Approach
The main goal of treatment is control of gastric acid hypersecretion with proton-pump inhibitors (PPIs). If a patient has localised disease, but not multiple endocrine neoplasia type 1 (MEN1) syndrome, surgery may be an option.
Metastases are treated depending on extrahepatic involvement.
Positive gastrin test and requiring long-term acid suppression
First-line treatment is control of gastric acid hypersecretion with a PPI; there is no preference between agents.[1]
In order to prevent complications of increased gastric acid secretion, it has previously been recommended that gastric acid output be controlled to <10 mEq/hour in patients with sporadic Zollinger-Ellison syndrome (ZES), and <5 mEq/hour in patients who have MEN1.[1][44] However, acid secretory studies are often not available and in most cases PPI therapy is initiated at an empirical maximised dosage.[18]
Intravenous PPI formulations may be used for patients who cannot tolerate oral formulations, or in the perioperative period.
When PPIs are unable to control gastric acid secretion, somatostatin analogues such as octreotide and lanreotide can be considered, as they reduce gastrin secretion. However, because of the unpredictability of the response to these and the requirement for parenteral administration, they are not first-line agents for symptomatic patients with hypergastrinaemia.[18]
The use of H2 antagonists has been replaced almost entirely by PPIs due to their higher efficacy. PPIs have a lower adverse-effect profile and do not demonstrate the tolerance that has been reported with H2 antagonists.[1][45]
Potential effects of long-term PPI therapy
Retrospective analyses suggest an association between PPI use and:[46][47][48][49][50]
Increased mortality
Type 2 diabetes mellitus
Increased fracture risk
Hypergastrinaemia
Development of pneumonia
Development of enteric infections
Microscopic colitis
Dementia
Magnesium malabsorption
Drug interactions
Multidrug-resistant organisms
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 infections 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]
Localised sporadic disease
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 gastrinomas if they are encountered during routine endoscopy. As with gastrinomas detected via other routes, surgical resection of the primary tumour 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] 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 and/or octreotide or lanreotide can be given. Gastric acid hypersecretion should be managed with high-dose PPIs.[24]
Localised disease: MEN1
There is considerable controversy in the literature regarding the management of ZES in patients with 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:
symptomatic functional tumours refractory to medical management
a tumour larger than 2 cm in size, or
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]
Patients with presence of metastasis with predominantly hepatic involvement
First-line medical therapy
Approximately one third of ZES patients present with metastatic disease to the liver. The presence of liver metastases is one of the most important prognostic factors for survival in patients with ZES, with survival decreasing with increasing extent of hepatic metastases.[18] Somatostatin analogues (e.g., octreotide, lanreotide) are used to treat the symptoms associated with excess gastrin secretion.[63] In patients undergoing abdominal surgery in whom octreotide or lanreotide treatment is planned, prophylactic cholecystectomy can be considered due to a higher risk of cholelithiasis in patients receiving somatostatin analogues.[24][64]
Patients are maintained on PPIs because they are still at risk of developing gastric acid hypersecretion and consequent peptic ulcer disease.
Liver-directed therapies
In some patients with limited hepatic metastases, complete surgical resection of the primary tumour and metastases with curative intent can be undertaken.[24][65]
When curative resection of metastases is not possible, the following liver-directed treatments can be considered:
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 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]
Progression of liver-predominant metastatic disease or presence of extrahepatic metastases
Everolimus or sunitinib: 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. 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]
Peptide receptor radionuclide therapy (PRRT): 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.
Systemic chemotherapy: 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 current 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. 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]
Metastases are still capable of excreting excessive amounts of gastrin and thus contribute to hypergastrinaemia-induced gastric acid hypersecretion. For this reason, it is common practice to maintain these patients on a sufficiently high dose of PPI to adequately control gastric acid hypersecretion.
Palliative radiotherapy is recommended for oligometastatic disease and/or symptomatic metastases (excluding mesenteric masses).[24]
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