Voriconazole Exposure Modifies Risk for Cutaneous Squamous Cell Carcinoma, Invasive Aspergillosis and Death in Lung Transplant Recipients.

Abstract

Purpose: To assess the impact of voriconazole exposure on squamous cell carcinoma, invasive aspergillosis, and death in lung transplant recipients. Methods: Utilizing a cohort of all lung transplant recipients at the University of California, San Francisco (UCSF) between October 1991 and December 2012 (n=455), we used survival analysis to test whether voriconazole exposure impacted development of squamous cell carcinoma, invasive aspergillosis, and death. Voriconazole exposure was assessed as either any exposure or cumulative dose exposure as a time varying covariate. Cox regression models were built with modified Allan-Cady backwards selection adjusting for sex, age at transplant, and race kept a priori, in addition to type and year of transplant and diagnostic category to calculate the adjusted hazard ratio. Results: Any voriconazole exposure was associated with a 2-fold increased risk for developing squamous cell carcinoma (HR=2.01, p=0.004), with each additional 12 g of exposure (equivalent to 200 mg BID for 30 days) increasing the risk by 3.0% (HR=1.03, p=<0.0001). Individuals with older-age at transplant (HR=1.53, p=.03), Male sex (HR=1.49, p=.05), White race (HR=4.79, p=<0.0001), or Lung Allocation Score (LAS) Group D diagnostic category (HR=1.55, p=0.04) were the most at risk. Drug exposure was also associated with a 39% risk reduction for developing invasive aspergillosis (HR=0.61, p=0.03) and a 53% risk reduction for death (HR=0.47, p=0.00). Conclusion: Voriconazole exposure is associated with a dose-dependent increased risk for developing squamous cell carcinoma in lung transplant recipients, but also significantly decreases risk for invasive aspergillosis and death. Physicians should consider patient-specific factors that modify the risk for developing skin cancer and reducing fungal infections and death when using voriconazole in the care of lung transplant recipients.