Combined Impact of Neoadjuvant Therapy and Preoperative Cachexia in Patients Undergoing Pancreatoduodenectomy: Is There a “Double Jeopardy”? A National Cohort Study Investigating the Association with Short- and Long-Term Outcomes

BACKGROUND: Cachexia is associated with worse postoperative outcomes, but the added role of neoadjuvant therapy (NAT) is unclear. This study evaluated whether preoperative cachexia and NAT act as a "double jeopardy" after pancreatoduodenectomy. PATIENTS AND METHODS: A nationwide observational cohort study was conducted using the Norwegian NORGAST registry (2016-2023). Adults undergoing pancreatoduodenectomy for malignancy were included. Cachexia was defined by consensus weight-loss criteria. Modified Poisson and Cox models (with a cachexia and NAT interaction term) estimated adjusted risk ratios (aRR) for textbook outcome (TO), prolonged length-of-stay (LOS), and adjusted hazard ratios (aHR) for overall survival. RESULTS: Of 1424 patients undergoing pancreatoduodenectomy, cachexia was present in 588 (41.3%). Having cachexia was associated with higher TO (aRR 1.28, 95% CI 1.13-1.46) with effect modification by body mass index (BMI) (interaction P = 0.047). Patients with cachexia had a lower risk of prolonged LOS (aRR 0.64, 95% CI 0.51-0.80). Cachexia was not independently associated with overall survival (aHR 1.15, 95% CI 0.97-1.36). NAT was associated with a higher hazard of death (aHR 1.44, 95% CI 1.09-1.92), likely reflecting confounding by indication. No statistically significant interaction between cachexia and NAT was observed for TO (P = 0.277) or for survival (P = 0.863). CONCLUSIONS: Preoperative cachexia was associated with higher rates of TO. Higher TO was attributed to patients with overweight or obesity, to a shorter index stay, and more frequent transfers to a secondary facility, but not fewer complications. Cachexia was not associated with worse long-term survival, and a "double jeopardy" between cachexia and receiving NAT was not found.