Impact of Frailty on the Outcomes of Patients with Pancreatic Cancer Undergoing Neoadjuvant Therapy

<b>Background</b>: Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Toxicities during NT are common, often leading to the inability to undergo surgical resection, yet risk factors for attrition are poorly understood. Therefore, we sought to evaluate the impact of baseline frailty on outcomes of patients with PDAC undergoing NT. <b>Methods</b>: All patients with potentially resectable (PR) or borderline resectable (BR) PDAC who initiated neoadjuvant chemotherapy and/or chemoradiation between 2019 and 2025 at a single institution were assessed retrospectively in an intention-to-treat fashion. The association between frailty as defined by the modified 11-item frailty index (mFI-11) and receipt of surgical resection as well as other secondary endpoints was assessed. Comprehensive functional frailty assessments were prospectively obtained in a subset of patients. <b>Results</b>: Among 252 eligible patients, the median age was 67 years, 56.7% were male, 90.9% were White, 49.6% had PR disease, and 5.2% were frail according to mFI-11. After a median 3.6 months of NT, 62.7% underwent surgical resection. Frail individuals had worse performance status and increased comorbidities compared with non-frail patients. On multivariable analysis, male sex, BR anatomic staging, initial use of Gemcitabine + nab-paclitaxel, and frailty (OR 0.09; 95%CI 0.02-0.44) were associated with reduced odds of undergoing resection. Along with increased baseline CA 19-9 levels, frailty was independently associated with worse overall survival (HR 3.00; 95%CI 1.46-6.20). Among 39 patients who underwent formal functional frailty assessment, only abnormal posture was associated with lower odds of surgical resection following NT (OR, 0.22; 95% CI, 0.05-0.92), and no aspects of functional frailty were associated with overall survival. <b>Conclusions</b>: Among patients with localized PDAC initiating NT, frailty as assessed by mFI-11 was associated with reduced odds of undergoing surgical resection and worse overall survival. Future research should focus on efforts to improve functional status during NT.