How is Zollinger-Ellison syndrome managed?

Management of Zollinger-Ellison Syndrome

The management of Zollinger-Ellison syndrome requires high-dose proton pump inhibitors as first-line therapy to control acid hypersecretion, with surgical resection attempted for localized sporadic gastrinomas, and somatostatin analogues reserved for metastatic or unresectable disease. 1, 2

Acid Hypersecretion Control

Proton pump inhibitors are the cornerstone of medical management and must be initiated immediately upon suspicion of ZES. 1, 2

Initial Dosing Strategy

• Start omeprazole at 60 mg once daily for pathological hypersecretory conditions, with dosages up to 120 mg three times daily administered as needed 2
• The FDA label explicitly states that daily dosages greater than 80 mg should be administered in divided doses 2
• In patients with Zollinger-Ellison syndrome requiring voriconazole, dose adjustment of omeprazole may be considered for those needing higher doses 2
• Never discontinue acid suppression except under controlled conditions, as patients cannot be managed safely without adequate acid control 3

Monitoring Requirements

• Measure basal acid output and adjust PPI doses to reduce acid secretion to <10 mmol/h (or <5 mmol/h in patients with previous gastric resection or severe esophageal disease) 3
• Once effective control is established, doses can often be reduced during long-term treatment 4
• Some patients have been treated continuously for more than 5 years 2

Critical pitfall: Discontinuing PPIs for 1-2 weeks is required for diagnostic gastrin measurement 1, 5, but this should only be done before diagnosis is confirmed—never stop acid suppression in established ZES without controlled monitoring.

Surgical Management

All sporadic localized gastrinomas should be surgically excised when possible, as this offers the only chance for cure. 1, 4

Patient Selection for Surgery

• Exploratory surgery with careful search for pancreatic and extrapancreatic gastrinomas is recommended for patients without metastatic disease 6
• The majority of gastrinomas are located in the duodenum, with the remainder in the pancreas 1
• Approximately 60% of gastrinoma patients develop metastases, with likelihood correlated to primary tumor size 1, 7

Surgical Approach Considerations

• When liver metastases are present, debulking may improve symptoms, survival, and facilitate medical treatment 4
• Controversy exists for gastrinomas associated with MEN1 syndrome—all patients with gastrinoma should be evaluated for MEN1 and undergo appropriate testing 1, 7
• Pancreatoduodenectomy should not be performed for unresectable tumor in the head of the pancreas due to considerable morbidity and mortality 6
• At least 20% of all ZES patients can be cured with appropriate surgical resection 6

Medical Management of Metastatic/Unresectable Disease

For metastatic or unresectable disease, somatostatin analogues are recommended as the primary antiproliferative therapy. 8, 1

Somatostatin Analogue Therapy

• The NCCN recommends somatostatin analogues for metastatic/unresectable disease 1
• Lanreotide autogel 60-120 mg/month or octreotide LAR 10-30 mg/month are standard options 8
• SSAs are useful in reducing gastric acid hypersecretion, serum gastrin, and gastric ECL cells 4
• In a 2022 observational study, 67% of ZES patients treated with SSAs had sustained response, with significantly better progression-free survival in responders (84 vs 2 months, p=0.004) 9
• SSAs are particularly effective given that gastrinoma is mainly a well-differentiated low-grade tumor (G1 or G2) with high somatostatin receptor expression 9

Additional Treatment Options

• Chemotherapeutic agents may be used for metastatic disease per ESMO guidelines 1
• Liver-directed therapies including radiofrequency ablation, UAE, TACE, and SIRT are options for hepatic metastases 8
• Peptide receptor radionuclide therapy (PRRT) with lutetium-177 DOTATATE may be considered for progressive disease to improve symptoms, though efficacy may not be durable 8
• Everolimus can be used off-label for uncontrolled symptoms in refractory cases with progressive disease, though not approved by EMA or FDA for this indication 8
• Liver transplantation may be considered in early therapy failure in young adults with high tumor burden, stable liver-only disease (rare indication) 8

Multidisciplinary Approach

• The American College of Gastroenterology recommends a multidisciplinary approach including both surgical and non-surgical therapies for advanced disease 1

Important caveat: Acute aggravation of symptoms (such as worsening diarrhea) may occur during or after PRRT and requires careful observation 8

Diagnostic Localization Before Treatment

Imaging Modalities

• Gallium-68 radiotracers with PET are currently the standard for tumor localization 1
• Multiphase CT and MRI scans play important roles in detecting gastrinomas 1
• Somatostatin receptor scintigraphy is useful for initial evaluation 1
• Endoscopic ultrasound and esophagogastroduodenoscopy should be performed for duodenal and gastric evaluation 1

Key monitoring consideration: Temporarily stop omeprazole at least 14 days before assessing chromogranin A levels, as PPI-induced decreases in gastric acidity cause secondary CgA elevation that may yield false positive results in neuroendocrine tumor investigations 2