Research on Anal Squamous Cell Carcinoma: Systemic Therapy Strategies for Anal Cancer

SIMPLE SUMMARY: Anal cancer is rare with an estimated 9000 new cases predicted to occur in the United States in 2021. However, rates of new anal cancer cases and deaths from the disease are increasing by about 2% and 3% per year respectively. In light of these trends it is critical to better understand the nature of this disease and progress in its management. The present review focuses on the history and development of the role of systemic therapy in the treatment of anal cancer. Major trials establishing the role of chemotherapy in the management of locoregional and metastatic anal cancer are summarized. In addition, the rapidly evolving role of immunotherapy is discussed. Finally, major insights into the molecular pathobiology of anal cancer and opportunities for advancement in precision medicine in treatment of the disease. ABSTRACT: Anal squamous cell carcinoma (ASCC) is a rare malignancy, with most cases associated with human papilloma virus and an increased incidence in immunocompromised patients. Progress in management of ASCC has been limited not only due to its rarity, but also the associated lack of research funding and social stigma. Historically, standard of care for invasive ASCC has been highly morbid surgical resection, requiring a permanent colostomy. Surgery was associated with disease recurrence in approximately half of the patients. However, the use of chemotherapy (5-fluorouracil and mitomycin C) concomitantly with radiation in the 1970s resulted in disease regression, curing a subset of patients and sparing them from morbid surgery. Validation of the use of systemic therapy in prospective trials was not achieved until approximately 20 years later. In this review, advancements and shortcomings in the use of systemic therapy in the management of ASCC will be discussed. Not only will standard-of-care systemic therapies for locoregional and metastatic disease be reviewed, but the evolving role of novel treatment strategies such as immune checkpoint inhibitors, HPV-based vaccines, and molecularly targeted therapies will also be covered. While advances in ASCC treatment have remained largely incremental, with increased biological insight, an increasing number of promising systemic treatment modalities are being explored.