Voriconazole tied to increased SCC risk in lung transplant recipients

Exposure to voriconazole is associated with increased risk of cutaneous squamous cell carcinoma (SCC) in lung transplant recipients, especially after prolonged exposure, a US study suggests.

Transplant recipients have an elevated risk for keratinocyte carcinomas (KCs) – cutaneous SCC and basal CC – the former being the most common, with substantial morbidity rates. [Int J Cancer 2013;132:1429-1438; Cancer Res 2017;77:4196-4203] “[The rates are] especially elevated among recipients of lung transplants,” said the researchers.

After a median follow up of 3 years following 9,793 lung transplants, 1,031 cutaneous SCC cases were reported (incidence, 322/10,000 person-years). [JAMA Dermatol 2020;doi:10.1001/jamadermatol.2020.1141]

Compared with lung transplant recipients unexposed to voriconazole, those who had voriconazole exposure (41 percent) experienced a gradually increasing risk for SCC (adjusted hazard ratio [adjHR], 1.09 [1–3 months], 1.42 [4–7 months], 2.04 [8–15 months], and 3.05 [>15 months]). For each 30-day exposure to voriconazole, SCC risk increased by 5 percent (adjHR, 1.05).

“These findings suggest that physicians caring for lung transplant recipients at high risk for aggressive KCs should limit voriconazole exposure when possible and encourage skin protection behaviours and more frequent cancer screenings,” said the researchers.

Voriconazole is a highly effective, broad-spectrum, oral antifungal medication, which is the recommended first-line treatment for aspergillosis, a primary cause of mortality among lung transplant recipients. [Clin Transplant 2019;33:e13544]

“[However, the] carcinogenic mechanisms [of voriconazole] are poorly understood,” pointed out the researchers. Evidence suggests that it could be due to the alteration of keratinocyte gene expression with voriconazole, as this may influence the genes associated with the cell cycle – including the FOXM1 pathway – which is linked to SCC. [Br J Dermatol 2017;176:816-820]

Another mechanism is the potential DNA damage and inhibition of apoptosis with the combined effect of ultraviolet-A radiation and voriconazole n-oxide. [Sci Rep 2018;8:5050] “Moreover, voriconazole can induce upregulation of cyclo-oxygenase 2, which is critical to SCC progression,” added the researchers.

Voriconazole was the most commonly used antifungal agent in the first year following transplant (20 percent of person-time). However, usage rate dropped to 10 percent during the second year, owing to clinicians’ adjusted perceptions due to evidence reflecting increased SCC risk with prolonged voriconazole use. [J Heart Lung Transplant 2012;31:1177-1181; Am J Transplant 2018;18:113-124] “[This] could have biased the associations,” noted the researchers. The absence of data on skin cancers prior to transplant might have also presented a limitation, they added.

Nonetheless, the large sample size enabled the team to adjust for confounders and evaluate alternative antifungal medications, noted the researchers. The link to pharmacy claims also provided ample data on medication exposure. The inclusion of smoking history, which is an SCC risk factor, could have also strengthened the findings, they added.

Given the high morbidity tied to SCC among transplant recipients, future trials should look into the risk-benefit ratio of shorter durations of voriconazole prophylaxis, or of potential alternatives (eg, posaconazole, itraconazole), noted the researchers.