Skin adverse events of anti-cancer treatments: An examination of drug-AE associations.
Authors: Salah Samir , Kerob Delphine , Pagès Cécile , Lacouture Mario E. , Sibaud Vincent 
Published: June 2023

e18885

Background: Although anti-cancer treatments, including chemotherapy (CTs), targeted therapies (TTs), radiation therapy, and immunotherapy (ITs), are effective to treat cancer, they can be associated with significant skin-related toxicities (AEs). These AEs can cause discomfort and even lead to the discontinuation of therapies. However, a comprehensive estimation of the associations between cancer drug use and skin AEs is currently lacking. This study aimed to investigate these associations using a large dataset. Methods: This study utilized the US FDA Adverse Reporting System (FAERS) dataset, with a focus on HCPs reports from January 2013 to September 2022. The dataset consists of 3399830 reports involving 3084 all-field drugs and 16347 AEs. To minimize false positives, we employed a nearest-neighbor matching model to identify 10 control reports for each case report based on cosine distance on demographic and severity factors. To manage multiple comparisons and control the family-wise error rate (FWER) to 5%, we applied the Bonferroni correction. Results: A total of 146 marketed anti-cancer drugs were identified in the database with at least 5 reports of skin AEs. Out of the 2757 drug-AE pairs, 708 displayed a significant reporting odds ratio (ROR) greater than one, consisting of 102 drugs and 135 skin AEs. The minimum ROR was 1.25, and 50% of the associations displayed a ROR above 11. Rash was significantly associated with 44 drugs and dry skin with 25 drugs. Methotrexate was significantly associated with 35 different AEs and anti-BRAF vemurafenib with 26 AEs. TCs were present in 57% of the pairs, CTS in 38%, and immune checkpoint blocking agents in 5%. Multikinase-I were present in 15% of the pairs, followed by antimetabolites (14%). Considering the relative weight of skin AEs on the safety profile of the drugs, skin AE were present on average in 11% of the drug reports, with a maximum of 51% for mechlorethamine. 12% of reports concerning CTs contained a skin AE, 11% for TTs, and 8% for ITs. For CTs, 13% of reports about antimetabolites contained a skin AE, followed by taxanes (12%). Vinca-alkaloids and topoisomerase-I were less impacted with 6% of skin AE reports. For TCs, 23% of reports about EGFR inhibitors contained a skin AE, followed by BRAF inhibitors (21%). PARP inhibitors and BTK inhibitors were less impacted with 8% of skin AE reports. Conclusions: This study used a large dataset to examine the associations between cancer drugs and skin AEs. 146 anti-cancer drugs were found to have skin AEs, with rash and dry skin being the most reported AEs in the associations. TTs were most associated with skin AEs, followed by CTs. Methotrexate and vemurafenib had the most important number of associations. These data don’t allow evaluation of the incidence of skin AE effect with anti-cancer drugs as they are probably under-reported, but the findings emphasize the importance of monitoring skin AEs in patients exposed to anti-cancer treatments.