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Clinical Policy Bulletin:
Pancreaticoduodenectomy (Whipple Resection) for Zollinger-Ellison Syndrome
Number: 0365


Aetna considers pancreaticoduodenectomy (also known as Whipple resection or proximal pancreatectomy) experimental and investigational for the treatment of members with Zollinger-Ellison syndrome because the value of pancreaticoduodenectomy in this condition remains to be established.  Furthermore, the morbidity and mortality related to this approach may outweigh its potential benefits.


Zollinger-Ellison syndrome (ZES) is characterized by severe peptic ulcer disease that results from non-beta islet cell tumors, gastrinomas, of the gastrointestinal tract.  The mean age at presentation is 45 to 50 years, and men are affected more often than women.  Gastrinomas can be subdivided into tumors that are sporadic, constituting about 75 % of patients with ZES, and those that are genetically transmitted and associated with multiple endocrine neoplasia type 1 (MEN 1), constituting about 25 % of patients with ZES.  Zollinger-Ellison tumors associated with MEN-1 occur at an earlier age than the sporadic tumors and have been characterized by some researchers to follow a more benign course.

Currently, the literature states that proton-pump inhibitors (PPIs) such as lansoprazole (Prevacid) and omeprazole (Prilosec) are the treatment of choice for ZES.  For patients who have difficulty controlling gastric acid hyper-secretion with oral PPIs, intravenous pantoprazole (Protonix I.V.) has been reported to be effective.  Most ZES patients (93 %) maintained effective control of acid output previously established with oral PPIs when switched to twice-daily 80 mg of intravenously administered pantoprazole.  In patients with sporadic ZES, the literature suggests that exploratory surgery with tumor resection is also appropriate.  According to accepted guidelines, surgical resection of a single gastrinoma may be attempted if there is no evidence that it has spread to other organs (e.g., lymph nodes or the liver).  Gastrectomy to control acid over-production is rarely indicated.  However, the role of pancreaticoduodenectomy (Whipple resection, or proximal pancreatectomy) in patients with sporadic gastrinomas and in patients with MEN-1 is controversial.  Furthermore, the effect of aggressive surgery, such as the Whipple resection, on survival is unclear.

In a review on surgical treatment and prognosis of gastrinoma, Norton (2005) noted that Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle.  However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple pancreaticoduodenectomy make its current role unclear until further studies are done.

Bartsch et al (2007) stated that gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with MEN-1 and a major determinant of mortality in this syndrome.  Whether routine surgical exploration should be performed in patients with MEN-1 associated ZES to possibly decrease the malignant spread and eventually increase survival still remains controversial.  There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available.

In a review on surgical management of ZES, Morrow and Norton (2009) stated that much has been learned about the diagnosis and treatment of ZES, and certain questions require further investigation.  Delay in diagnosis of ZES is still a significant problem, and clinical suspicion should be elevated.  The single best imaging modality for localization and staging of ZES is somatostatin receptor scintigraphy.  Goals of surgical treatment for ZES differ between sporadic and MEN-1-related cases.  All sporadic cases of ZES should be surgically explored (including duodenotomy) even with negative imaging results, because of the high likelihood of finding and removing a tumor for potential cure.  Surgery for MEN-1-related cases should be focused on prevention of metastatic disease, with surgery being recommended when pancreatic tumors are greater than 2 cm.  The authors noted that the role of Whipple procedure, especially for MEN-1 cases, should be explored further.  Laparoscopic and endoscopic treatments are more experimental, but may have a role.

An UpToDate review on “Pancreaticoduodenectomy (Whipple procedure): Techniques” (Reber, 2013) does not mention Zollinger-Ellison syndrome as an indication of pancreaticoduodenectomy.  Furthermore, an UpToDate review on “Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)” (Goldfinger, 2013) does not mention pancreaticoduodenectomy as a therapeutic option.

Coolsen and colleagues (2013) stated that few randomized controlled trials (RCTs) have been performed in patients undergoing pancreatico-duodenectomy (PD).  An important factor contributing to this is the large number of patients needed to adequately power RCTs for relevant clinical single endpoints.  A PD-specific composite end-point (CEP) could solve this problem.  The aim of the present study was to develop a PD-specific CEP, consisting of complications related to PD, allowing reduction in sample sizes and improving the ability to compare outcomes.  PD-specific CEP components were selected after a systematic review of the literature and consensus between 25 international pancreatic surgeons.  Ultimately, prospective cohorts of patients who underwent PD in 2 high-volume HPB centers (London, UK, and Maastricht, NL) were used to assess the event rate and effect of implementing a PD-specific CEP.  From a total of 18 single-component end-points, 8 were selected to be included the PD-specific CEP: (i) intra-abdominal abscess, (ii) sepsis, (iii) post-PD hemorrhage, (iv) bile leakage, (v) gastro-jejunostomy leakage, (vi) leakage of the pancreatic anastomosis, (vii) delayed gastric emptying, and (viii) operative mortality within 90 days.  All 8 components had consensus definitions and a Dindo-Clavien classification of 3 or more.  The incidence of the PD-specific CEP was 24.7 % in the Maastricht cohort and 23.3 % in the London cohort.  These incidence rates led to a 2-fold reduction in the theoretical calculated sample size for an adequately powered RCT on PD using this CEP as a primary end-point.  The authors concluded that the proposed PD-specific CEP enables clinical investigators to adequately power RCTs on PD and increases the feasibility, comparability, and utility in meta-analysis.

CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes not covered for indications listed in the CPB:
ICD-9 codes not covered for indications listed in the CPB:
251.5 Abnormality of secretion of gastrin [Zollinger-Ellison syndrome]

The above policy is based on the following references:
  1. Del Valle J, Scheiman JM. Zollinger-Ellison syndrome. In: Textbook of Gastroenterology. Vol. I. 3rd ed. T Yamada, et al., eds. Philadelphia, PA: Lippincott Williams & Wilkins; 1999; Ch. 65:1445-1462.
  2. Wolfe MM, Jensen RT. Zollinger-Ellison syndrome: Current concepts in diagnosis and management. N Engl J Med. 1987;317(19):1200-1209.
  3. MacFarlane MP, Fraker DL, Alexander HR, et al. Prospective study of surgical resection of duodenal and pancreatic gastrinomas in multiple endocrine neoplasia type 1. Surgery. 1995;118(6):973-979; discussion 979-980.
  4. Meko JB, Norton JA. Management of patients with Zollinger-Ellison syndrome. Ann Rev Med. 1995;46:395-411.
  5. Jensen RT. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med. 1998;243(6):477-488.
  6. Wells SA, Jr. Surgery for the Zollinger-Ellison syndrome. N Engl J Med. 1999;341(9):689-690.
  7. Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med.1999;341(9):635-644.
  8. Maton PN. Review article: The management of Zollinger-Ellison syndrome. Aliment Pharmacol Ther. 1993;7(5):467-475.
  9. Metz DC, Forsmark C, Lew EA, et al. Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Am J Gastroenterol. 2001;96(12):3274-3280.
  10. Witzigmann H, Max D, Uhlmann D, et al. Quality of life in chronic pancreatitis: A prospective trial comparing classical Whipple procedure and duodenum-preserving pancreatic head resection. J Gastrointest Surg. 2002;6(2):173-179; discussion 179-180.
  11. Norton JA, Jensen RT. Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1). Surg Oncol. 2003;12(2):145-151.
  12. Norton JA, Jensen RT. Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome. Ann Surg. 2004;240(5):757-773.
  13. Campana D, Piscitelli L, Mazzotta E, et al. Zollinger-Ellison syndrome. Diagnosis and therapy. Minerva Med. 2005;96(3):187-206.
  14. Norton JA. Surgical treatment and prognosis of gastrinoma. Best Pract Res Clin Gastroenterol. 2005;19(5):799-805.
  15. Pellicano R, De Angelis C, Resegotti A, Rizzetto M. Zollinger-Ellison syndrome in 2006: Concepts from a clinical point of view. Panminerva Med. 2006;48(1):33-40.
  16. Norton JA, Fraker DL, Alexander HR, et al. Surgery increases survival in patients with gastrinoma. Ann Surg. 2006;244(3):410-419.
  17. Bartsch DK, Langer P, Rothmund M. Surgical aspects of gastrinoma in multiple endocrine neoplasia type 1. Wien Klin Wochenschr. 2007;119(19-20):602-608.
  18. Pedicone R, Adham M, Hervieu V, et al. Long-term survival after pancreaticoduodenectomy for endocrine tumors of the ampulla of Vater and minor papilla. Pancreas. 2009;38(6):638-643.
  19. Mortellaro VE, Hochwald SN, McGuigan JE, et al. Long-term results of a selective surgical approach to management of Zollinger-Ellison syndrome in patients with MEN-1. Am Surg. 2009;75(8):730-733.
  20. Morrow EH, Norton JA. Surgical management of Zollinger-Ellison syndrome; state of the art. Surg Clin North Am. 2009;89(5):1091-1103.
  21. Reber HA. Pancreaticoduodenectomy (Whipple procedure): Techniques. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2013.
  22. Goldfinger SE. Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma). UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2013.
  23. Coolsen MM, Clermonts SH, van Dam RM, et al. Development of a composite endpoint for randomized controlled trials in pancreaticoduodenectomy. World J Surg. 2013 Dec 24. [Epub ahead of print]

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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