Abstract

Background: This study aimed to comprehensively investigate the complex association between the use of fluoroquinolone (FQ) antibiotics and cancer risk, with a specific focus on patients with interstitial lung disease (ILD)—a unique clinical population characterized by a high inflammatory burden and a high susceptibility to infections. Methods: We conducted a large-scale retrospective cohort study using a high-quality clinical database. A total of 7906 matched patients (3953 pairs) were included after propensity score matching (PSM). Three complementary statistical models were applied: the standard Cox proportional hazards model, the time-dependent Cox regression model, and the Fine–Gray competing-risks model, to provide a multidimensional assessment of cancer risk. Results: A total of 7906 matched patients (3953 pairs) were followed. After strictly defining the index date to eliminate immortal time bias, FQ exposure was associated with an increased risk of all-cause cancer in the standard Cox model (adjusted HR 1.45; 95% CI, 1.20–1.76) and the competing risk model (adjusted SHR 1.28; 95% CI, 1.06–1.55). Site-specific analyses revealed elevated risks for certain malignancies, notably prostate cancer. Importantly, when modeled as a continuous variable, the cumulative dose of fluoroquinolones showed no significant dose–response relationship with overall cancer risk (adjusted HR 0.99; 95% CI, 0.99–1.00). Conclusions: After correcting for immortal time bias, the previously hypothesized protective effect of fluoroquinolones on cancer risk was not observed. The increased risk observed in categorical models, coupled with a lack of a continuous dose–response, strongly suggests that these findings are driven by confounding by indication and reverse causation (i.e., frequent infections masking undiagnosed malignancies or reflecting severe underlying ILD), rather than a direct pharmacological effect.

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