Introduction: A positive microscopic margin (R1) following resection of pancreatic ductal adenocarcinoma (PDAC) can occur in up to 80% of patients and is associated with reduced survival and increased recurrence. Our aim was to characterize the impact of neoadjuvant therapy (NAT) on survival and recurrence in patients with PDAC following an R1 resection. Methods: A retrospective analysis of patients with PDAC who underwent pancreatectomy from 2008 to 2017 was performed. Patients were staged according to the American Joint Committee on Cancer 8th edition and stratified based on resection margin (R0 vs. R1) and treatment sequence (NAT vs. surgery first [SF]). Conditional survival analysis was performed using Cox regression and inverse probability weighted estimates. Results: Among 580 patients, 59% received NAT and 41% underwent SF. On final pathology, the NAT cohort had smaller tumors and less lymph node (LN) positivity (p < 0.05). NAT was not associated with an R1 resection (50%, p = 0.653). Compared with the R1 cohort, the R0 cohort had a higher median overall survival (OS; 39.6 vs. 22.8 months; hazard ratio [HR] 1.6, p < 0.001) and disease-free survival (DFS; 19 vs. 13 months; HR 1.35, p = 0.004). After risk adjustment, NAT was not associated with OS, regardless of margin status (R0, 95% confidence interval [CI] (−)7.31–27.07, p = 0.26; or R1, 95% CI (−)36.99–15.25, p = 0.42). However, NAT was associated with improved DFS in the R1 cohort (95% CI 1.79–11.91, p = 0.008) but not in the R0 cohort (95% CI (−)11.22–10.54, p = 0.95). Conclusion: An R0 resection remains an important determinant of overall and disease-free survival, even when NAT is administered. For patients with an R1 resection, receipt of NAT may prolong DFS.
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