A risk-adjusted evaluation of the impact of neoadjuvant therapy on pancreatic fistula development after pancreatoduodenectomy

Background: Most patients undergoing pancreatoduodenectomy after neoadjuvant therapy for periampullary malignancies have pancreatic adenocarcinoma, a known protective factor against postoperative pancreatic fistula. Accordingly, the perceived lower postoperative rates of pancreatic fistula after neoadjuvant therapy might result from selection bias toward a lower-risk population. Accurate evaluation of neoadjuvant therapy effects requires adjustment for risk. Methods: Consecutive patients who underwent pancreatoduodenectomy from 2015 to 2022 for all periampullary malignancies were studied at 4 international specialty units. Risk adjustment used the original and alternative Fistula Risk Scores and multivariable analysis. Results: Of 2,240 patients, 80.5% had pancreatic adenocarcinoma; 19.5% had other periampullary malignancies. Neoadjuvant therapy was applied in 39.2%, and patients with pancreatic adenocarcinoma received neoadjuvant therapy more often than those with nonpancreatic ductal adenocarcinoma (47.6% vs. 4.3%, P < .001). Postoperative pancreatic fistula occurred in 289 patients (12.9%), more commonly after upfront resection (15.1%) versus neoadjuvant therapy (9.5%), P < .001. Rates of postoperative pancreatic fistula after neoadjuvant therapy (vs upfront resection) were significantly lower in the setting of pancreatic adenocarcinoma (9.1% vs 12.8%, P = .015), but not in nonpancreatic ductal adenocarcinoma malignancies (26.3% vs 20.3%, P = .73); this is despite patients with pancreatic ductal adenocarcinoma receiving neoadjuvant therapy having a significantly greater median Fistula Risk Score than those patients with pancreatic ductal adenocarcinoma receiving upfront resection (3 vs 2, P < .001). The protection of neoadjuvant therapy (vs upfront resection) was insignificant with blood loss >700 mL (12.8% vs 18.8%, P = .17). Concurrent radiotherapy did not decrease postoperative pancreatic fistula beyond chemotherapy alone (9.9% vs 8.9%, P = .77). Multivariable analysis confirmed a protective association between neoadjuvant therapy and postoperative pancreatic fistula (odds ratio, 0.51; 95% confidence interval, 0.36-0.70, P < .001) for pancreatic adenocarcinoma. Conclusion: In the setting of pancreatic adenocarcinoma, neoadjuvant therapy appears to reduce postoperative pancreatic fistula, with reductions significant only with low blood loss. Furthermore, neoadjuvant radiotherapy did not provide added mitigation in this series. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.