Influence of time to first therapy (TTFT) variable on survival outcomes of neoadjuvant chemotherapy versus upfront surgery approach in resectable pancreatic ductal adenocarcinoma.

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720 Background: Evidence demonstrating overall survival (OS) benefit of neoadjuvant chemotherapy (NAC) followed by surgical resection over upfront surgical resection for resectable pancreatic ductal adenocarcinoma (PDAC) has been mixed. The time to first therapy (TTFT) variable has not been studied as a contributing factor. Methods: A nationwide retrospective analysis using the National Cancer Database to evaluate patients with clinical stage T1 and T2 PDACs from 2010 to 2020. Cox proportional hazards model was used to evaluate the impact of NAC followed by definitive surgery compared to upfront surgery on OS with and without TTFT. Results: Total of 43,196 patients were included – 9,880 patients with clinical stage T1 and 33,316 patients with T2 PDACs. There were increasing trends in the NAC approach from 2.9% in 2010 to over 25% by 2020 and decreasing trends in the upfront surgery approach from 69.35% in 2010 to 31.84% by 2020. There were significant differences in TTFT according to the treatment choice with upfront surgery group having a significantly shorter TTFT – proportion of those receiving first treatment within the 1 st week was 24.32% in the upfront surgery compared to 4.22% in the NAC group. In the adjusted cox regression without the TTFT variable, there was a 25% higher rate of death in the upfront surgery compared to the NAC group (HR 1.25, 95% CI 1.19 – 1.30). When the adjusted regression was performed with addition of a TTFT interaction term, there was survival disadvantage of upfront surgery approach in patients whose TTFT occurred after 1 week, but not in those with TTFT occurring in less than 1 week (HR 1.01, 95% CI 0.86 - 1.17). Conclusions: Our study emphasizes the importance of incorporating TTFT variable when comparing NAC versus upfront surgery approach in PDAC. Future studies comparing NAC to upfront surgery in resectable PDAC should consider incorporating the TTFT variable.