PANCREATIC FISTULA IN THE ERA OF NEOADJUVANT CHEMOTHERAPY IS AN UNCOMMON COMPLICATION BUT MAY HAVE A MAJOR IMPACT ON LONG-TERM SURVIVAL
Thomas P. Hank*, Marta Sandini, Cristina R. Ferrone, Clifton Rodrigues, Maximilian Weniger, Motaz Qadan, Andrew L. Warshaw, Keith D. Lillemoe, Carlos Fernández-del Castillo
Surgery, Massachusetts General Hospital, Boston, MA
Background: Neoadjuvant therapy (NAT) is the standard of care for patients with borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to assess postoperative complications in patients undergoing pancreatectomy following NAT, with a particular emphasis on clinically relevant postoperative pancreatic fistula (CR-POPF) and to compare them with a contemporaneous cohort of patients undergoing upfront resection. We then investigated whether POPF-related morbidity affects long-term outcomes in NAT and upfront resected patients by comparing patients with and without CR-POPF.
Methods: Patients who underwent either NAT followed by surgery or upfront resection for PDAC at the Massachusetts General Hospital between 2007 to 2017 were identified from a prospectively maintained database. Data on demographics, perioperative fistula determinants, pathology and outcomes were collected and analyzed. All postoperative complications and severity were classified and graded according to the Clavien-Dindo Classification and ISGPS recommendations. Follow-up and survival analyses for NAT and upfront resection groups were performed.
Results: 753 patients were identified, of whom 346 (45.9%) received NAT and 407 (54.1%) underwent upfront resection. Patients in the NAT group were younger, had lower BMI and lower CA19-9 levels after completion of NAT than those who underwent upfront resection. NAT was also associated with more favorable post-treatment pathologic findings, including smaller tumor size, lesser frequency of lymph node involvement, lower tumor grade, and higher frequency of negative resection margins. There were no significant differences in overall complications, Clavien-Dindo grade ≥3 complications, or 90-day postoperative mortality rates between the two groups. The rate of CR-POPF was 3.6-fold lower in the NAT group compared with the upfront resections (3.8% vs. 13.8%; p<0.001). In addition, the determinants of CR-POPF changed in the NAT group, where only soft pancreatic texture was associated with a higher risk of CR-POPF (p<0.001), and not duct diameter, BMI or intraoperative blood loss. While no differences in survival were seen in patients with and without CR-POPF after upfront resection (26 vs. 25 months; p=0.656), long-term postoperative survival was significantly reduced in the NAT cohort when CR-POPF occurred (17 vs. 34 months; p=0.002). This effect was independent of other established predictors of overall survival on multivariate analysis.
Conclusions: Neoadjuvant therapy is associated with a significant reduction in the rate of postoperative fistula formation. However, once this occurs, it is associated with a significant reduction in long-term survival. Additionally, standard determinants of POPF appear to be no longer applicable following NAT.
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