Efficacy and toxicities of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy for unresectable pancreatic cancer: a systematic review and meta-analysis

Objective Modified FOLFIRINOX (mFFX) and gemcitabine plus nab-paclitaxel (GnP) are both recommended as standard first-line regimens for unresectable pancreatic cancer (PC). However, direct head-to-head comparative evidence remains scarce, and prior studies have largely failed to distinguish mFFX from standard FOLFIRINOX (sFFX). We systematically compared mFFX with GnP to evaluate their efficacy and toxicities. Methods We searched for randomized controlled trials (RCTs) and observational studies comparing mFFX with GnP as first-line therapy for unresectable PC published between January 2013 and May 2026. Overall survival (OS) and progression-free survival (PFS) were assessed using hazard ratios (HRs). Objective response rate (ORR) and disease control rate (DCR) were evaluated using risk ratios (RRs). Events of toxicities were assessed using odds ratios (ORs). Results Five studies (three RCTs and two retrospective studies) involving 1204 patients (578 in the mFFX arm and 626 in the GnP arm) were included. Compared with GnP, mFFX was associated with a shorter OS (HR 1.26, 95% CI 1.09–1.45; P = 0.002) and PFS (HR 1.21, 95% CI 1.04–1.40; P = 0.01), along with a borderline lower DCR (RR 0.90, 95% CI 0.81–1.00; P = 0.05; I 2 = 62%), which was consistent across RCTs (RR 0.88, 95% CI 0.81–0.94; I 2 = 0%) but not observed in retrospective studies (RR 0.96, 95% CI 0.71–1.29; I 2 = 87%), and ORR did not differ significantly between the two regimens. As for toxicity profiles, mFFX showed an elevated incidence of grade ≥3 diarrhea (OR 5.63) and anorexia (OR 4.44). By contrast, grade ≥3 neutropenia (OR 0.66) and white blood cell decrease (OR 0.49) occurred more frequently under GnP. Conclusions GnP was associated with more favorable OS and PFS than mFFX, a borderline DCR advantage, and distinct toxicity profiles. Given the modest effect size and the limitations of this study, clinical decision-making should integrate patient age, performance status, and anticipated second-line therapy. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420251175959.