approach

Management of patients with VIPoma includes the prompt treatment of symptoms associated with the clinical syndrome. Evaluation by a multidisciplinary team including surgeons, gastroenterologists, and medical oncologists at a centre with experience of treating VIPoma is recommended.[32]

​Fluid and electrolyte replacement are given to manage fluid and electrolyte imbalance. Short-acting somatostatin analogues, which suppresses vasoactive intestinal peptide (VIP) secretion, allow for rapid symptom control.

Surgical resection of the primary tumour and metastasis is recommended if feasible, aiming for improved symptom control and remission.

Medical treatment should be considered if tumours are unresectable or if there is disease progression.

Management of symptoms

Fluid and electrolyte replacement

Initial treatment of VIPoma involves the correction of dehydration with saline-based intravenous fluids and the repletion of electrolytes with standard electrolytes (e.g., potassium chloride, magnesium sulfate, phosphorus).[3][17][33]

Somatostatin analogues

Somatostatin analogues (e.g., octreotide, lanreotide) are the standard of care for controlling VIPoma related symptoms, including diarrhoea, and decreasing VIP secretion.[3]​​[32][33]​​ Up to 80% of patients with VIPoma achieve a clinical response (e.g., improvement in diarrhoea) with somatostatin analogues, and a small percentage also have tumour shrinkage.[34][35]

Patients are initiated on a short-acting somatostatin analogue (e.g., octreotide) for rapid symptom control. Patients are transitioned to a long-acting somatostatin analogue (either octreotide or lanreotide), with dose titration for optimal symptom control. Short-acting analogues may be used to manage breakthrough symptoms.[3]

Patients with VIPoma often require lifelong somatostatin analogue therapy to maintain symptom control.[32]

Patients receiving somatostatin analogues in the long term may develop gallstones due to biliary stasis.[36]​ Cholecystectomy may be performed if long-term use of somatostatin analogues is expected, based on the patient’s clinical course.

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

Tumour control

The management of VIPoma tumour control is as follows:[3][32][37]

  • Somatostatin analogues: anti-tumour effects

  • Additional therapies

    • Peptide receptor radionuclide therapy: utilises radiolabelled somatostatin analogues to deliver targeted radiation to tumour cells, helping to control tumour growth, especially in metastatic disease

    • Targeted therapies: everolimus, sunitinib

  • Chemotherapy: especially for metastatic and progressive disease

  • Surgery

    • Resection

    • Debulking surgery

Treatment for localised disease

Complete surgical resection of localised 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 tumour.[3] Pancreaticoduodenectomy is the standard approach for large primary tumours (>2 cm) located at the head of the pancreas. Distal pancreatectomy (with or without splenectomy) is the standard approach for large tumours 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.[38]

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

Treatment for metastatic disease

More than half of patients with VIPoma will have distant metastasis (most commonly to the liver) at the time of diagnosis.[39]

Surgery, embolisation, or ablation

Surgical treatment in the metastatic setting is palliative and should be individualised based on patient factors (e.g., age, comorbidities) and disease factors (e.g., location, distribution, and grade of metastases).[40]​ Patients with metastatic disease may undergo surgical resection to remove the primary tumour and regional lymph nodes, and debulking of metastatic lesions (e.g., surgical resection, radiofrequency ablation, cryoablation) to reduce tumour burden and alleviate symptoms.[3][24][38]

Patients who are not candidates for surgical resection of hepatic metastasis may undergo liver-directed therapies such as transarterial embolisation, transarterial chemoembolisation, radiofrequency ablation, cryoablation, or selective internal radiotherapy to ablate functional tumours.[3][41][42] Generally, ablation is only considered if hepatic metastases are small (<3 cm) and there are no more than 4 lesions.[3]

Liver transplantation has been successfully performed in highly selected patients with resected primary tumour who have long-term stable and unresectable metastatic disease limited to the liver.[43][44] However, it is rarely used.

Medical treatment

Medical treatment can help control tumour growth and treat tumour-related symptoms.[24]​​ Optimal sequencing of medical treatment is unclear.[3]

Somatostatin analogues (e.g., octreotide, lanreotide) are recommended for initial medical treatment if not already used.[3][32]​​​ As well as controlling diarrhoea, these agents may have an antiproliferative effect.​[40][45]​​​​​ In phase 3 studies, octreotide and lanreotide both significantly prolonged progression-free survival compared with placebo.[46][47]

Everolimus (a mammalian target of rapamycin [mTOR] inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) prolonged progression-free survival in randomised placebo-controlled trials of patients with pancreatic neuroendocrine tumours.[48][49][50] These agents may be combined with a somatostatin analogue or used as an alternative therapy; however, their specific use in VIPoma has not been evaluated in clinical trials.[3][51][52]

Chemotherapy can be considered for patients who have clinically significant tumour burden or symptomatic progressive disease.[3][32]​​ Combination chemotherapy regimens containing streptozocin or temozolomide are often used (e.g., streptozocin plus fluorouracil; streptozocin plus fluorouracil plus doxorubicin; temozolomide plus capecitabine).[53][54][55][56]​ A somatostatin analogue can be given in combination with chemotherapy to improve the control of syndromic symptoms.[17]

Peptide receptor radionuclide therapy with lutetium Lu 177 dotatate (a radiolabelled somatostatin analogue) is an option for patients with somatostatin receptor-positive tumours (confirmed by somatostatin receptor-based imaging) who have progressed following treatment with conventional and/or long-acting somatostatin analogues.[3][32][57]​​​​ In a phase 3 trial of patients with advanced or progressive somatostatin receptor-positive midgut neuroendocrine tumours, lutetium Lu 177 dotatate significantly improved progression-free survival and response rate compared with high-dose, long-acting octreotide.[58] Final analysis of overall survival favoured lutetium Lu 177 dotatate, but was not statistically significant.[59]

Refractory disease

For patients with persistent refractory symptoms despite medical and surgical therapy, corticosteroids may be used for short-term symptom control.[60]

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

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