Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial

Pancreaticoduodenectomy is a commonly performed surgical procedure at many institutions, being used for various malignant and benign diseases of the pancreas and periampullary region. In many centers the perioperative death rate for pancreaticoduodenectomy is now less than 5%, 1–5 with the leading causes of postoperative death hemorrhage, cardiac events, and sepsis. 6 In contrast to this low death rate, the incidence of major postoperative complications after pancreaticoduodenectomy approaches 40% to 50%. 1–6 In most series, the three most common complications are early delayed gastric emptying, wound infection, and pancreatic fistula (resulting from a pancreatic-enteric anastomotic leak). In the setting of pancreaticoduodenal resection, pancreatic fistula is variably defined as the persistent drainage of 50 mL or more of amylase-rich fluid on or after postoperative day 3 through 10. The incidence of pancreatic anastomotic leak varies from 5% to 25% in most series. Because pancreatic fistula has been identified as such a common problem after pancreaticoduodenectomy, numerous techniques for managing the pancreatic remnant (body and tail of the pancreas) have been studied. 7 These techniques have included suture ligation of the pancreatic duct without enteric drainage, 8 pancreatic ductal occlusion with polymers, 9,10 and various modifications of the pancreaticojejunal anastomosis (e.g., end-to-end vs. end-to-side, invagination vs. duct-to-mucosa, isolated Roux-en-Y limb). 11–13 Pancreatic drainage to the stomach has also been evaluated by many groups, 14,15 with the only prospective randomized trial finding similar pancreatic fistula rates (11–12%) when comparing pancreaticogastrostomy and pancreaticojejunostomy. 16 A pharmacologic approach to reduce the rate of pancreatic fistula has been proposed that involves perioperative inhibition of pancreatic exocrine secretion. This concept originated in 1979, using a continuous perioperative infusion of the native tetradecapeptide somatostatin at a dosage of 250 μg/hour in patients undergoing pancreaticoduodenectomy, with the authors reporting a reduced complication rate. 17 Octreotide is a synthetic octapeptide analog of native somatostatin, which is more potent and has a longer half-life. 18,19 To date, four randomized, controlled, double-blind, multiinstitution studies from Europe have evaluated subcutaneous octreotide as prophylaxis against complications in patients undergoing elective pancreatic resection. 20–23 Each of these four trials reported that octreotide (at a dosage of 100 μg three times a day) significantly reduced the overall complication rate. Two of the four trials reported that octreotide was associated with a significantly lower incidence of pancreatic fistula. However, these trials are not without criticism. 24 All included many types of pancreatic resections (e.g., pancreaticoduodenectomy, distal pancreatectomy, enucleations), the pancreatic fistula rates in the control groups were high (≥19%), and in none of the trials was there a significant decrease in the overall death rate. Nonetheless, these four European trials have influenced the practice of many surgeons, who now routinely administer octreotide to patients undergoing elective pancreatic resection. 25,26 Also, a recent meta-analysis has used these four European octreotide trials to conclude that the use of octreotide is a cost-effective strategy in patients undergoing elective pancreatic resection. 27 In contrast to the published studies supporting the use of octreotide, Lowy et al 28 have reported data in direct opposition to the European multicenter trials and the meta-analysis results. This prospective, randomized trial from the M.D. Anderson Cancer Center evaluated 110 patients undergoing only pancreaticoduodenectomy. The rates of clinical pancreatic fistula and perioperative complications were 6% and 25% in the control group and 12% and 30% in the octreotide group. This study showed no benefit to the use of octreotide. The current prospective, randomized, double-blinded, placebo-controlled, single-institution trial was designed to evaluate the primary endpoints of complications (specifically pancreatic fistula and total complications) and death in patients undergoing pancreaticoduodenectomy. A secondary analysis was performed to evaluate cost issues regarding the use of octreotide.