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 center with experience of treating VIPoma is recommended.[35]

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

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

Medical treatment should be considered if tumors 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][36]

Somatostatin analogs

Somatostatin analogs (e.g., octreotide, lanreotide) are the standard of care for controlling VIPoma related symptoms, including diarrhea, and decreasing VIP secretion.[3]​​[35][36]​​ Up to 80% of patients with VIPoma achieve a clinical response (e.g., improvement in diarrhea) with somatostatin analogs, and a small percentage also have tumor shrinkage.[37][38]

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

Patients with VIPoma often require lifelong somatostatin analog therapy to maintain symptom control.[35]

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, based on the patient’s clinical course.

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

Tumor control

The management of VIPoma tumor control is as follows:[3][35][40]

  • Somatostatin analogs: antitumor effects

  • Additional therapies

    • Peptide receptor radionuclide therapy: utilizes radiolabeled somatostatin analogs to deliver targeted radiation to tumor cells, helping to control tumor growth, especially in metastatic disease

    • Targeted therapies: everolimus, sunitinib

  • Chemotherapy: especially for metastatic and progressive disease

  • Surgery

    • Resection

    • Debulking surgery

Treatment for localized disease

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]

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.[42]

Surgery, embolization, or ablation

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]​ Patients with metastatic disease 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]

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]

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.

Medical treatment

Medical treatment can help control tumor growth and treat 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]

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 given 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]

Refractory disease

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]

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