Dual protection in IPF: antifibrotic therapy and reduced lung cancer incidence- a systematic review and meta-analysis

Background Idiopathic pulmonary fibrosis (IPF) significantly increases lung cancer risk, with cumulative incidence exceeding 50% at 10 years. We evaluated whether antifibrotic therapies provide cancer-protective effects beyond their established antifibrotic actions.Methods We conducted a systematic review searching MEDLINE, EMBASE, and Cochrane databases through July 2025 per PRISMA guidelines. Observational studies comparing lung cancer incidence in IPF patients receiving antifibrotics (pirfenidone or nintedanib) versus untreated controls were included. Random-effects meta-analysis with sequential sensitivity analyses was performed.Results Four observational studies with 15,582 participants were included. Primary pooled risk ratio was 0.39 (95% CI: 0.13–1.14; I2 = 98%). Sequential sensitivity analyses addressing confounding by indication and biological heterogeneity demonstrated statistically significant risk reductions: 73% (RR 0.27; 95% CI: 0.16–0.48; I2 = 44%) and 76% (RR 0.24; 95% CI: 0.08–0.69; I2 = 67%) in pirfenidone-specific analyses.Conclusions Pirfenidone specifically may reduce lung cancer risk in IPF patients by 73–76%, though evidence is limited by observational designs, geographic restriction to East Asian populations, and biological heterogeneity between mechanistically distinct antifibrotic agents. Insufficient data exist for nintedanib. Agent-specific prospective randomized controlled trials are warranted.Protocol registration: PROSPERO identifier CRD420251119104