Anal squamous cell carcinoma - State of the art management and future perspectives.

Anal squamous cell carcinoma (ASCC) is associated with infection with high-risk strains of human papilloma virus (HPV) in 70-90% of cases and a rise in incidence has been observed in the last decades. Definitive chemoradiotherapy (CRT) using 5-fluorouracil and mitomycin C constitutes the standard treatment for localized disease, but about 30% of patients do not respond or relapse locally. Phase I/II trials testing targeted agents, such as epidermal-growth-factor receptor (EGFR) inhibitors, have failed to improve clinical outcome and resulted in increased toxicities. Modern imaging methods and biomarkers, also in the context of HPV status, should be further explored to improve patient stratification. In the present review, we will discuss the current clinical evidence and future perspectives in the management of ASCC. HPV-positive ASCC is more immunogenic with a higher density of tumor infiltrating lymphocytes that correlate with better response to CRT and more favorable prognosis compared to HPV-negative tumors. Immunotherapies including immune checkpoint inhibitors have brought new hope and promising results were recently demonstrated in metastatic ASCC. The addition of immunotherapies to CRT for localized disease is tested in early phase trials, and these results could have a profound impact on the way we treat ASCC in near future. Further research and novel approaches are expected to enhance our understanding of tumor biology and immunology, and improve patient stratification and treatment adaptation in the context of personalized medicine.