Combination of Acitretin and Clarithromycin As a Novel Therapeutic Approach for Treating High-Risk Cutaneous Squamous Cell Carcinomas

Background: There are few effective treatment options for patients with recurrent or advanced cutaneous squamous cell carcinoma (CSCC). Acitretin demonstrated no therapeutic effect in patients with high-risk CSCC, though a preventive effect has been reported on new primary non-melanoma skin cancers in post-transplantation recipients. This study aimed to investigate the synergic efficacy of combined acitretin and clarithromycin for the treatment of high-risk CSCC. Methods: All patients of high-risk CSCC were treated with acitretin combined with clarithromycin in our department, and then anti-tumor effects and adverse drug reaction were followed up from 2008 to 2019. A. The potential synergistic mechanisms of acitretin and clarithromycin were further evaluated in vitro and in vivo using two human carcinoma cell lines A431 and KB. Findings: Five cases of high-risk CSCC were identified during the study period and complete remission were achieved in all lesions after 2 to 24 months of combination therapy. Four of five patients remain alive without recurrence of CSCC. During treatment, mucocutaneous dryness was noted in three patients and pseudotumor cerebri was found in one patient. The combination of acitretin and clarithromycin showed synergistic anti-tumor activity through inhibition of cell growth and induction of apoptosis in both A431 and KB cell lines. Tumor growth was significantly suppressed in a KB cell xenograft model by the combination therapy. Interpretation: Combined acitretin and clarithromycin therapy could represent a novel treatment approach with robust anti-tumor activity and a manageable safety profile in patients with unresectable high-risk CSCC. Funding Statement: This study was supported by grants from Fujian Provincial High-Tech research program (2016Y0036), the Key Research Program of Fujian Provincial Heath and Education Joint Committee (WKJ2016-2-24) and National Collaboration Center in Immuno-Oncology (No. 2016sysbz02). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the medical technology clinical application and ethics committee of the First Affiliated Hospital of Fujian Medical University (No. [2015]084). All procedures performed in studies involving animals were approved by the Fujian Medical University Institutional Animal Care and Use Committee (IACUC, NO. 2017-031) in accordance with the ethical standards.