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This prospective, randomized, single-institution trial was designed to evaluate the role of prophylactic gastrojejunostomy in patients found at exploratory laparotomy to have unresectable periampullary carcinoma.Between 25% and 75% of patients with periampullary cancer who undergo exploratory surgery with intent to perform a pancreaticoduodenectomy are found to have unresectable disease. Most will undergo a biliary-enteric bypass. Whether or not to perform a prophylactic gastrojejunostomy remains unresolved. Retrospective reviews of surgical series and prospective randomized trials of endoscopic palliation have demonstrated that late gastric outlet obstruction, requiring a gastrojejunostomy, develops in 10% to 20% of patients with unresectable periampullary cancer.Between May 1994 and October 1998, 194 patients with a periampullary malignancy underwent exploratory surgery with the purpose of performing a pancreaticoduodenectomy and were found to have unresectable disease. On the basis of preoperative symptoms, radiologic studies, or surgical findings, the surgeon determined that gastric outlet obstruction was a significant risk in 107 and performed a gastrojejunostomy. The remaining 87 patients were thought by the surgeon not to be at significant risk for duodenal obstruction and were randomized to receive either a prophylactic retrocolic gastrojejunostomy or no gastrojejunostomy. Short- and long-term outcomes were determined in all patients.Of the 87 patients randomized, 44 patients underwent a retrocolic gastrojejunostomy and 43 did not undergo a gastric bypass. The two groups were similar with respect to age, gender, procedure performed (excluding gastrojejunostomy), and surgical findings. There were no postoperative deaths in either group, and the postoperative morbidity rates were comparable (gastrojejunostomy 32%, no gastrojejunostomy 33%). The postoperative length of stay was 8.5+/-0.5 days for the gastrojejunostomy group and 8.0+/-0.5 days for the no gastrojejunostomy group. Mean survival among those who received a prophylactic gastrojejunostomy was 8.3 months, and during that interval gastric outlet obstruction developed in none of the 44 patients. Mean survival among those who did not have a prophylactic gastrojejunostomy was 8.3 months. In 8 of those 43 patients (19%), late gastric outlet obstruction developed, requiring therapeutic intervention (gastrojejunostomy 7 patients, endoscopic duodenal stent 1 patient; p < 0.01). The median time between initial exploration and therapeutic intervention was 2 months.The results from this prospective, randomized trial demonstrate that prophylactic gastrojejunostomy significantly decreases the incidence of late gastric outlet obstruction. The performance of a prophylactic retrocolic gastrojejunostomy at the initial surgical procedure does not increase the incidence of postoperative complications or extend the length of stay. A retrocolic gastrojejunostomy should be performed routinely when a patient is undergoing surgical palliation for unresectable periampullary carcinoma.