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Original Investigation
August 14, 2019

Association Between Pancreatic Fistula and Long-term Survival in the Era of Neoadjuvant Chemotherapy

Author Affiliations
  • 1Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
JAMA Surg. Published online August 14, 2019. doi:10.1001/jamasurg.2019.2272
Key Points

Question  Have the frequency and long-term implications of clinically relevant pancreatic fistula after resection for pancreatic cancer changed in the era of neoadjuvant therapy?

Findings  In this cohort study of 346 patients receiving neoadjuvant therapy of overall 753 individuals with resected pancreatic cancers, the occurrence of clinically relevant pancreatic fistula was markedly reduced (3.6 times) compared with upfront resections, and classic clinically relevant pancreatic fistula factors—except for soft pancreatic texture—are no longer applicable. Yet, if clinically relevant pancreatic fistula occurs in this setting, long-term overall survival may be impaired.

Meaning  Despite being uncommon, clinically relevant pancreatic fistula following neoadjuvant therapy for pancreatic cancer may have a major and independent association with long-term survival, and patients might benefit from closer follow-up and further systemic interventions.


Importance  In the past decade, the use of neoadjuvant therapy (NAT) has increased for patients with borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Data on pancreatic fistula and related overall survival (OS) in this setting are limited.

Objective  To compare postoperative complications in patients undergoing either upfront resection or pancreatectomy following NAT, focusing on clinically relevant postoperative pancreatic fistula (CR-POPF) and potential associations with OS.

Design, Setting, and Participants  This retrospective cohort study was conducted on data from patients who underwent pancreatic resection for PDAC at the Massachusetts General Hospital from January 1, 2007, to December 31, 2017,

Exposures  Pancreatic cancer surgery with or without NAT.

Main Outcomes and Measures  Overall morbidity and CR-POPF rates were compared between NAT and upfront resection. Factors associated with CR-POPF were assessed with univariate and multivariate analysis. Survival data were analyzed by Kaplan-Meier curves and a Cox proportional hazards regression model.

Results  Of 753 patients, 364 were men (48.3%); median (interquartile range) age was 68 (61-75) years. A total of 346 patients (45.9%) received NAT and 407 patients (54.1%) underwent upfront resection. At pathologic examination, NAT was associated with smaller tumor size (mean [SD], 26.0 [15.3] mm vs 32.7 [14.4] mm; P < .001), reduced nodal involvement (102 [25.1%] vs 191 [55.2%]; P < .001), and higher R0 rates (257 [74.3%] vs 239 [58.7%]; P < .001). There were no significant differences in severe complication rate or 90-day mortality. The rate of CR-POPF was 3.6-fold lower in patients receiving NAT vs upfront resection (13 [3.8%] vs 56 [13.8%]; P < .001). In addition, factors associated with CR-POPF changed after NAT, and only soft pancreatic texture was associated with a higher risk of CR-POPF (38.5% vs 6.3%; P < .001). Survival analysis showed no differences between patients with or without CR-POPF after upfront resection (26 vs 25 months; P = .66), but after NAT, a worse overall survival rate was observed in patients with CR-POPF (17 vs 34 months; P = .002). This association was independent of other established predictors of overall survival by multivariate analysis (hazard ratio, 2.80; 95% CI, 1.44-5.45; P < .002).

Conclusions and Relevance  Neoadjuvant therapy may be associated with a significant reduction in the rate of CR-POPF. In addition, standard factors associated with CR-POPF appear to be no longer applicable following NAT. However, once CR-POPF occurs, it is associated with a significant reduction in long-term survival. Patients with CR-POPF may require closer follow-up and could benefit from additional therapy.

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