High azathioprine dose and lip cancer risk in liver, heart, and lung transplant recipients: A population-based cohort study

Abstract

Iatrogenic immunosuppression is a risk factor for lip cancer but the determinants are unknown. We sought to quantify the association between the type, dose, and duration of iatrogenic immunosuppression and lip cancer risk in solid organ transplant recipients. We conducted a population-based cohort study of all adult Australian liver, heart, and lung transplant recipients from 1984 to 2006 (n=4141). We abstracted longitudinal data from medical records and ascertained incident lip cancer (n=58) and deaths (n=1434) by linkage with national registries. We estimated multivariable hazard ratios (HR) for lip cancer using the Fine and Gray proportional subdistribution hazards model, accounting for death as a competing risk. Lip cancer risk (n=58) increased with high mean daily dose of azathioprine (HR 2.28, 95% confidence interval [CI] 1.18-4.38), longer duration of immunosuppression (HR 9.86, 95% CI 2.10-46.3), increasing year of age at transplantation (HR 1.14, 95% CI 1.04-1.25), earlier transplantation era (HR 8.73, 95% CI 1.11-68.7), and history of smoking (HR 2.71, 95% CI 1.09-6.70). Data on potential confounders such as personal solar ultraviolet radiation exposure were not available. Higher doses of azathioprine increase lip cancer risk, with implications for managing immunosuppressed populations and our understanding of the relationship between solar ultraviolet radiation and lip cancer.