mPDAC: Historical Milestones and Selecting the Right First-Line Regimen

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The evolution of pancreatic cancer treatment has progressed significantly since 2011, when FOLFIRINOX first demonstrated superiority over single-agent gemcitabine in the PRODIGE-4 trial, achieving 11.1 months median overall survival in metastatic disease. This breakthrough was followed by the MPACT trial in 2013, showing gemcitabine plus nab-paclitaxel efficacy with 9.6 months survival. The recent NAPOLI-3 trial in 2023 established NALIRIFOX as another effective option, matching FOLFIRINOX’s 11.1-month survival benchmark in metastatic pancreatic adenocarcinoma.

Treatment selection between triplet regimens requires careful consideration of patient-specific factors and toxicity profiles. For locally advanced disease, many oncologists favor FOLFIRINOX due to longer clinical experience, though NALIRIFOX may be preferred in patients with baseline neuropathy concerns due to reduced oxaliplatin dosing. The NAPOLI-3 trial demonstrated higher objective response rates with NALIRIFOX (42%) compared with historical FOLFIRINOX data (approximately 30%), though cross-trial comparisons require cautious interpretation.

Clinical decision-making must account for the prolonged treatment duration typical in locally advanced pancreatic cancer, making long-term toxicity management crucial. The choice between FOLFIRINOX and NALIRIFOX often depends on individual patient factors including baseline neuropathy risk, performance status, and treatment goals. Randomized trials specifically comparing these regimens in the neoadjuvant setting remain absent, necessitating careful extrapolation from metastatic data for locally advanced treatment planning.